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。

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Runt-related transcription factor 2 (RUNX2), also called core-binding factor subunit alpha-1 (CBFA1), is the bone-specific transcription factor considered the master gene in osteogenesis, contains a crucial RUNT domain for DNA binding, and is regulated by multiple mechanisms. During the initial stages of osteogenesis, the expression levels of RUNX2 are primarily elevated and then gradually decrease during the formation of osteoblasts and osteocytes.1 Abnormal levels of RUNX2 can severely affect osteoblasts and skeletal structure. RUNX2 mutations are linked to cleidocranial dysplasia (CCD), a rare autosomal dominant skeletal disorder characterized by abnormal skeletal phenotypes.2 Our previous data demonstrate that RUNX2 mutations alter the modulation of p53 levels.2 However, despite the documented involvement of the RUNX2 protein in numerous cellular pathways beyond osteogenic differentiation, there are no in-depth studies on the impact of these mutations on cellular homeostasis. To explore the effects of mutations in the RUNT domain of RUNX2, here, we examined the cellular impact of the RUNX2 mutation c.505C > T in induced mesenchymal stem cells (iMSCs) obtained from induced pluripotent stem cells derived from one 26-year-old female CCD patient (Fig. S1). Our research provides the first molecular studies of this RUNX2 mutation in a CCD patient.

Hypertrophic cardiomyopathy (HCM) is a prevalent inherited cardiac condition, affecting approximately 1 in 500 individuals.1 Recent research highlights immune cell involvement in HCM, with altered levels of various immune populations associated with the disease.2 However, whether these changes are causative or merely correlational is still uncertain. This study aims to investigate the causal effects of 731 immune cell types on HCM using comprehensive bidirectional Mendelian randomization (MR), a robust method for assessing causal inference in observational studies.3

First described by Meredith in 1987, retinal venous beading (RVB) is an extremely rare and potentially vision-threatening disease,1 which is characterized by beading or sausage-like configuration of retinal veins. It can present with episodes of increased vascular permeability accompanied by lipid exudation, foveal edema, recurrent branch vein occlusion, retinal ischemia with retinal neovascularization, and vitreous hemorrhage,1 or exist solely and asymptomatically.2 Most reported RVB cases exhibited an autosomal dominant inheritance pattern, but some cases are still termed idiopathic or sporadic with no familial history.2 Up to now, the exact genetic background and pathogenesis of RVB are yet unclear.

Cleft lip/palate (CL/P) is generally divided into two main types, non-syndromic and syndromic CL/P, with a global incidence of approximately 1 in 700.1 Previous studies have identified various susceptibility genes associated with non-syndromic CL/P, while the pathogenic gene of syndromic CL/P and the related mechanisms are not well documented. Ectrodactyly–ectodermal dysplasia–cleft lip/palate (EEC) syndrome is a representative syndromic CL/P, which is characterized by mild-to-severe symptoms such as missing or irregular fingers or toes, cleft lip or palate, distinctive facial features, and abnormalities of the eyes and urinary tract. The mutations in TP63 have been associated with some EEC cases. Meanwhile, there were other reported EEC cases without mutations in TP63 or other certain genes, suggesting other potential pathogenic genes involved in EEC syndrome. ARHGAP29 encodes Rho GTPase-activating protein 29, broadly expressed in various tissues such as blood, liver, and heart, especially in the palatal shelf.2, 3, 4 Arhgap29 mutant mice presented abnormal oral epithelial adhesions,5 ARHGAP29 has also been regarded as the susceptible gene of non-syndromic CL/P since 2012. Our whole exome sequencing also identified a new missense mutation(c.451C>T, p.Leu151Phe) in ARHGAP29 in a Chinese non-syndromic CL/P pedigree (Fig. S2C).

Ishina Irina A.，Zhiyanov Anton P.，Kurbatskaia Inna N.，Mamedov Azad E.，Nersisyan Stepan A.，Ziganshin Rustam H.，Eliseev Igor E.，Petrusenko Yunna S.，Nikonova Anastasia V.，Zhbanova Elizaveta S.，Salnikova Maria A.，Ovchinnikova Leyla A.，Mamedov Ilgar Z.，Davydov Alexey N.，Nurbaeva Kamila S.，Lisitsyna Tatiana A.，Reshetnyak Tatiana M.，Lila Alexander M.，Nasonov Evgeniy L.，Lomakin Yakov A.，Belogurov Alexey A. Jr.，Zhang Hongkai，Tonevitskiy Alexander G.，Rubtsov Yury P.，Gabibov Alexander G.，Zakharova Maria Y.

