Genes&Diseases

语种：英文出版周期：双月刊

E-ISSN：2352-3042P-ISSN：2352-4820

主管单位：重庆市教育委员会主办单位：重庆医科大学

Genes and Diseases是本由重庆医科大学于2014年创办的双月刊，也是国内第一本分子医学与转化医学相结合的全英文综合期刊，并入选“中国科技期刊卓越行动计划”高起点新刊项目。

过刊浏览

Iron metabolism plays a vital role in maintaining physiological homeostasis, and its dysregulation is implicated in a range of pathological consequences and illnesses, including Alzheimer's disease (AD). Prior studies have demonstrated that Tau protein and amyloid precursor protein are involved in iron homeostasis disorder. Ferroptosis, an iron-dependent form of regulated cell death, has emerged as a key contributor to AD pathogenesis and a promising therapeutic target. Acyl-CoA synthetase long-chain family 4 (ACSL4) is a lipid metabolizing enzyme that enhances ferroptosis sensitivity by promoting the incorporation of oxidizable polyunsaturated fatty acids into membrane phospholipids. Beyond ferroptosis, ACSL4 also plays crucial roles in neuroinflammation and oxidative stress, which are implicated in AD progression. Therefore, targeting ACSL4 is fantastic and has a lot of promise for treating AD. Nevertheless, the precise mechanisms through which ACSL4 contributes to AD pathology have yet to be fully elucidated. This review reveals a potentially vital role of ACSL4 in AD, focusing on its involvement in ferroptosis, oxidative stress, and neuroinflammation. Additionally, we describe some natural and synthetic compounds targeting ACSL4 with therapeutic potential in AD. Building on the theoretical findings of earlier studies about focused interventions of the ACSL4 path, our evaluation provided a broad basis for the clinical transformation in the treatment of AD strategies.

Inflammatory bowel disease (IBD), a prevalent chronic inflammatory disorder with unsatisfactory therapeutic outcomes, significantly increases the risk of colorectal cancer. The cyclic GMP-AMP synthase (cGAS) and stimulator of interferon gene (STING), highly expressed in human IBD, are potential anti-inflammatory and anti-tumor immunotherapeutic targets. However, conflicting evidence regarding the dual roles of the STING pathway has significantly hindered its development as a therapeutic target for innovative treatments. Previous studies have predominantly suggested that hyperactivation of the STING pathway contributes to colitis development, while simultaneously enhancing anti-tumor immunity and inhibiting cancer progression. On the other hand, specific contexts, such as STING deficiency in T cells or prolonged, excessive STING activation within tumors, paradoxically promote disease progression. We also thoroughly analyzed the origin of STING activation in these diseases to offer insights into the identification of novel druggable targets. Crucially, “cell context-dependency, treatment timing and duration, and biased signal transduction” are likely the mechanistic basis underlying STING pathway’s dual roles, proposing spatiotemporal-specific STING modulators as future therapeutics.

Diabetes is a multifactorial metabolic disease involving complex disruptions in cellular homeostasis and multiple forms of regulated cell death. Among them, the interaction between autophagy and ferroptosis has recently gained increasing attention. Autophagy is a catabolic process essential for degrading damaged organelles and misfolded proteins, thus preserving cellular integrity. Ferroptosis, on the other hand, is a newly identified, iron-dependent form of cell death characterized by excessive lipid peroxidation. Emerging evidence suggests that these two processes are intricately linked through shared regulatory pathways involving iron metabolism, lipid homeostasis, and the antioxidant system. Their crosstalk plays crucial roles in key diabetic pathologies, including pancreatic β-cell dysfunction, insulin resistance, and vascular complications. This review provides a comprehensive overview of the molecular mechanisms underlying autophagy–ferroptosis interactions in diabetes and highlights how their cooperative or antagonistic actions contribute to disease progression. Additionally, we discuss novel therapeutic strategies aimed at modulating this interplay, which may offer promising avenues for improving outcomes in diabetes and its complications. Further studies are needed to define precise molecular targets and facilitate clinical translation.

This review examines the advancements in cancer immunotherapies, particularly focusing on dendritic cell (DC)-based vaccines developed through in vitro methods. DCs are essential for connecting innate and adaptive immunity and serve as powerful antigen-presenting cells. They play an essential role in the anti-tumor immune response by activating cytotoxic T lymphocytes and natural killer cells. DC vaccines, which involve engineering DCs to express tumor-associated antigens and administering them to patients, potentially enhance the T-cell-mediated destruction of tumor cells. The review details the progression of DC vaccine preparation from simple antigenic peptide pulsing to advanced genetic modification and cell fusion techniques. It discusses the use of envelope fusogenic membrane glycoproteins and chemical agents, such as polyethylene glycol, to facilitate the fusion of DCs with tumor cells, creating fusion cell vaccines that exhibit anti-tumor efficacy in both preclinical and clinical settings. Recent developments of DC vaccines have utilized alternative vectors, addressing some limitations of previous vaccine generations. Additionally, the review examines the integration of DC vaccines with other immunotherapies to combat tumor-induced immunosuppression. Despite their potential, DC vaccines face challenges that necessitate further refinement of therapeutic strategies and clinical validation. In conclusion, this review underscores the pivotal role of DC vaccines in cancer therapy and elucidates ongoing endeavors to augment their efficacy via combination therapies and advanced preparation techniques.

Tumor cells alter several critical metabolic pathways to satisfy their demands for rapid proliferation and survival. Maladjustment of cholesterol metabolism is present in diverse types of tumor cells. 3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is a critical enzyme in regulating cholesterol biosynthesis and metabolism. Many studies have demonstrated the up-regulated expression of HMGCR in various tumor cells and the correlation with tumor progression by modulating key cancer characteristics, especially the reprogramming of cellular metabolism, maintaining proliferative signaling and evasion of cell death, and promoting invasion and metastasis. Targeting HMGCR can inhibit tumor cell proliferation, increase apoptosis, reverse resistance to chemotherapy, and inhibit metastasis, implicating HMGCR as a promising target for cancer therapies. Although challenges, such as side effects, remain significant, small-molecule inhibitors of HMGCR with potential anti-tumor properties have been developed for use alone or in combination with other anti-cancer agents. This review systematically integrates recent advances from HMGCR biology to therapeutic strategies by bridging mechanistic insights with translational challenges. The review aims to redefine HMGCR targeting as a multifaceted therapeutic paradigm in precision oncology.

Forkhead Box A2 (FOXA2) is a transcription factor essential for endodermal development and the formation and function of several metabolic organs, including the liver and pancreas. Within the pancreatic lineage, FOXA2 plays a crucial role in orchestrating islet development, maintaining β-cell identity, and regulating genes central to glucose sensing and insulin secretion. This review provides a comprehensive overview of FOXA2's dual role in both developmental and mature stages of pancreatic islets, highlighting its function as a gatekeeper of lineage specification and metabolic homeostasis. We describe FOXA2's dynamic expression patterns during embryogenesis, its regulatory interactions with other key transcription factors, such as PDX1 and NKX6.1, and its influence on chromatin accessibility during islet cell differentiation. Furthermore, we discuss the consequences of FOXA2 dysregulation, including impaired α- and β-cell maturation, loss of functional identity, and contributions to the pathogenesis of diabetes. Insights from mouse models, human stem cell-derived islets, and patient genetics underscore the clinical relevance of FOXA2 in monogenic and complex forms of diabetes. By integrating developmental biology, genomics, and disease modeling approaches, this review highlights FOXA2 as a central regulator connecting pancreatic organogenesis with long-term metabolic control. Understanding FOXA2's regulatory networks may open new avenues for therapeutic strategies aimed at restoring or preserving β-cell function in diabetes.

FOXK2 is a transcription factor known to regulate a wide range of biological processes that are critically involved in determining cell fate. Increasing evidence shows aberrant FOXK2 expression in some tumors, with crucial biological and clinical impacts. It is important to note that the molecular mechanisms contributing to FOXK2 gene deregulation are poorly understood for most cancers. In this review, we systematically describe the FOXK2 gene expression profile across distinct tumor types and discuss its potential utility as a prognostic and diagnostic molecular marker. Notably, we explore emerging mechanisms accounting for FOXK2 deregulation, focusing on genetic and transcriptional modifications, such as gene methylation, mutation and copy number variations.

The tumor microenvironment is increasingly recognized as a complex ecosystem in which the intra-tumoral microbiota (comprising bacteria, fungi, viruses, etc.) plays a pivotal, underappreciated role in cancer biology. This review systematically summarizes the latest research into the origins, diversity, and functional mechanisms of intra-tumoral microbiota, emphasizing their dual roles in tumor formation, progression, and response to treatment. Using high-throughput sequencing, spatial multi-omics, and integrative bioinformatics, we identify the multifactorial origins of tumor-resident microbiota, including translocation from adjacent tissues, hematogenous dissemination, and viral genomic integration. We also examine the significant inter- and intra-tumoral microbial heterogeneity influenced by anatomical, environmental, and immunological factors, and the tissue-specific functional effects of important microbial species. We detail the mechanisms by which the intra-tumoral microbiota modulate innate and adaptive immunity through pattern recognition receptor signaling, microbial antigen presentation, and microbial metabolite production, ultimately influencing tumor microenvironment composition, immune cell dynamics, and therapeutic efficacy. Finally, we critically evaluate emerging microbiota-targeted therapeutic strategies, including engineered bacteria, antibiotics, bacteriophages, and oncolytic viruses, while outlining the technical, mechanistic, and regulatory challenges that hinder their clinical translation. Our synthesis highlights the need for rigorous multi-omics profiling, causal inference, and smart delivery systems to exploit the intra-tumoral microbiota for precision oncology. This paradigm shift offers unprecedented opportunities for personalized diagnosis and therapy, marking a new frontier in cancer research and treatment.

The KCNE single-span transmembrane subunits modulate the function of voltage-gated potassium (Kv) channels, which are critical for maintaining electrical excitability and signal transduction across various tissues, by interacting with different Kv channel α-subunits to form diverse channel complexes with unique biophysical properties and regulatory mechanisms. These interactions profoundly impact physiological processes. Mutations or altered expression of KCNE genes have been implicated in a range of pathophysiological conditions. Emerging research has provided significant insights into the dynamic interactions between the KCNE gene and Kv channels, highlighting their critical roles in channel function modulation. This increasing understanding paves the way for designing novel therapeutic strategies to address ion channel-related disorders. To deepen the understanding of research advancements, this review seeks to elucidate the roles of KCNE across various organs and to provide constructive recommendations for future research.

Lactylation, a type of post-translational modification (PTM) of proteins driven by cancer metabolic reprogramming, not only offers new perspectives on the Warburg effect but also has drawn increasing attention due to its critical roles in tumorigenesis and therapeutic resistance. Given its significant potential for precision cancer therapy, this review first integrates recent advancements in lactylation research by systematically summarizing newly identified lactylation writers, readers, and erasers, as well as their involvement in feedback loops and crosstalk with other modifications. Subsequently, we elaborate on how histone and non-histone lactylation contribute to both intrinsic and acquired resistance to radiotherapy, chemotherapy, targeted therapy, and immunotherapy. Key mechanisms encompass maintaining cancer stemness, enhancing DNA damage repair, reprogramming metabolic pathways, inhibiting ferroptosis, and promoting an immunosuppressive tumor microenvironment. Finally, we evaluate preclinical strategies targeting lactylation, including inhibition of lactate metabolic pathways and direct modulation of lactylation-modifying enzymes or lactylated proteins, while critically assessing mechanistic challenges and early-phase clinical trial outcomes. Our analysis establishes a theoretical framework and actionable roadmap for the development of lactylation-based precision therapies in oncology.

Lgr6 has attracted significant attention in biomedical research in recent years. As a member of the G protein-coupled receptor family, Lgr6 plays a crucial role in the occurrence and development of various diseases, including diabetic cardiomyopathy, bone regeneration defects, and skin injury repair, where it is vitally involved in cellular signal transduction. This study endeavors to investigate the distribution and functions of Lgr6+ cells across organisms, particularly during homeostasis and damage scenarios. Lgr6+ expression occurs across skin, mammary glands, kidneys, and intestines, crucial for development and tissue repair. Abnormal expression of Lgr6 is also observed in the onset and progression of major systemic diseases, especially in tumors. Thus, Lgr6 has been identified as a promising therapeutic target for cancer and other diseases, influencing their onset, progression, and treatment.

MicroRNAs are a class of non-coding short-stranded RNAs with important biological roles as post-transcriptional regulators of gene expression, involved in a variety of biological processes, such as cell growth, apoptosis, and angiogenesis. miR-23b, a well-studied miRNA, is aberrantly expressed in a variety of cancers. In this paper, we used the literature review method to sort out the biological roles and regulation of miR-23b in different types of cancers, including digestive system cancers, reproductive system cancers, head and neck cancers, genitourinary system cancers, and lung cancers. The data show that miR-23b can target both oncogenes and tumor suppressors, and its expression regulation in different types of cancers shows heterogeneity, which mainly acts through affecting signaling pathways, such as Wnt/β-catenin for tumorigenesis, and apoptotic proteins, such as BCL2 or oncogenes. The expression of miR-23b is closely related to the overall survival rate, disease-free survival rate, and prognosis in many cancers. Meanwhile, various in vivo and ex vivo studies have shown that miR-23b is a potential therapeutic target for cancer. It is important to understand the relationship between miR-23b and cancer development. miR-23b has the potential to serve as a clinically relevant molecular biomarker for cancer prognosis/diagnosis as well as a potential therapeutic target.

Mitochondria are double-membrane organelles in eukaryotic cells, which play an important role in energy metabolism, cell cycle and apoptosis. Therefore, mitochondrial abnormalities can affect various physiological and pathological processes. Extensive research over a long period of time has shown that mitochondrial dysfunction is considered a hallmark of several diseases, including cardiovascular diseases, neurodegenerative diseases, respiratory diseases, and even cancer. Mitochondrial transplantation has emerged in recent years as a novel approach for treating mitochondria-related diseases. This therapy involves transferring viable, functionally intact mitochondria into cells or tissues, either directly or indirectly, to replace dysfunctional mitochondria and restore mitochondrial function, thereby achieving therapeutic goals. Research has indicated that mitochondrial transplantation can alleviate the progression of lung diseases and improve disease outcomes. In this review, we explore the mechanisms underlying mitochondrial dysfunction in lung disease and the potential application of mitochondrial transplantation in the treatment of lung disease.

Advances in DNA technology are revolutionizing the landscape of illness prevention, providing new opportunities to combat hereditary abnormalities and chronic diseases before they manifest. CRISPR-Cas9 gene editing, epigenetic alterations, somatic cell genome editing, and RNA-based therapies are all significant advancements in this field. These techniques enable precise changes to DNA and gene expression, potentially preventing a wide range of illnesses at their genetic origins. The following discussion delves into the transformative potential of these technologies. CRISPR-Cas9 is notable for its precision in fixing defective genes, offering promise for avoiding diseases, such as cystic fibrosis and sickle cell anemia. Epigenetic modifications caused by environmental factors are also opening up new avenues for preventing chronic illnesses and malignancies. Furthermore, somatic cell genome editing is a potential, ethically viable strategy as it targets non-reproductive cells, preventing heritable genetic alterations. Along with these developments, RNA-based therapies are emerging as a new avenue for disease prevention. This paper will explore each of these advancements, their applications, and the ethical and technical challenges involved.

The myosin heavy chain 9 (MYH9) gene encodes non-muscle myosin heavy chain IIA (NMIIA), a vital protein involved in fundamental cellular activities, including movement, cell division, and signal transmission. Mutations in MYH9 were initially linked to autosomal dominant disorders collectively termed MYH9-related diseases (MYH9-RD). In recent years, MYH9 has gained significant attention for its pivotal roles in various cancers. However, despite extensive research, its exact contributions to cancer progression remain incompletely understood. Targeting MYH9 through approaches such as non-coding RNAs, small molecules, or gene therapy presents a promising avenue for advancing cancer treatment. Additionally, the dual role of MYH9 in MYH9-RD and cancer raises the intriguing question: are individuals with MYH9 mutations predisposed to or protected from cancer? This review aims to present the structure, functional significance, and clinical associations of MYH9, with an emphasis on its contributions to MYH9-RD and cancer progression. Furthermore, it examines MYH9’s regulatory interactions with non-coding RNAs and its potential applications as a therapeutic target, offering insights into strategies such as RNA interference and CRISPR-based gene editing for cancer treatment.

This review comprehensively summarizes the interaction mechanisms between Megalin and several key ligands, including calcium ions, gentamicin, ApoE, ANKRA2, FVIII, TTR, STC1, RAP, and MMP-9, focusing on the specific amino acid binding sites involved. The analysis highlights the structural basis of these interactions and their clinical relevance, particularly concerning diseases such as nephrotoxicity, Alzheimer’s disease, metabolic disorders, and renal pathologies. This review comprehensively summarizes the specific binding sites of Megalin with its ligands and explores the mechanisms, including protein reabsorption, blood coagulation, and neuroprotection, by integrating the results of animal studies and human clinical studies. This review proposes a theoretical framework for designing therapeutic strategies that target the binding sites of Megalin with its ligands. Gene editing technology and monoclonal antibody therapy aim to regulate Megalin receptor–ligand interactions to achieve therapeutic effects on related diseases.

Owing to transformative improvements in diagnosis and treatment, survival rates for cancer patients have improved significantly across the globe. However, toxicity induced by oncotherapy remains a major concern and markedly affects disease prognosis. In recent years, research on the association between circular RNAs (circRNAs) and oncotherapy-induced toxicity has received extensive attention. CircRNAs are a class of single-stranded closed-loop molecules that play a regulatory role in the occurrence and development of tumors. An integral role of circRNAs in the development of cancer treatment-induced toxicity, as well as in pathological processes such as oxidative damage, mitochondrial damage, apoptosis, dysregulation of calcium homeostasis, and dysregulation of vascular homeostasis has been deciphered. With regards to chemotherapy, radiotherapy, and immunotherapy for cancer treatment, circRNAs play crucial functions in modulating the effects of oncotherapy-induced toxicity. The current review focuses on the mechanisms by which circRNAs function in regulating cancer treatment-induced toxicity, which leads to apoptosis, mitochondrial damage, oxidative stress, DNA damage, and fibrosis. In addition, this review summarizes the potential circRNA biomarkers, treatment strategies and future challenges, which may help translate circRNA research into clinical practice for early detection and improvement of cancer treatment-induced toxicity in the future.