Rheumatoid arthritis (RA) is an autoimmune disorder characterized by synovial joint damage and progressive loss of mobility. The human leukocyte antigen (HLA) class II alleles HLA-DRB1∗01:01 and HLA-DRB1∗04:01 are strongly linked to RA susceptibility. Several autoantigenic peptides were reported to bind to RA-associated HLA-II and trigger autoreactive CD4+ T cell response. Here, we propose a dual combinatorial approach to identify novel autoantigenic peptides presented by HLA-II. We generated a phage library containing fragments of human autoantigens to screen for peptide ligands binding RA-associated HLA-II. Concurrently, the HLA-II immunopeptidome of peripheral blood mononuclear cells from RA patients was analyzed using liquid chromatography with tandem mass spectrometry (LC-MS/MS). This approach led to the identification of a panel of RA-associated HLA-II peptide ligands, confirmed via in vitro binding assay. Identified autoantigens include fragments of annexin A11, endoplasmic reticulum chaperone BiP, calreticulin, and vimentin. Finally, we demonstrated that the annexin A11 fragment, in the complex with HLA-DRB1∗01:01, can activate CD4+ T cells from RA patients.

Inter-subtype recombination is the main force for the complexity of HIV-1 genetic diversity, which increases the difficulty of preventing HIV-1 infection and administering antiretroviral therapy for people living with HIV. To date, 143 circulating recombinant forms (CRFs) have been reported globally, 43 of which were identified in China.1 Moreover, HIV-1 strains that are produced by second-generation combinations, including unique recombinant forms and CRFs, such as CRF105_0108, CRF123_0107, and CRF134_0185, have been commonly reported in recent years. The present study identified a novel second-generation recombinant form of HIV-1 comprising CRF07_BC and subtype C and designated CRF144_07C. To our knowledge, this was the first report of HIV CRFs comprising CRF07_BC and subtype C, further indicating the complexity of HIV genetic diversity in China.

Global developmental delay/intellectual disability (GDD/ID) with a prevalence of 1%–3% represents one of the biggest medical and social challenges in our society.1 Genetic factors are the main causes of GDD/ID and early diagnosis is crucial to improving the prognosis of GDD/ID children.2 Chromosomal microarray analysis, as a first-tier clinical test,3 remains limited because of the insufficient to detect small variations while whole exome sequencing (WES) can detect both single-nucleotide variants (SNVs) and copy-number variants (CNVs), effectively improving the diagnostic yield of GDD/ID.4 Various adverse risk factors could contribute to GDD/ID and the effects of a genetic variant can vary depending on the presence or absence of adverse preceding events.5 Herein, to evaluate the contribution of the genetic etiology to GDD/ID and to investigate the association between known risk factors and genetic etiology in children with GDD/ID, and further, to explore candidate pathogenic genes of GDD/ID, we conducted WES of a Chinese GDD/ID cohort.

Clonal hematopoiesis (CH) is a phenomenon in which hematopoietic stem cells carry genetic mutations with advantageous growth potential, resulting in aberrant expansion of immature and mature hematopoietic cell populations over time.1,2 Loss-of-function heterozygous mutations in TET2 (tet methylcytosine dioxygenase 2) are among the most prevalent and significant drivers of CH and myelodysplastic syndromes, an age-related hematological disease.3 In addition, certain diseases, or environmental conditions, for example, atherosclerosis drive the onset and trajectory of TET2 deficiency-related CH (TedCH).4 Our previous study suggest inflammation play a positive role in driving TedCH. To further explore the potential drivers of CH (i.e. LPS-induced inflammation), we assessed the impact of another four different environmental factors on TedCH and confirmed that accelerated TedCH depends on the establishment of an inflammatory environment (here colitis-induced).5