Selenoproteins represent a distinct class of proteins that incorporate selenocysteine (Sec), whose biosynthesis and translational integration are dependent on selenium availability and the presence of a selenocysteine insertion sequence (SECIS). These proteins are indispensable for redox regulation, antioxidant defense, and thyroid hormone metabolism, among other vital biological processes. Remarkably, selenoproteins act as critical regulators of cellular fate decisions, a function that hinges on Sec-a residue whose biosynthesis and translational incorporation into protein involve machinery far more intricate than that of canonical amino acids. This evolutionary adaptation, whether arising from stochastic mutational events or as an obligatory trade-off for functional precision, underscores the sophisticated molecular regulatory strategies in living organisms. In this review, we comprehensively outline the uptake and metabolic pathways of selenoamino acids in eukaryotes, with particular emphasis on the biosynthetic mechanism of Sec and its unique translational incorporation into selenoproteins. We systematically elucidate the multi-layered regulatory networks that govern these biological processes within cells. Furthermore, we present a taxonomic classification and functional synthesis of eukaryotic selenoproteins, accompanied by an in-depth analysis of their molecular roles in various pathological states. Special emphasis is placed on the glutathione peroxidase (GPX) family, especially GPX4, in ferroptosis regulation and its sophisticated control mechanisms. Additionally, this review summarizes key challenges in current selenoproteins research and explores potential therapeutic strategies for cancer treatment by targeting selenoproteins.

Intervertebral disc degeneration (IDD) is a common cause of low back pain that causes significant debilitation. The intricate mechanisms governing intervertebral disc homeostasis are substantially impacted by cellular senescence, which plays crucial roles in both pathological and physiological contexts. In this review, we provide a comprehensive overview of cellular senescence in the pathogenesis of IDD. Specifically, we summarize the merits and limitations of the methodologies utilized in prior investigations to determine cellular senescence and the potential regulatory mechanisms underlying it in the progression of IDD. Furthermore, we describe therapeutic strategies that aim to inhibit cellular senescence, which may alleviate the pathogenesis of IDD. At last, we discuss the challenges and prospects of translational research on targeting cellular senescence in IDD treatment.

The study of nerve–tumor interactions has emerged as a rapidly advancing and interdisciplinary field with profound implications for understanding cancer progression, prognosis, and therapeutic innovation. While this area holds significant promise for transformative discoveries, the mechanisms of nerve–tumor interactions and their translation into clinical applications remain at an early stage. This review focuses on the role of peripheral nerves in non-neurogenic solid tumors, discussing the prevalence and clinical impact of nerve–tumor interactions, their underlying forms and mechanisms, advancements in research technologies, therapeutic potential, and future challenges. By synthesizing current knowledge, integrating methodologies for studying nerve–tumor interactions, and identifying critical gaps, this work aims to provide a foundational resource to guide experimental design and stimulate interest in clinical trials targeting neural influences in cancer progression.

Developmental and epileptic encephalopathies (DEEs) are a phenotypically and genetically heterogeneous group of severe epilepsy accompanied by intellectual disability. Mutations in the KCNA2 gene have been identified as a potential cause of DEE.1 The KCNA2 gene encodes the Kv1.2 channel, which plays a critical role in the initiation and propagation of action potentials, thereby influencing firing patterns and regulating neuronal excitability.2 KCNA2-DEE has a broad spectrum of diseases, including drug-resistant seizures, cognitive impairment, and ataxia. Encouragingly, treatments for KCNA2-DEE have evolved from traditional anti-epileptic seizure therapies to gene-targeted strategies. 4-Aminopyridine (4-AP), a non-specific inhibitor of voltage-gated potassium channels, was reported to be effective in treating KCNA2-DEE in 2021.3 To date, 9 of 11 patients have benefited from treatment with 4-AP.3 However, further clinical evidence is necessary to determine the generalizability of these effects, particularly in adult patients with a long course beginning in childhood. Here, we report an adult patient with a 30-year history of epileptic encephalopathy beginning in infancy, carrying the KCNA2 gain-of-function variant p.(Arg297Gln), who benefited from treatment with 4-AP.

Pyroptosis, a form of pro-inflammatory programmed cell death mediated by gasdermin (GSDM) proteins, has been shown to synergize with immune checkpoint inhibitors to improve tumor eradication.1 The key regulators of pyroptosis are inflammasomes, particularly NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), which can be activated by cytoplasmic mitochondrial DNA.2 Our previous studies identified apurinic/apyrimidinic endonuclease 1 (APE1), a DNA repair protein, as a key factor in inducing pyroptosis in non-small cell lung cancer (NSCLC) upon its deficiency.3 However, the molecular mechanism by which APE1 inhibition leads to pyroptosis in NSCLC remains to be elucidated. To investigate the mechanism of APE1-mediated cell pyroptosis, we used specific shRNA to construct APE1 knockdown cells (hereafter referred to as APE1-KD) based on two human NSCLC cell lines (A549 and NCI-H460) and a murine LLC cell line (Fig. S1A and S1B). The indicative pyroptotic morphology was detected in these APE1-KD cells (Fig. 1A; Fig. S1C). It was found that the release of pro-inflammatory cytokines, including interleukin 18 (IL-18), interferon-gamma (IFN-γ), and IL-2, and chemokines, including C-C motif chemokine ligand 5 (CCL5) and C-X-C motif chemokine ligand 10 (CXCL10), was increased in the APE1-KD cells (Fig. 1B; Fig. S1D–S1H). Additionally, the lactate dehydrogenase (LDH) level was higher in the APE1-KD groups than in the control group (Fig. S1I). The APE1-KD tumor cells also showed an incomplete cell membrane as indicated by Hoechst/propidium iodide staining (Fig. 1C; Fig. S1J). Mechanistically, APE1 depletion specifically activated the caspase-3–GSDME pyroptosis pathway, without affecting GSDMA, GSDMB, GSDMC, GSDMD, or caspase-1 (Fig. 1D; Fig. S1K and S1L). To further explore the mechanism by which APE1 depletion leads to pyroptosis in NSCLC cells, RNA sequencing (GEO: GSE220807) was performed to investigate the potentially regulated signaling pathway. Gene Set Enrichment Analysis (GSEA) revealed that the pathways associated with DNA binding were enriched in the APE1-KD cells (Fig. 1E). Consistently, the APE1-KD tumor cells showed higher levels of cytoplasmic dsDNA compared with the wild-type (WT) cells (Fig. S2A). Previous studies have identified that APE1 inhibition leads to an increase in the amount of mtDNA copy number in tumor cells.4 Using quantitative PCR to detect mtDNA levels by targeting the D-loop region (the origin of mtDNA replication), we found that the expression of cytoplasmic mtDNA in the APE1 depletion cells was higher than that in the control cells (Fig. S2B). To determine whether APE1 inhibition promotes pyroptosis through cytoplasmic mtDNA accumulation, we depleted mtDNA, which resulted in reduced caspase-3 activation and GSDME cleavage (Fig. 1F–H; Fig. S2C and S2D).

Friedreich's ataxia (FA), a progressive neurodegenerative disorder, stems from Frataxin (FXN) gene mutations, leading to a deficiency in frataxin, a crucial protein for mitochondrial function and iron–sulfur cluster biogenesis.1 Frataxin loss impacts key regions of the central nervous system (CNS), like the cerebellum and spinal cord, contributing to neurological deficits that can involve destabilization of the actin cytoskeleton and hinder axonal regeneration in affected neurons.2 These underlying mechanisms highlight potential therapeutic avenues, with mitochondrial restoration being a key focus, although the complex issue of tissue-specific iron dysregulation presents challenges for treatment development.3 Notably, PGC-1α, a key regulator of mitochondrial biogenesis, could be diminished in FA, making it a promising therapeutic target.4 However, arctigenin (ATG) activates PGC-1α; its poor solubility and extensive metabolism limit its clinical use.5 Herein, we developed ARC-18, a novel ATG derivative with enhanced pharmacological properties (Supplementary data). ARC-18 effectively restored mitochondrial function by restoring the levels of key proteins involved in mitochondrial dynamics (DRP1, OPA1, and MFN1) and biogenesis/mitophagy (PINK1/Parkin) and respiratory complex activity in cellular and mouse models of FA with frataxin deficiency. Concurrently, ARC-18 improved motor coordination and neuronal pathology in YG8R mice, which was dependent on the activation of PGC-1α. Mechanistically, FXN deficiency suppressed PGC-1α, while ARC-18 treatment restored its expression; this ARC-18 effect was abated by SR-18292 (a PGC-1α inhibitor), confirming pathway dependence.

The annualized rate of breast cancer recurrence is 10.4% within the first five years after surgery, with the highest risk (15.2%) occurring during the first two years.1 Despite the integration of mammography, MRI, CT, and PET scans into follow-up protocols, recurrence remains the leading cause of breast cancer–related mortality, accounting for an estimated 42,250 deaths in the United States in 2024. Early detection of tumor recurrence is therefore critical to improving the prognosis of breast cancer patients by enabling timely and targeted therapies. Circulating tumor DNA (ctDNA), which originates from tumor cells and enters the bloodstream (Fig. S1), has emerged as a promising biomarker for real-time monitoring of tumor burden. ctDNA is typically double-stranded and shorter than 200 nucleotides. Notably, its half-life ranges from 16 min to 2.5 h, supporting its utility as a dynamic biomarker.2 Measuring ctDNA in blood samples has evolved into a non-invasive liquid biopsy approach capable of predicting tumor recurrence prior to clinical diagnosis. Here, we performed a meta-analysis to evaluate ctDNA as a biomarker for early-stage breast cancer recurrence, with the goal of supporting its integration into clinical decision-making.

Non-syndromic cleft lip with or without cleft palate (NSCL/P) represents the most common craniofacial malformation worldwide, with an incidence of approximately 1:700 live births. Summary-data-based Mendelian randomization (SMR) integrative analysis of genome-wide association study (GWAS) and expression quantitative trait loci (eQTL) summary data identified FAM49A as an NSCL/P risk gene. The variant rs4240230 (PP4 = 0.99) exhibited causal effects on NSCL/P risk and FAM49A expression in Bayesian co-localization. Chromatin conformation capture (3C) revealed that the rs4240230 locus exhibits frequent physical interactions with the FAM49A gene, and the enhancer activity was validated by chromatin immunoprecipitation (ChIP) and CRISPR activation (CRISPRa). The G allele recruited less HLTF and reduced enhancer activity compared with the A allele in dual-luciferase reporter assays, ChIP and electrophoretic mobility shift assays (EMSAs). FAM49A deficiency inhibited proliferation and increased apoptosis and migration in mouse cranial neural crest cells (O9-1) while disrupting collagen fibril organization, extracellular matrix organization and bone development pathways. Deficient fam49a expression in zebrafish led to shortened body length, spinal curvature, ethmoid plate defects, and elevated mortality/deformity. In conclusion, the variant G allele of rs4240230 reduced HLTF binding affinity to FAM49A, suppressed FAM49A expression, and contributed to NSCL/P susceptibility.

Centromere protein M (CENPM) is a critical component of the constitutive centromere-associated network, playing a significant role in the assembly of kinetochores and the organization of chromosomes.1 Emerging evidence suggests that centromere protein family members contribute to cancer progression through multifaceted regulatory mechanisms,2,3 with CENPM overexpression implicated in tumor advancement through its oncogenic pathways.4 However, the biological implications and immune significance of CENPM in pan-cancer remain to be further understood. Through integrative multi-omics analysis of 33 cancer types, we revealed that CENPM is aberrantly overexpressed in 28 malignancies and serves as a robust prognostic predictor across multiplecancer types. Mechanistically, CENPM was observed to fuel genomic instability via synergistic interactions with tumor mutational burden (TMB), microsatellite instability (MSI), and mismatch repair (MMR) pathways, while concurrently shaping immunosuppressive microenvironments through myeloid-derived suppressor cell (MDSC) infiltration. Functional enrichment analyses further implicated CENPM in ribosome biogenesis and cell cycle regulation, bridging mitotic dysregulation to tumor progression. Critically, we demonstrate that CENPM operates as an immunological “switch” determining MDSC infiltration’s clinical impact. These findings reveal CENPM as both a prognostic indicator and a promising target for immunotherapy strategies across diverse malignancies.

Neuroinflammation plays a significant role in neurodevelopmental and neuropsychiatric disorders (NPDs), such as autism spectrum disorder, schizophrenia, and major depressive disorder. Microglia, the resident immune cells of the central nervous system, are essential for brain development, engaging in neurogenesis, synaptic pruning, and immune surveillance. Elevated cytokine levels and gene expression, leading to increased microglial activity, have been previously detected in autism spectrum disorder patients, suggesting a link with certain copy number variants (CNVs).1 The role of CNVs in the progression of NPDs linked to microglial dysfunction remains largely unknown. Therefore, we generated an in vitro microglial model system from patient-derived induced pluripotent stem cells (iPSC) carrying a deletion or duplication at the 1q21.1 chromosomal region, previously associated with developmental delay, autism spectrum disorder, and schizophrenia. Our study demonstrates a morphological dissimilarity, dysregulation in microglial cytokine production, and responsiveness in the presence of 1q21.1 CNV. Furthermore, our findings underscore the up-regulation of key genes regulating the inflammation and immune response, such as ICAM1, TRAF6, STAT3, and IFNRG1 in 1q21.1 CNV, suggesting a link between immune dysfunction and genetic abnormality at the cellular level.

Hepatocellular carcinoma (HCC), globally the fourth-leading cause of cancer death, shows marked heterogeneity.1 In China, advanced HCC first-line therapies include sorafenib and oxaliplatin-based chemotherapy to improve overall survival, also used in conversion therapy for unresectable tumors.2,3 However, only 30% of patients respond, with most progressing within six months. Resistance causes adverse effects and significant financial burdens; non-personalized management worsens healthcare inefficiencies.4 Current prognostic systems [e.g., Barcelona Clinic Liver Cancer (BCLC) staging, TNM staging] fail to predict therapy responses or survival due to oversimplified criteria,5 urgently requiring biomarkers reflecting HCC's molecular complexity.

Mitochondrial complex I (CI), also known as NADH-ubiquinone oxidoreductase, represents the largest and most intricate component of the mitochondrial oxidative phosphorylation (OXPHOS) system, which is composed of 44 different subunits in humans and is assembled from the 14 core subunits.1 CI, a key component of the electron transport chain, represents a crucial site for the physiological production of reactive oxygen species (ROS) during cellular respiration, commonly recognized as being intimately linked to the oxidative damage that occurs subsequent to hypoxic exposure.2 Complex I is a distinctive boot-shaped structure composed of 14 core protein subunits organized into two main domains. The N module, located at the top of the matrix arm, assumes a pivotal role in catalyzing the oxidation of NADH. Meanwhile, the Q module functions as a vital connector between the substrate arm and the membrane arm, facilitating the transfer of electrons. The Q module comprises a set of proteins, including NDUFS2, NDUFS3, NDUFS7, NDUFS8, NDUFA9, and notably NDUFA5, which serves as a nuclear-encoded structural accessory subunit positioned within the peripheral segment of Complex I’s Q model. Previous studies have conclusively demonstrated that the lack of the NDUFA5 subunit leads to the loss of the membrane arm subcomplex. One of the interacting subunits of NDUFA5 is NDUFS2, which is a core subunit of mitochondrial complex I and is encoded by nuclear DNA. NDUFS2 plays a crucial role in the catalytic activity and assembly of mitochondrial complex I.3,4 Mitochondrial diseases are a group of inherited metabolic disorders with a high degree of clinical and genetic heterogeneity.5 Epidemiological data revealed that CI deficiency carries a grave prognosis, with approximately 50% of affected patients succumbing within the initial two years of life, while merely a quarter manage to reach 10 years old. Lactic acidosis is a common feature of the disease caused by CI variants and is accompanied by other symptoms, such as cardiomyopathy or leukodystrophy. In this study, we described a four-month-old child with progressive neurological deficits, postpartum lactic acidosis, encephalopathy, developmental abnormalities, metabolic abnormalities, and respiratory failure. Whole genome sequencing (WGS) identified two heterozygous variants of the NDUFA5 gene. A series of in vitro functional experiments were conducted and demonstrated that the NDUFA5 gene was associated with CI functional defects for the first time.

Anti-programmed death 1 (PD-1) and epidermal growth factor receptor (EGFR)-based neoadjuvant therapy was confirmed to be effective for the treatment of head and neck squamous cell carcinoma (HNSCC). However, a previous study found that nearly 1/3 of HPV-negative HNSCC experienced no significant reduction or even increase in tumor size.1 Up till now, few studies have demonstrated the clinicopathological patterns of PD-L1+ EGFR+ HNSCC patients. Therefore, single-cell RNA-sequencing (scRNA-seq) analysis was applied in our retrospective study of 1077 HPV-negative HNSCC patients to characterize the immune patterns of the tumor microenvironment (TME) after anti-PD-1 and EGFR-based neoadjuvant therapy. In this study, we identified for the first time that most PD-L1+ EGFR+ HNSCC patients were in an advanced clinical stage and suffered lymph node metastasis. HPV-negative HNSCC patients experienced a significant reduction of tumor size after receiving 1 course of anti-PD-1 and EGFR-based neoadjuvant therapy. Meanwhile, PD-L1+ EGFR+ HNSCC patients have stronger invasive ability. The CXCL11/CXCR3 pair in PD-L1+ EGFR+ HNSCC cells contributed to the construction of an immunosuppressive TME by recruiting plasmacytoid dendritic cells, regulatory T cells, dendritic cells and CD8+ T cells. CD73, OX40, and TIM-3 are potential targets for immunotherapy sensitization in HPV-negative HNSCC. Our finding provides an immunotherapeutic sensitization strategy for PD-L1+ EGFR+ HNSCC.

Juvenile idiopathic arthritis (JIA) is a heterogeneous group of idiopathic inflammatory arthritis affecting children before 16 years of age.1 Although the pathogenesis of JIA remains unclear, viral infection is a potential environmental risk factor in JIA development.2 The retinoic acid-inducible gene I (RIG-I), a key cytosolic pathogen recognition receptor (PRR) responsible for detecting viral double-stranded RNA (dsRNA), serves as a critical gatekeeper of antiviral immunity through type I interferon (IFN) induction.3 Recent study suggests that the S144F variant is associated with increased disease severity and poorer treatment outcomes in pediatric rheumatic patients.4 However, the potential contribution and mechanism of RIG-I genetic variants to JIA susceptibility has never been systematically explored. In this study, we show that the RIG-I S144F variant is significantly enriched in JIA patients. S144F variant reduces its binding with the E3 ligase TRIM25, leading to decreased K63-linked polyubiquitination of RIG-I. Consequently, this results in impaired type I interferon signaling activation, higher viral load, and aggravated NF-κB signaling. In summary, we uncover a critical role of the RIG-I S144F variant in suppressing antiviral immunity, and shed light on immune pathogenesis of JIA.