Skeletal muscle formation (myogenesis) is a complex process, and transcription factors (TFs) play an important role in controlling the phases of developmental myogenesis, particularly in myoblast proliferation and differentiation.1 However, the functions of numerous TFs in myoblast development and myogenesis remain unclear. To systematically identify TFs regulating myogenesis in skeletal muscle, we performed a genome-scale CRISPR-Cas9 loss-of-function (LOF) screen in mouse myoblast cells to identify TFs whose loss contributes to skeletal muscle proliferation. After screening, we identified 855 TFs closely associated with C2C12 cell proliferation. Functionally, we validated that Zfp607b improved skeletal muscle differentiation and regeneration using RNA interference knockdown in vitro and lentiviral injection in vivo. For the top fold-change genes in the TF knockout cell library, we explored potential mechanisms using transcriptomics and immunofluorescence. In conclusion, we constructed a genome-wide TF knockout cell library in myoblast and identified a novel TF, Zfp607b, that significantly participated in myogenesis and skeletal muscle regeneration. Our findings contribute to the understanding of the ZFP family involved in myogenesis and regeneration and provide a platform for studying the biological function of TFs in the future. Furthermore, our study offers valuable resources for understanding skeletal muscle development and human muscle-related diseases.

The incidence of thyroid cancer (TC) has continuously risen worldwide in the past three decades. While most TC patients have a good prognosis, 60% of them still suffer from lymph node metastasis, which is significantly associated with patient prognosis.1 Circular RNAs (circRNAs) are a large class of noncoding RNAs that function as tumor suppressors or tumor promoters in multiple human cancers, including TC.2 In the previous study, we found one circRNA (circSSU72) was significantly up-regulated in both tissues and cell lines of papillary thyroid carcinoma.3 However, the biological role and associated mechanisms of circSSU72 in TC, especially in the field of metastasis, have not been well elucidated.

Preeclampsia (PE) poses a grave threat to both maternal and fetal health, yet its intricate cellular and molecular mechanisms remain shrouded in mystery.1 Recent research has increasingly focused on the role of maternal-impaired decidualization in the development of PE.2 In this context, the obesity-associated protein FTO has emerged as a significant factor, acting as a demethylase for N6-methyladenosine (m6A) modification. Our study aimed to unravel how FTO enhanced glycolysis and vascular formation during decidualization. Mechanistically, FTO reduced the m6A methylation of IGF1R (insulin-like growth factor 1 receptor) transcripts, thereby stabilizing IGF1R and augmenting its expression through a YTHDF2 (YTH m6A RNA binding protein F2)-dependent pathway, an essential process for stromal cell decidualization. Additionally, IGF1R was required for regulating COX2 (cytochrome C oxidase assembly factor) and VEGFA (vascular endothelial growth factor A) expression, while also modulating AKT (protein kinase B) activity during decidualization. Intriguingly, we unearthed that FTO and IGF1R expression in the decidua were negatively correlated with systolic blood pressure. In summary, our study uncovers a novel mechanism involving FTO-mediated m6A demethylation orchestrating IGF1R mRNA modification through YTHDF2, thereby offering promising avenues for targeted FTO modulation in the treatment of hypertensive disorders in PE, ultimately translating to improved outcomes for both mothers and fetuses.

Prostate cancer is one of the most prevalent cancers in men, and there is no cure when it advances to a late stage. Antiandrogens are routinely used in clinics for prostate cancer treatment, and darolutamide (Daro) is the latest FDA-approved antiandrogen drug.1 Despite its efficacy, potential drug resistance poses significant challenges in the clinical setting. This study seeks to uncover the molecular mechanisms behind darolutamide resistance and identify potential therapeutic targets to overcome this resistance.

Ulcerative colitis is a major type of inflammatory bowel disease characterized by chronic idiopathic mucosal inflammation in the rectum to the colon. Patients with ulcerative colitis exhibit a life expectancy of five years shorter than the general population, and within five years of diagnosis, 7% undergo colectomy. As of 2023, the global prevalence of ulcerative colitis is estimated to be higher than five million cases, and the incidence rate is increasing. However, the precise etiology remains unclear.1 A previous genome-wide association study (GWAS) reported that the ring finger protein 186 gene (RNF186) is a potent pathogenesis-related factor of ulcerative colitis. RNF186 protein plays a pivotal role in intestine homeostasis through the regulation of the expression of occludin, a major gut barrier component, by polyubiquitination. Moreover, the colitis symptoms of RNF186 gene knockout mice were more severe compared with wild-type mice. In addition, the two genetic variants A64T (rs41264113) and R179X (rs36095412) that result in an altered form of RNF186 protein were shown to be associated with the pathomechanism of ulcerative colitis in a Caucasian population.2,3 Additionally, both the A64T and R179X variants result in changes in amino acids in the protein. However, the A64T variant confers susceptibility to ulcerative colitis, while the R179X variant confers resistance to ulcerative colitis.

Patients with primary biliary cholangitis (PBC) may have a poor prognosis, with approximately 40% of them developing cirrhosis within 10 years of diagnosis. Recent studies suggest that some metabolites are causally associated with both PBC and ulcerative colitis (UC). UC may increase the risk of PBC in the European population, which may suggest the etiology of PBC.1 Meanwhile, poor prognosis in patients with PBC has been shown to be closely associated with UC in many case reports. Additionally, it is hypothesized that the increased levels of lipopolysaccharides and inflammation or immune response are related to the higher permeability of the small intestines in PBC. Moreover, UC is a chronic and progressive inflammatory disease that disrupts the intestinal epithelial barrier and damages the colonic mucosa. Research on the mechanism of comorbid PBC and UC has significant clinical importance for intervention and early recognition of the disease. In this study, we aimed to explore the co-expressed differentially expressed genes (DEGs) and hub genes of PBC and UC, as well as analyze the possible regulatory factors of these genes. This research is conducive to further studying the molecular mechanisms of PBC and UC.

ISG15, the first identified ubiquitin-like protein stimulated by type I interferon, has multiple functions in the different vertebrate species and biological processes, such as anti-infection, autophagy, proliferation, cell death, and tumorigenesis.1 ISG15 has also been related to inflammation: human ISG15 deficiency results in necrotizing skin lesions through systemic type I IFN inflammation2; intracellular free ISG15 acts as a negative regulator of IFN-α/β-dependent autoinflammation by keeping USP18 stabilization.3 Despite these findings, the detailed molecular mechanisms how ISG15 regulates inflammation, especially neuroinflammation, remain largely elusive. This study used human microglia (HM cell line) and astrocytes (U87-MG cell line) to explore the molecular mechanisms underlying the association of neuroinflammation with ISG15 and find a negative regulatory mechanism of inflammation by ISG15. ISG15 post-translationally modified Ubc13, inhibiting the binding between Ubc13 and ubiquitin and preventing the K63 polyubiquitination of TRAF6, leading to the NF-κB signaling pathway inactive and then resulting in suppressed expression levels of pro-inflammatory cytokines and NLRP3. Furthermore, ISG15 positively regulated anti-inflammatory cytokines (IL-10, TGF-β, IL-35, IL-37, and IL-38) to prevent the expansion of the inflammatory response. Our finding suggests that ISG15 is a potential therapeutic target for inflammation.

Recurrence and metastasis are the main causes of cancer-related death and significantly decrease the survival rate of tumor patients. Cancer metastasis can initiate in the very early stage of malignant progression. Unfortunately, cancer patients may not necessarily feel or be diagnosed until metastatic clinical symptoms appear several months or years later.1 Metastatic cancer patients have lower five-year survival rates and the tumor often relapses.2 Cancer recurrence remains a major troublesome clinical problem which usually leads to treatment failure. Many cancer patients developed in situ recurrence or metastatic recurrence within five years after tumor resection.3 Accurate prediction of cancer recurrence and metastasis facilitates identifying high-risk patients and guiding appropriate treatment, offering the opportunity to prolong patients' survival.

Extracting exosomes from bodily fluids offers a promising approach to overcoming inherent limitations, enabling the identification of potential biomarkers, especially those present in low abundance.1 PC-3 cells, known for their high metastatic potential compared with LNCaP cells, are widely used as a model for prostate cancer progression.2,3 However, the mechanisms underlying their metastatic characteristics remain unclear. Therefore, there is a critical need to investigate diagnostic methods for prostate cancer, as current techniques have various limitations that can lead to overtreatment due to their lack of precision.3 This study isolated exosomes from PC-3 and LNCaP cells through sequential ultracentrifugation to analyze their proteomic profiles using nano-liquid chromatography coupled to tandem mass spectrometry. Western blotting and quantitative reverse transcription-PCR validation revealed a higher abundance of CD146 (MCAM) in PC-3 exosomes, indicating that aggressive prostate cancer exhibits elevated levels of adhesion or cohesion proteins.4 We demonstrated that knocking out CD146 in PC-3 cells via the CRISPR-Cas9 system inhibited cell proliferation and invasion. Overall, CD146 was strongly associated with PC-3 cell mobility in vitro, suggesting that CD146 is a valuable candidate biomarker for prostate cancer progression.

Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene located at 10q23.3 and serves as a crucial negative regulator of the PI3K-AKT signaling cascade by dephosphorylating phosphatidylinositol (3,4,5)-triphosphate and inhibiting AKT activation. PTEN hamartoma tumor syndrome (PHTS) is an umbrella term employed to describe a spectrum of disorders caused by germline PTEN variants, including Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome. While distinct entitles included in PHTS have their unique diagnostic criteria, they also share common phenotypic features such as benign hamartomas of the three germ layers, macrocephaly, and an increased predisposition to malignancies in specific organs.1

Deoxyribonuclease 2 (DNASE2) is associated with tumor proliferation and apoptosis, innate immune signaling, chronic inflammation, and systemic autoinflammatory diseases. However, the role and mechanism of DNASE2's action in gliomas remain unclear. In this study, the difference analysis showed that after supplementing normal tissue samples from the Genotype-Tissue Expression (GTEx) dataset, DNASE2 mRNA levels in 30 tumors from The Cancer Genome Atlas (TCGA) showed significant differences, correlated with a poor prognosis in patients with glioblastoma multiforme (GBM). DNASE2 down-regulation also reduced GBM cell proliferation, migration, and invasion. DNASE2 affected the immune activity of GBM cells. Furthermore, we found that interleukin-17, Toll-like receptor, North signaling pathway, secreted phosphoprotein 1 (SPP1), and S100 calcium-binding protein A8/9 (S100A8/9) genes may be crucial to regulate GBM immunity via DNASE2. In conclusion, DNASE2 expression is elevated in patients with GBM and influences the development of GBM, possibly through various immune-related pathways. Therefore, DNASE2 may serve as a potential prognostic biomarker for GBM. The overall workflow of this study is shown in Figure 1A.

Short stature is clinically defined as a standing height less than two standard deviations below the mean height at the same age, ethnicity, and sex. As a typical complex symptom, height has a high heritability of 80%, which is affected by multiple genes and gene–gene interactions. A genome-wide association study (GWAS) revealed that 23.3% of the heritability of short stature could be explained by 697 independent variants.1 Whole exome sequencing of a large sample size demonstrated that 83 rare and low-frequency variants could explain 1.7% heritability of height, and variants with minor allele frequency <5% have an average effect 10 times greater than that of common variants.2 Here, we analyzed the whole exome sequencing data of 787 short-stature children to find new genes contributing to short stature in Chinese children.

Exosomes encompass a great deal of valuable biological information and play a critical role in tumor development. However, the mechanism of exosomal lncRNAs remains poorly elucidated in bladder cancer (BCa). In this study, we identified exosomal lnc-TAF12–2:1 as a novel biomarker in BCa diagnosis and aimed to investigate the underlying biological function. Dual luciferase reporter assay, RNA immunoprecipitation (RIP), RNA pulldown assays, and xenograft mouse model were used to verify the competitive endogenous RNA mechanism of lnc-TAF12–2:1. We found exosomal lnc-TAF12–2:1 up-regulated in urinary exosomes, tumor tissues of patients, and BCa cells. Down-regulation of lnc-TAF12–2:1 impaired BCa cell proliferation and migration, and promoted cell cycle arrest at the G0/G1 phase and cell apoptosis. The opposite effects were also observed when lnc-TAF12–2:1 was overexpressed. lnc-TAF12–2:1 was transferred by intercellular exosomes to modulate malignant biological behavior. Mechanistically, lnc-TAF12–2:1 packaged in the exosomes relieved the miRNA-mediated silence effect on ASB12 via serving as a sponger of miR-7847–3p to accelerate progression in BCa. ASB12 was also first proved as an oncogene to promote cell proliferation and migration and depress cell cycle arrest and cell apoptosis in our data. In conclusion, exosomal lnc-TAF12–2:1, located in the cytoplasm of BCa, might act as a competitive endogenous RNA to competitively bind to miR-7847–3p, and then be involved in miR-7847–3p/ASB12 regulatory axis to promote tumorigenesis, which provided a deeper insight into the molecular mechanism of BCa.