MAFA is a transcription factor expressed in the pancreas and dorsal root ganglion neurons. The panniculus carnosus, also referred to as the cutaneous trunk muscle, cutaneous trunci, or cutaneous maximus, is a cutaneous muscle situated in the deep layer of human skin. We developed a MAFA-cre mouse and employed morphological and optogenetic techniques to investigate MAFA expression in the skin and its associated functions. Our novel findings indicate that MAFA is expressed in the panniculus carnosus muscles, and activation of these MAFA-expressing muscles induces twitching in the back.

Benign prostatic hyperplasia (BPH) is the most common benign condition associated with lower urinary tract symptoms in aging males, significantly impacting their quality of life.1 Accumulating evidence suggests that BPH is intricately associated with chronic inflammation.2 With the availability of large-scale Genome-Wide Association Study (GWAS) data and advancements in analysis methods, we investigated the causal relationship between the immune-related genes and BPH using multi-omics quantitative trait loci data. Notably, butyrophilin subfamily 3 member A2 (BTN3A2) emerged as a priority level 1 candidate gene, demonstrating consistent correlations with BPH across all analytical levels. The identification of BTN3A2-associated mechanisms provides novel insights into tissue-specific immune modulation in BPH management.

Neuropathic pain (NP) is a chronic condition with complex molecular mechanisms. Jakyakgamcho-tang (JGT) is derived from Paeoniae Radix and Glycyrrhizae Radix et Rhizoma, and shows a significant therapeutic potential for pain management,1 but its underlying mechanisms remain unclear. This study aimed to elucidate the mechanism of action of JGT in NP by systematically investigating the key NP-associated transcription factors (TFs) and signaling pathways regulated by JGT and its compounds. Additionally, we analyzed the transcriptome of JGT-treated PC12 cells and performed in vitro experiments to confirm the regulation of target genes.

The potassium inwardly rectifying channel subfamily J member 10 (KCNJ10) gene encodes the Kir4.1 inwardly rectifying potassium channel, which is predominantly expressed in the central nervous system, inner ear, and kidneys. Loss-of-function mutations in KCNJ10 can result in EAST (epilepsy, ataxia, sensorineural deafness, tubulopathy) or SeSAME (seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance) syndrome.1, 2, 3 The Kir4.1 channels are vital for the brain's functioning, particularly in the cortex, hippocampus, thalamus, and brainstem, where they play a crucial role in regulating astrocyte resting membrane potential, differentiation, and potassium balance. Disruption of these processes can significantly affect cognitive development, motor function, and seizure susceptibility.4 In EAST/SeSAME syndrome, seizures are often the earliest and most common symptom to appear in infancy. Broad-spectrum anti-seizure medications (ASMs), such as valproic acid, carbamazepine, oxcarbazepine, lamotrigine, and topiramate, have been shown to be effective.5 We present a unique case involving a child with EAST/SeSAME syndrome who has a homozygous missense mutation in KCNJ10 (c.523C > T, p.Arg175Trp), born to consanguineous parents. The child's seizures began at 48 days old and initially responded well to oxcarbazepine. After a subsequent relapse, topiramate was successful in controlling the seizures, while lacosamide not only failed to prevent another relapse but also aggravated the seizure activity. Considering that KCNJ10 loss-of-function mutations can compromise Kir4.1 channel activity, ASMs that target sodium channels are theoretically effective for epilepsy associated with this genetic anomaly, as seen in most documented cases. However, the seizure exacerbation observed with lacosamide treatment in this case prompts further investigation into the underlying mechanisms involved.

Craniofacial microsomia (CFM) is a congenital malformation resulting from abnormal development of cranial neural crest cells (CNCCs) and the first and second pharyngeal arches, affecting an estimated 1 in 3600 to 5600 live births. CFM encompasses a spectrum of abnormalities, ranging from isolated microtia to maxillary and mandibular hypoplasia, facial asymmetry, underdevelopment of the orbit, facial soft tissue, and/or facial nerve. The role of genetic factors in the occurrence of CFM is well-established. Although most cases of CFM are sporadic, both autosomal dominant and recessive inheritance patterns have been observed. Several genes, including SF3B2, HOXA2 and FOXI3, have been identified as pathogenic contributors to CFM.1 Haploinsufficiency of SF3B2 accounts for approximately 3% of sporadic CFM cases and about 25% of familial cases. To date, six families with microtia caused by HOXA2 variants have been reported. Additionally, approximately 3.1% of CFM cases are associated with pathogenic variants of FOXI3. Despite the identification of several causative genes, the genetic etiology of CFM remains unresolved for a significant proportion of cases.

Renal cell carcinoma (RCC) is the third most common urological malignancy. Due to its high metastatic potential, approximately 20% of patients present with metastases at diagnosis. Autophagy, a form of programmed cell death (PCD) characterized by autophagosome formation and lysosome-mediated degradation, plays a crucial role in tumor biology. Given that membrane dynamics are essential throughout the autophagic process, RAB proteins, which are key regulators of membrane trafficking, have garnered increasing attention. Among them, RAB24 stands out as an atypical member due to its roles in basal autophagy and endosomal degradation. However, its function in clear cell RCC (ccRCC) remains largely unexplored, prompting us to investigate this research gap.

Regulatory factor X 3 (RFX3), a member of the highly conserved RFX family of transcription factors, has recently been identified to be essential for human pancreatic endocrine development and β-cell function. Recently, we showed that loss of RFX3 during pancreatic differentiation of human induced pluripotent stem cells (iPSCs) disrupts endocrine gene regulation, reduces islet hormone-secreting cells, impairs β-cell function, and notably leads to increased cell death and aberrant specification toward enterochromaffin cells.1 Non-coding RNAs (ncRNAs), including microRNAs (miRNAs) and long ncRNAs (lncRNAs), play critical roles in regulating pancreatic development, especially in the formation and function of pancreatic islets and β-cells.2 While RFX3’s role in gene regulation is established, its impact on ncRNA networks during pancreatic differentiation remains poorly understood.

Ribonucleotide reductase (RNR) is the key enzyme converting ribonucleotides to deoxyribonucleotides.1 It forms a heterotetramer consisting of two regulatory subunits (R1) (encoded by RRM1) and two catalytic subunits (R2) (encoded by RRM2).1 Here we report that the catalytic minichromosome maintenance (MCM4/6/7) proteins,2 which are essential for DNA replication, interact with R1, but not R2. These studies were initiated after we had found a positive correlation between R1 expression and survival in patients with lung cancer.3 We found that R1 interacted with catalytic MCM4/6/7 in M-phase cells and MCM7 in non-M-phase cells, and that R2 overexpression did not disrupt these R1/MCM interactions. While knockdown of R1 decreased the protein and mRNA levels of MCM7 and arrested cells at the G2/M phase, overexpression of MCM7 in R1 knockdown cells relieved the G2/M arrest, leading to cell proliferation. dNTP pools do not affect cell growth in control and R1 knockdown cells, suggesting that R1's function in RNR does not influence R1's function in cell proliferation. Furthermore, there was a positive correlation between R1 and MCM7 expression in a cohort of lung cancer patient samples. Overall, our findings suggest that R1 regulates cell cycle progression through modulation of MCM7 levels, implicating that RNR and MCMs collaborate in cell cycle regulation.

Mutations in splicing factor 3b subunit 1 (SF3B1), particularly the K700E hotspot mutation, have been implicated in the pathogenesis of several hematological malignancies, including myelodysplastic syndromes (MDS), chronic lymphocytic leukemia, and acute myeloid leukemia. Despite the availability of various murine models for studying SF3B1 mutations, there remains a notable discrepancy between the disease manifestations in these models and the human condition. Murine models often fail to fully recapitulate the spectrum of human blood cancers, particularly in terms of the transcriptional dysregulation observed in patients. This gap underscores the necessity for alternative models that can more accurately mirror the human disease phenotype to elucidate the underlying mechanisms of SF3B1 mutations in oncogenesis.1 It is not understood what transcriptional dysregulation events are specifically induced by SF3B1 mutation and are pivotal in the early stage of blood cancers.

Double primary malignant tumors refer to the presence of two independent primary malignancies in the same or different organs.1 In recent years, the detection rate of double primary malignant tumors has significantly increased, of which double primary cancers related to lung cancer account for 10%–15%.2 This is mainly due to the increase in the incidence rate of lung cancer, the long-term side effects of chemotherapy or radiation therapy, and continuous innovations in cancer-related detection techniques.3,4 However, research on double primary malignant tumors (such as lung cancer and thyroid cancer: DPLT) involving lung cancer is still limited. The lack of experimental evidence and clinical data related to double primary tumors, especially the unique genomic and transcriptome characteristics, poses difficulties for the prevention and treatment of double primary tumors.5 In this study, we used single-cell RNA sequencing and large-panel sequencing to investigate multiomics changes during DPLT progression and revealed their gene mutation characteristics and tumor microenvironment heterogeneity, thereby providing novel insights for clinical detection and therapeutic strategies in DPLT patients.

Cancer stem cells (CSCs) are resistant to anti-tumour therapies and are associated with metastasis and recurrence. High concentrations of lactic acid can promote the maintenance of tumour cell stemness.1 We previously reported that SOX2 promotes the malignant phenotype and stemness of ECCs and ECSC.2 SP1 is a transcription factor. It promotes the proliferation and invasion of endometrial cancer (EC) cells.3 In lung adenocarcinoma, SP1 promotes stemness by modulating the expression of key stemness genes, including OCT4, Nanog, and CTGF.4 Immunotherapy represents a potential treatment option for patients with advanced EC. However, only a limited number of patients benefit from the currently available regimens. Studies have shown that the TGF-β/PD-L1 bispecific antibody can enhance anti-tumor immunity,5 which provides new insights for the treatment of endometrial cancer.

Mesenchymal stem cells (MSCs) respond to diverse growth factors and signaling cascades that coordinately regulate their osteogenic differentiation potential. Bone Morphogenetic Protein 9 (BMP9), a member of the TGF-β superfamily, is one of the most potent inducers of osteogenic differentiation of MSCs.1 DNA methylation plays a role in osteogenesis as an epigenetic regulatory mechanism. Previous studies demonstrated that hypermethylation of the BMP2 promoter regions silenced osteogenic genes.2 The tet-eleven translocation (Tet) family of dioxygenases promotes DNA demethylation through oxidizing 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC) and its derivatives in an Fe(II)/α-ketoglutarate-dependent oxidation reaction.3 While all three TET family members (Tet1, Tet2, Tet3) are expressed in MSCs, Tet2 has been identified as the most significantly upregulated member upon osteogenic induction and is critically involved in lineage determination. Furthermore, studies have shown that Tet2, rather than Tet1 or Tet3, plays a dominant role in the transcriptional activation of key osteogenic factors like Runx2.4 Here, by employing a multiplex-siRNA system to effectively silence Tet2 expression in MSCs, we demonstrate that the loss of Tet2 expression significantly hampers BMP9-induced osteogenic differentiation and ectopic bone formation, confirming our hypothesis in which Tet2-mediated DNA demethylation plays a significant regulatory role in osteogenic differentiation of MSCs.

The aberrant differentiation and state transition of the T cell lineage underpin the pathogenesis of non-Hodgkin lymphoma (NHL). Tumor cells originating from B or T cells form the complicated dynamic network with components in the tumor microenvironment (TME).1 To orchestrate a tumor-supportive and immunosuppressive environment, tumor cells mainly build contact-dependent communication and paracrine signaling to reshape non-malignant host cells in the TME and remodel the extracellular matrix (ECM).2,3 Angiogenic switching, T cell dysfunction, and ECM crosslinking in the TME make significant contributions to tumor survival, infiltration, and progression. However, the mechanisms driving these processes remain poorly understood.

HER2-positive breast cancer exhibits high aggressiveness, a propensity for recurrence, and a poor prognosis.1 Approximately 16%–22% of early stage patients still experience recurrence, and 22%–25% of patients with metastatic HER2+ breast cancer exhibit primary or acquired resistance. Therefore, it is necessary to investigate the molecular mechanisms that regulate HER2 status in order to develop new therapeutic strategies. Ubiquitin carboxyl-terminal hydrolase-L1 (UCH-L1), also known as protein gene product 9.5 (PGP9.5), is a member of the ubiquitin C-terminal hydrolase (UCH) family.2 UCH-L1 can play either a pro- or anti-tumorigenic role in different types of cancer because UCH-L1 acts by regulating different substrates. The overexpression of UCH-L1 has been observed to induce G0/G1 cell cycle arrest and apoptosis by stabilizing p53. In another independent study, UCH-L1 was observed to interact with AKT in MCF-7 cells, resulting in the up-regulation of phosphorylated AKT and an increase in the invasive capacity of MCF-7 cells. Therefore, it is crucial to investigate the mode of action of UCH-L1 in different cancers.3

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal solid tumors, ranking as the fourth leading cause of cancer-related mortality worldwide. Despite advances in therapeutic strategies, the five-year survival rate remains less than 10%.1 This poor prognosis stems primarily from late diagnosis, intrinsic resistance to adjuvant therapy, and a profoundly immunosuppressive tumor microenvironment. Chronic inflammation is well recognized as a major risk factor and driver of PDAC tumorigenesis, with pancreatitis representing a significant precursor lesion.2 Among the proinflammatory mediators involved, interleukin (IL)-1 family cytokines have garnered attention due to their central role in immune modulation, tumor cell survival, and response to treatment.

The androgen receptor (AR) signaling axis is regarded as the key driver of prostate cancer (PCa). Besides acting as a well-characterized transactivator of diverse targets, accumulating evidence suggests that AR can also function as a transrepressor. However, AR-repressed targets and their significance in PCa and castration-resistant PCa (CRPC) remain poorly understood. Among multiple mechanisms, intratumoral androgen biosynthesis is regarded as an important factor responsible for persistent AR signaling in CRPC. Previously, we characterized that the nuclear receptor LRH-1 (NR5A2) plays a key role in the promotion of intratumoral androgen biosynthesis in CRPC via its direct transcriptional control of multiple key steroidogenic enzymes. However, the transcriptional control of LRH-1 in PCa is still undefined. In this study, we show that androgen-activated AR could suppress, whereas antiandrogen-suppressed AR could up-regulate the LRH-1 expression in PCa cells. Furthermore, our genomics analysis showed that the transcriptional repression of NR5A2 by ligand-activated AR was mediated through the induction of a distinct androgen-dependent chromatin looping formed within the topologically associated domain of NR5A2 via direct binding of AR to the regulatory elements of NR5A2. Our present study demonstrates the significance of decreased androgen levels in androgen-deprivation therapy, resulting in the relief or up-regulation of LRH-1 toward intratumoral androgen biosynthesis in CRPC.

Copper (Cu2+) is a known contributor to the pathogenesis of Alzheimer's disease (AD). However, it is uncertain whether proteins regulating copper homeostasis affect Cu2+ in microglia. Antioxidant protein 1 (ATOX1) plays a key role in Cu2+ homeostasis, oxidative stress, and cell protection. Despite its critical functions, the role of ATOX1 in AD pathology remains poorly defined. This study aims to examine the effects of ATOX1 on oxidative stress, apoptosis, and neuroinflammation in microglia by modulating Cu2+ homeostasis. In vivo, a 5 × FAD mouse model was used to investigate the localization and expression of ATOX1 in AD by immunofluorescence and three-dimensional reconstruction. The Aβ1-42 oligomer was used to establish an AD model in vitro. The role of ATOX1 in Cu2+ homeostasis regulation in microglia was further studied using co-immunoprecipitation, Western blotting, quantitative real-time PCR, and spectrophotometry. A reduction in ATOX1 expression was noted in Aβ-plaques-associated microglia compared with normal microglia. Cu2+ levels were elevated in the in vitro AD model, and ATOX1 directly regulated copper homeostasis via P1B-ATPase (ATP7B) in microglia. Excessive Cu2+ induced oxidative stress, neuroinflammation, and apoptosis. Overexpression of ATOX1 alleviated this neurotoxicity, indicating its potential to alleviate oxidative stress, cell apoptosis, and neuroinflammation in AD. ATOX1 overexpression offers protective effects on microglia through Cu2+ homeostasis, which may lead to potential therapeutic strategies for AD.

Strategies that enhance the function of chimeric antigen receptor-modified T (CAR-T) cells for solid tumors are critical. Inhibitory immuno-checkpoints blockade could potentially enhance CAR-T cell function. TIM-3 is an important negative regulator of T cell activity, but whether TIM-3 blockade could affect CAR-T cell function remains unclear. In our study, we successfully constructed TIM-3-silenced CAR-T cells by dual-promoter lentivirus vectors that simultaneously express the TIM-3 targeting short hairpin RNA (shRNA) and a third-generation CAR recognizing HER2. We demonstrated that down-regulation of TIM-3 did not affect the phenotype of CAR-T cells. CAR-T cells with TIM-3 blockade exhibited higher lytic cytotoxicity to target cells in vitro. Additionally, TIM-3-silenced CAR-T cells displayed robust anti-tumor activity in a murine xenograft model, which is comparable to standard CAR-T cells. Our study demonstrates the effect of down-regulation of immune checkpoint TIM-3 on the anti-tumor function of CAR T cells, providing new ideas for improving the potency of CAR-T cell therapies in solid tumors.

Systemic juvenile idiopathic arthritis (sJIA) is an autoinflammatory disorder characterized by systemic immune dysregulation, yet reliable biomarkers to predict its unpredictable disease course are lacking. Identifying immune cell subsets and molecular drivers of disease progression is essential for improving prognosis and developing targeted therapies. Here, we performed comprehensive immunophenotypic profiling of PBMCs from sJIA patients across five clinical centers. We identified an unrecognized CD14+CXCL10+ monocyte subset in sJIA distinguished by a unique transcriptomic signature enriched in immune regulatory genes. Deconvolution analysis with longitudinal follow-up in the Chongqing cohort revealed a previously unrecognized CD14+CXCL10+ monocyte subset that was markedly expanded during active sJIA and diminished during remission, correlating strongly with disease activity. Flow cytometry confirmed its dynamic changes, and in vitro inflammatory stimulation promoted the differentiation of monocytes into the CXCL10 phenotype. To validate these observations in vivo, we used Ube2d1 knockout mice, which exhibit impaired CXCL10 induction and attenuated arthritis severity, highlighting the pivotal role of Ube2d1 in driving this inflammatory program. Furthermore, a cross-disease single-cell reference atlas demonstrated that this monocyte subset displayed a distinct expression profile in sJIA compared with other JIA subtypes and inflammation-related diseases. Collectively, our findings indicate that UBE2D1-driven CD14+CXCL10+ monocytes are central to sJIA pathogenesis and may represent both a biomarker and a therapeutic target for disease monitoring and intervention.