Head and neck squamous cell carcinoma (HNSCC) ranks as the sixth most common cancer globally. Most studies in HNSCC demonstrated that regulatory T (Treg) cells confine the anti-tumor activity of effector T cells which may contribute to the immune escape and uncontrolled tumor progression. Here, we uncovered that the specific abrogation of Bcl6 in Treg cells resulted in significantly delayed malignant transformation of 4NQO-induced tumorigenesis. Bcl6 deficiency impairs the lineage stability of Treg cells by down-regulating the histone H3K4 trimethylation. Importantly, Bcl6 inhibition repressed the tumor growth of murine HNSCC and exhibited synergistic effects with immune checkpoint blockade therapy. These findings suggest that Bcl6 can be exploited as a promising therapeutic target for HNSCC treatment.

Osteoarthritis (OA) is a chronic degenerative joint disease. Currently, OA is incurable. Abnormal activation of canonical Wnt/β-catenin or Indian hedgehog (Ihh) signaling could lead to OA development and progression. This study aimed to determine if targeting β-catenin and Ihh signaling could yield an effective therapeutic intervention for OA disease. CRISPR/CasRx is a new RNA interference tool that can precisely and efficiently cleave single-strand RNAs. In this study, we screened CRISPR-derived RNA (crRNA) targeting Ctnnb1 and Smo in vitro and selected two optimal crRNAs for each gene. CasRx-mediated Ctnnb1 and Smo knockdown showed high efficiency and specificity with no obvious off-target effects in vitro. We then performed intra-articular injection of selected crRNAs driven by the adeno-associated virus into an OA mouse model. Micro-CT, histological, and histomorphometric analyses were conducted to evaluate the efficacy of CasRx approach on OA treatment. We found that the knockdown of Ctnnb1 and Smo decelerated pathological damage in the keen joint of the experimental OA mouse model. Our findings suggest that CasRx-mediated Ctnnb1 and Smo knockdown could be a potential strategy for OA treatment.

Genetic factors are the major causes of epilepsies, such as developmental and epileptic encephalopathy (DEE) and idiopathic generalized epilepsy (IGE). However, the etiology of most patients remains elusive. This study performed exon sequencing in a cohort of 173 patients with IGE. Additional cases were recruited from the matching platform in China. The excess and damaging effect of variants, the genotype-phenotype correlation, and the correlation between gene expression and phenotype were studied to validate the gene–disease association. CSMD1 compound heterozygous variants were identified in four unrelated cases with IGE. Additional CSMD1 variants were identified in five cases with DEE featured by generalized seizures from the matching platform, including two with de novo and three with compound heterozygous variants. Two patients were refractory to antiseizure medications and all patients were on long-term therapy. The CSMD1 variants presented a significantly high excess of variants in the case-cohort. Besides de novo origination, the DEE cases had each of the paired variants located closer to each other than the IGE cases or more significant alterations in hydrophobicity. The DEE-associated variants were all absent in the normal population and presented significantly lower minor allele frequency than the IGE-associated variants, suggesting a minor allele frequency-phenotype severity correlation. Gene expression analysis showed that CSMD1 was extensively expressed throughout the brain, particularly in the cortex. The CSMD1 temporal expression pattern correlated with the disease onset and outcomes. This study suggests that CSMD1 is associated with epilepsy and is a novel causative gene of DEE and generalized epilepsies.

The incidence of heart failure with preserved ejection fraction (HFpEF) increases with the ageing of populations. This study aimed to explore ageing-associated gene signatures in HFpEF to develop new diagnostic biomarkers and provide new insights into the underlying mechanisms of HFpEF. Mice were subjected to a high-fat diet combined with L-NG-nitroarginine methyl ester (l-NAME) to induce HFpEF, and next-generation sequencing was performed with HFpEF hearts. Additionally, separate datasets were acquired from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were used to identify ageing-related DEGs. Support vector machine, random forest, and least absolute shrinkage and selection operator algorithms were employed to identify potential diagnostic genes from ageing-related DEGs. The diagnostic value was assessed using a nomogram and receiver operating characteristic curve. The gene and related protein expression were verified by reverse transcription PCR and western blotting. The immune cell infiltration in hearts was analysed using the single-sample gene-set enrichment analysis algorithm. The results showed that the merged HFpEF datasets comprised 103 genes, of which 15 ageing-related DEGs were further screened in. The ageing-related DEGs were primarily associated with immune and metabolism regulation. AGTR1a, NR3C1, and PRKAB1 were selected for nomogram construction and machine learning-based diagnostic value, displaying strong diagnostic potential. Additionally, ageing scores were established based on nine key DEGs, revealing noteworthy differences in immune cell infiltration across HFpEF subtypes. In summary, those results highlight the significance of immune dysfunction in HFpEF. Furthermore, ageing-related DEGs might serve as promising prognostic and predictive biomarkers for HFpEF.