Snail1, encoded by SNAI1 gene, is an essential protein that regulates epithelial–mesenchymal transition, which leads to extracellular matrix accumulation and kidney fibrosis, but with unclear cellular and molecular mechanisms. This study compared the cellular proteome of SNAI1-overexpressed renal tubular cells with that of vector-control cells by label-free quantitative proteomics, followed by functional assessments using various assays. A total of 233 proteins showed significant changes in their levels by ectopic SNAI1 expression. Of these, immunoblotting confirmed the decreases in HSP60 and HSP70 and the increase in DDX1. Bioinformatic analyses revealed the top 10 transcription factors as key upstream regulators of the altered cellular proteome, and translational regulation, ribosome, cell cycle regulation, and cellular senescence were primarily associated with these altered proteins. Gene ontology enrichment showed that focal adhesion, the structure where cells maintain their interior-extracellular matrix interactions, was one of the major affected cellular components. Experimental validations demonstrated that SNAI1-overexpressed cells displayed increases in nucleophosmin, nucleolar organizer regions, cell size, granularity, p21, γH2AX, MMP-9 secretion, and paxillin expression, confirming the bioinformatic predictions. This study has broadened our knowledge of Snail1 functions beyond its established role as the epithelial–mesenchymal transition regulator. In addition to alterations in the cellular proteome, ectopic SNAI1 expression induced nucleolar stress, ribosome biogenesis, senescence, and DNA damage response in renal tubular cells. Moreover, Snail1 also affected the dynamics of focal adhesion, which is imperative for cell migration, by regulating paxillin expression. These findings may offer new therapeutic targets related to Snail1-dependent mechanisms for effective management of kidney fibrosis.

Cholestatic liver diseases, including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), are characterized by disrupted bile acid (BA) homeostasis and subsequent liver injury. Emerging evidence indicates that circadian rhythms significantly influence liver metabolism and the pathogenesis of liver diseases. CD36 has been identified as a regulator of the hepatic circadian clock and metabolic processes; however, the specific mechanisms by which CD36 links circadian rhythms to cholestatic liver disease remain unclear. In this study, we employed bile duct ligation (BDL) mice and liver-specific CD36 knockout (CD36 LKO) mice to examine the role of CD36 in BA metabolism and circadian gene expression. BDL mice presented disrupted rhythms in both liver clock and BA metabolism, accompanied by increased diurnal expression of CD36. Conversely, in the context of BDL, CD36 LKO reduced cholestatic liver injury, improved BA metabolism, and restored diurnal variation of BA levels. Transcriptomic analysis revealed that BA metabolism genes were regulated by CD36, particularly those involved in synthesis, which displayed diurnal variation. Targeted inhibition of CD36 expression effectively mitigated liver injury and inflammation in BDL mice by restoring the rhythmicity of HMGCR/CYP7A1 and normalizing the BA pool size. These findings suggest that CD36 plays a pro-cholestatic role through its regulation of rhythmic BA synthesis and that its inhibition may represent a promising therapeutic strategy for cholestatic liver diseases.

Colorectal cancer (CRC) is a highly heterogeneous malignancy that is divided into four consensus molecular subtypes (CMSs), with CMS4 considered to be the worst type of CRC. The CMS classification has not been translated into clinical practice through the transcriptomic data; thus, the identification of a novel biomarker that can identify CRC subpopulations is imperative. Using bioinformatic analysis and immunohistochemical verification, we found that PLXNC1 mRNA and protein expression were significantly up-regulated in CRC tissues. High PLXNC1 was found to be significantly associated with aggressiveness and poor prognosis and thus was confirmed as an independent prognostic factor for CRC. CMS4 CRC could be distinguished from other subtypes based on PLXNC1 expression. The tumor microenvironment was investigated by deconvolution algorithms through bulk and single-cell RNA-sequencing data. CRC with high PLXNC1 expression exhibited a distinct mesenchymal phenotype, accompanied by high infiltration of stromal components, angiogenesis, complement activation, and an immunosuppressive microenvironment. The functions of PLXNC1 were assessed by proliferation, migration, and invasion assays in CRC cells in vitro. A subcutaneous tumor model and liver metastasis model of CRC were generated to explore the effects of PLXNC1 in vivo. Combined with RNA-sequencing analysis, PLXNC1 promoted CRC growth and metastasis by regulating epithelial–mesenchymal transformation and immune escape. Knockdown of PLXNC1 reduced the CMS4-related phenotypes in CRC. In vitro co-culture and in vivo experiments revealed that PLXNC1 could impair the cytotoxicity of CD8+ T cells, thus facilitating immune evasion by CRC cells. We demonstrate that PLXNC1 may predict poor prognosis of CRC, exhibit pro-oncogenic effects, and accelerate tumor immune escape in CRC progression. Our study uncovers a novel biomarker for CMS4 CRC and suggests PLXNC1 as an indicator for prognosis and a potential drug target of high-risk CRC.

Cancer cells adopt multiple strategies to avoid detection and destruction by the immune system, including exploiting immune checkpoint pathways. B7x (B7-H4, B7S1, or VTCN1), a member of the B7/CD28 family, is frequently expressed in advanced bladder cancer, yet its role in bladder cancer progression and resistance to therapy remains poorly understood. Resistance to PD-1/PD-L1 immune checkpoint blockade immunotherapy significantly limits durable responses, with only 20%–25% of patients with muscle-invasive bladder cancer (MIBC) achieving long-term benefits. Here, we demonstrated that B7x mRNA and protein expression were associated with poor survival outcomes in MIBC patients and mouse models of bladder cancer, respectively. Stable expression of B7x in immune-competent bladder cancer mouse models resulted in enhanced tumor growth and splenomegaly, driven by the exclusion and suppression of tumor-infiltrating antitumor immune cells and the enrichment of pro-tumor and immunosuppressive cells. Consistently, in the IMvigor210 clinical trial, high B7x mRNA expression was correlated with poorer survival in MIBC patients treated with PD-L1 blockade. Notably, combination therapy targeting B7x alongside PD-1/PD-L1 or CTLA-4 blockade reduced tumor burden and overcame resistance to monotherapy. These findings establish B7x as a substantial driver of immune evasion in bladder cancer and highlight its potential as a therapeutic target to improve immune checkpoint blockade efficacy in MIBC.

Maternal infections can have profound effects on embryonic heart development, yet the precise pathways through which these impacts manifest are still largely unexplored. This research explores the influence of maternal exposure to lipopolysaccharide (LPS) and polyinosinic-polycytidylic acid [Poly(I:C)] on metabolic profiles and mitochondrial function of offspring. At embryonic day 16.5, pregnant female C57BL/6J mice received either LPS or Poly(I:C) treatment. Human induced pluripotent stem cells were differentiated into cardiomyocytes (hiPSC-CMs) to evaluate the effects of various interventions on cardiomyocyte differentiation. mRNA sequencing and untargeted metabolomics were performed to analyze metabolic alterations. The findings from mRNA sequencing indicated that both LPS and Poly(I:C) caused metabolic pathway disturbances in the offspring's heart, with differentially expressed genes enriched in lipid, energy, and amino acid metabolism. Additionally, untargeted metabolomics showed a notable elevation in polyunsaturated fatty acids following LPS or Poly(I:C) treatment. Moreover, both LPS and Poly(I:C) treatment significantly impaired mitochondrial function, increased reactive oxygen species, and heightened lipid peroxidation within offspring mouse hearts. Mitochondrial dysfunction was mitigated through the application of antioxidant agents, such as N-acetylcysteine and ferrostatin-1. During hiPSC-CM differentiation, Poly(I:C) treatment led to similar mitochondrial dysfunction, while LPS treatment had minimal effects on ATP levels and lipid peroxidation. These findings indicate that maternal infection impairs metabolic signaling and mitochondrial function in the developing heart, with oxidative stress and lipid peroxidation playing key roles in these effects.

Traumatic brain injury (TBI) is characterized by high rates of death and disability. Necroptosis is reported to be involved in neuronal death after TBI. However, additional molecules and related mechanisms underlying necroptosis, particularly during TBI, remain to be elucidated. mTOR and two of its three substrates (4EBP1 and ULK1) are involved in necroptosis. However, direct evidence linking necroptosis to S6K, another key substrate of mTORC1, has been lacking. In this study, we aimed to investigate the regulated role of “S6K1-glucocorticoid-inducible kinase-1 (SGK1)” pathway in neuronal necroptosis after TBI. We first showed that the “S6K1–SGK1” pathway was activated during neuronal necroptosis in TNF-α/Smac mimics/Z-VAD-FMK-induced necroptotic cell model and mouse TBI model. Then, inhibition of the “S6K1–SGK1” pathway could decrease necroptosis by regulating the MLKL activation. Next, a rescue assay indicated that S6K1 may regulate necroptosis through modulating SGK1 expression, while not through binding with SGK1. Finally, S6K1 inhibition alleviated neuronal necroptosis, neuro-inflammation, and functional damage via SGK1 in mice after TBI. Our results showed a non-canonical role of “S6K1–SGK1” pathway in neuronal necroptosis following TBI in mice, which will provide a potential therapeutic target for necroptosis treatment in TBI and other necroptosis-related disorders.

Poly (ADP-ribose) polymerase inhibitors (PARPi) demonstrate effective treatment outcomes in ovarian cancer patients with BRCA1/2 mutations or homologous recombination (HR) repair deficiencies, leveraging the principle of synthetic lethality. However, PARPi resistance and HR proficiency remain significant challenges in the clinical management of PARPi, necessitating the development of novel strategies for PARPi therapy in ovarian cancer. Our previous research identified PAK1's involvement in replication stress-induced cytotoxicity. Nonetheless, whether PAK1 also affects HR repair and PARPi sensitivity in ovarian cancer remains unresolved. In this research, we found that the expression of PAK1 correlated with an unfavorable prognosis in ovarian cancer. Depletion of PAK1, introduction of a kinase-dead mutation, or treatment with the inhibitor IPA-3 could reduce HR repair efficiency and increase ovarian cancer cell sensitivity to the PARP inhibitor olaparib. The combination of olaparib and IPA-3 synergistically increased olaparib-induced DNA replication stress and double-stranded breaks. Using cell line-derived xenograft, patient-derived organoid, and patient-derived xenograft models, we discovered that IPA-3 potentiated the therapeutic efficacy of olaparib both in vivo and ex vivo. Collectively, our findings suggest that targeting PAK1 might offer a new avenue for increasing the sensitivity of olaparib and improving the outcomes of ovarian cancer patients.

One of the leading causes of human subfertility is the continuous decline in semen quality, contributing to a global fertility crisis. Over half of subfertile men suffer from asthenozoospermia and teratozoospermia, with mechanisms still largely unknown. Traditional small noncoding RNA sequencing (sncRNA-seq) primarily targets miRNAs, failing to capture the broader spectrum of small noncoding RNAs (sncRNAs), including abundant transfer RNA-derived small RNAs (tsRNAs) and ribosomal RNA-derived small RNAs (rsRNAs). These sncRNAs possess complex RNA modifications and non-canonical terminal structures, impeding their accurate profiling. In this prospective cohort study, we addressed these limitations by combining our state-of-the-art PANDORA-seq with traditional sncRNA-seq, which generated the most comprehensive sncRNA landscape of human sperm from 25 participants with asthenozoospermia, teratozoospermia, or normozoospermia. PANDORA-seq significantly improved the annotation efficiency of sncRNAs and delivered a more detailed characterization for tsRNAs and rsRNAs, which were strongly correlated with key clinical indicators of sperm quality, thereby enhancing our understanding of the landscape of human sperm sncRNAome and its association with male subfertility. Importantly, machine learning with Lasso regression identified specific tsRNA/rsRNA signatures as highly effective clinical biomarkers (AUC ≥ 0.83) for predicting sperm abnormalities, offering significant improvements over World Health Organization-based semen quality assessments and novel insights for clinical diagnosis.

Lung cancer is the leading cause of cancer-related death and has the second-highest incidence worldwide. For patients with advanced EGFR-mutated non-small cell lung cancer, EGFR tyrosine kinase inhibitors (EGFR-TKIs) are the preferred treatment option; however, acquired resistance to TKIs is inevitable. Gefitinib and osimertinib, the first-generation and third-generation EGFR-TKI, have shown promising results in patients with EGFR-mutated lung cancer in clinical treatment. Here, we identified that pyruvate dehydrogenase kinase 1 (PDK1) was up-regulated in gefitinib- and osimertinib-resistant cell lines, and PDK1 knockdown rendered cells more sensitive to TKI treatment. PDK1 expression levels were significantly increased in lung, colon, liver, and breast cancer tissues compared with those in normal tissues. Histone demethylase KDM3A was also induced in TKI-resistant cell lines, and demethylated histone H3 lysine 9 to facilitate PDK1 expression to regulate TKI resistance. Further study demonstrated that METTL16 promoted the m6A modification of PDK1 mRNA, and the m6A reader IGF2BP1 directly recognized and enhanced PDK1 mRNA stability. Interestingly, KDM3A also induced METTL16 expression. Moreover, PDK1 inhibitor JX06 rendered cancer cells more sensitive to gefitinib treatment in vivo, and JX06 and gefitinib combination treatments have a synergic effect to inhibit tumor growth. In conclusion, the KDM3A/METTL16/PDK1 axis plays an important role in cancer development and TKI resistance, which may offer new prognostic biomarkers and therapeutic targets for TKI resistance in the future.

Parkinson’s disease (PD) is a prevalent neurodegenerative disorder accompanied by neuroinflammation. Many studies have demonstrated that interleukin-6 (IL-6) exhibits both anti-inflammatory and pro-inflammatory effects in the central nervous system, yet its role in PD remains controversial. In this study, Il6−/− (knockout), Il6+/−, and wild-type mice were utilized to investigate the impact of IL-6 on the pathology of MPTP- or α-SynucleinA53T-induced PD mice. Our findings revealed that Il6 deficiency exacerbated motor dysfunction in both female and male mice. MPTP intoxication resulted in earlier and more extensive injuries to the dopaminergic system and heightened glial reaction in the nigrostriatal pathway of female Il6−/− mice compared with male Il6−/− mice, which only displayed more severe dopaminergic neuronal loss at 7 days after MPTP administration. Toxic α-Synuclein overexpression in the substantia nigra region caused earlier motor dysfunction and aggravated dopaminergic neurodegeneration in female Il6−/− mice. In Il6+/− mice, MPTP-induced depletion of dopaminergic nerve fibers was unaffected, although astrocyte activation was attenuated. Moreover, intraperitoneal administration of recombinant IL-6 (rIL-6) partially ameliorated MPTP-induced motor dysfunction and striatal dopaminergic terminal depletion in both wild-type and knockout mice. Our findings underscore the crucial role of IL-6 in the inflammatory pathology of PD, highlighting sex-dependent differences, and suggest that rIL-6 holds potential promise for PD therapy.

Although the cellular role of uncoupling protein 2 (UCP2) in tumorigenesis has been reported in various solid tumor models, its role in leukemogenesis remains elusive. Herein, we demonstrated that UCP2 was highly expressed in AML and significantly associated with poor prognosis and chemoresistance, suggesting that UCP2 can be used as a potential biomarker in acute myeloid leukemia. Mechanistically, in vitro and in vivo silencing of UCP2 significantly impairs acute myeloid leukemia cell growth and survival, accompanied by the disruption of mitochondrial homeostasis. Interestingly, RNA-sequencing analysis and metabolic mass spectrometry revealed that silencing UCP2 resulted in accumulated branched-chain amino acids (BCAAs), which induced oxidative stress through the PI3K/AKT/mTOR signaling pathway. Additionally, the lack of BCAAs restored leukemic cell growth and survival and decreased mitochondrial ROS production induced by inhibiting UCP2. More importantly, supplementation of BCAA enhanced the anti-tumor activity of genipin, a selective inhibitor that targets UCP2, resulting in significantly reduced acute myeloid leukemia blasts, increased mouse survival, and magnified oxidative stress. Taken together, our study elucidates the rationale of targeting the UCP2-BCAA-PI3K/AKT/mTOR signaling axis in leukemogenesis and provides a novel strategy for leveraging the metabolic dependencies of leukemic cells.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), as vital targeted therapies in cancer treatment, show significant clinical effectiveness but raise increasing safety concerns. Current safety studies mainly focus on dermatologic, hepatic, and pulmonary toxicities.1 The common toxicities of EGFR-TKIs (e.g., rash, diarrhea, interstitial lung disease) are more noticeable and often reported, so they have traditionally received more attention in clinical trials and guidelines; this has somewhat overshadowed renal adverse reactions, which are less common or more subtle. Moreover, early signs of nephrotoxicity are mostly non-specific; additionally, cancer patients often have pre-existing kidney disease or are on other nephrotoxic chemotherapies, making nephrotoxicity challenging to diagnose accurately. Furthermore, initial EGFR-TKI trials primarily focused on efficacy outcomes, with limited follow-up and no specific renal function monitoring included in the protocols, resulting in inadequate data on the incidence and characteristics of nephrotoxicity.

Recent developments in multimodal artificial intelligence (AI) have begun to transform how clinicians approach cancer prognosis and treatment selection. In a recent study, Xiang et al1 present MUSK (Multimodal Unified Self-supervised learning for Oncology), a foundation model that integrates more than 50 million whole-slide pathology images and over 1 billion oncology-related clinical text tokens. MUSK uses a unified transformer architecture to simultaneously capture morphological and semantic features, enabling the integrated image–text interpretation essential for oncology (Fig. 1A). The model was pretrained in two stages: the first stage employed masked modeling using unpaired data from each modality, while the second stage used approximately one million paired image–text samples with contrastive learning to align histologic and linguistic representations. This approach enabled robust cross-modal understanding, supporting downstream diagnostic and prognostic applications.