Non-alcoholic fatty liver disease (NAFLD) patients have multiple metabolic disturbances, with markedly elevated levels of lactate. Lactate accumulations play pleiotropic roles in disease progression through metabolic rearrangements and epigenetic modifications. Monocarboxylate transporter 4 (MCT4) is highly expressed in hepatocytes and responsible for transporting intracellular lactate out of the cell. To explore whether elevated MCT4 levels played any role in NAFLD development, we overexpressed and silenced MCT4 in hepatocytes and performed a comprehensive in vitro and in vivo analysis. Our results revealed that MCT4 overexpression down-regulated the genes for lipid synthesis while up-regulating the genes involved in lipid catabolism. Conversely, silencing MCT4 expression or inhibiting MCT4 expression led to the accumulation of intracellular lipid and glucose metabolites, resulting in hepatic steatosis. In a mouse model of NAFLD, we found that exogenous MCT4 overexpression significantly reduced lipid metabolism and alleviated hepatocellular steatosis. Mechanistically, MCT4 alleviated hepatic steatosis by regulating a group of hub genes such as Arg2, Olr1, Cd74, Mmp8, Irf7, Spp1, and Apoe, which in turn impacted multiple pathways involved in lipid metabolism and inflammatory response, such as PPAR, HIF-1, TNF, IL-17, PI3K-AKT, Wnt, and JAK-STAT. Collectively, our results strongly suggest that MCT4 may play an important role in regulating lipid metabolism and inflammation and thus serve as a potential therapeutic target for NAFLD.

The long non-coding RNA taurine up-regulated gene 1 (TUG1) has been reported to be involved in various cancers, but its role in chondrosarcoma (CHS) remains a mystery. This research aimed to examine the function of TUG1 in CHS. We found that TUG1 expression was elevated in CHS. Functional assays demonstrated that TUG1 had a crucial role in the CHS cell progression. Mechanistically, TUG1 recruited ALYREF to maintain the stabilization of enhancer of zest homolog 2 (EZH2) mRNA and expression of H3K27me3, repressing the transcription of the tumor-suppressor gene CPEB1. Additionally, exosomal TUG1 enhanced the polarization of M2 tumor-associated macrophages, which increased the proliferation and metastasis of CHS. Taken together, this study revealed the oncogenic role of TUG1 in CHS and its interactions with the downstream regulatory axis, offering novel insights into the tumorigenic mechanism of CHS.

Nicotinamide adenine dinucleotide (NAD+) kinase (NADK) phosphorylates NAD+ to generate NADP+, which plays a crucial role in maintaining NAD+/NADP+ homeostasis, cellular redox balance, and metabolism. However, how human NADK activity is regulated, and how dysregulation or mutation of NADK is linked to human diseases, such as cancers, are still not fully understood. Here, we present a cryo-EM structure of human tetrameric NADK and elaborate on the necessity of the NADK tetramer for its activity. The N-terminal region of human NADK, which does not exist in bacterial NADKs, modulates tetramer conformation, thereby regulating its activity. A methylation-deficient mutant, R45H, within the N-terminal region results in increased NADK activity and confers cancer chemotherapy resistance. Conversely, mutations in NADK identified among cancer patients alter the tetramer conformation, resulting in NADK inactivation and increasing the sensitivity of lung cancer cells to chemotherapy. Our findings partially unveil the structural basis for NADK regulation, offering insights into the cancer etiology of patients carrying NADK mutations.

The mesenchymal-epithelial transition factor (MET) proto-oncogene plays important roles during tumor development. Recently, evidence has revealed MET signaling may impact tumor immunogenicity and regulate the immune response. Here we conducted a comprehensive bioinformatic and clinical analysis to explore the characteristics of MET mutation and its association with the outcomes in pan-cancer immunotherapy. In 4149 patients with 12 tumor types treated with immune checkpoint inhibitors, MET mutation indicated favorable overall survival (hazard ratio = 0.61; 95% CI, 0.50–0.74; P < 0.001), progression-free survival (hazard ratio = 0.74; 95% CI, 0.60–0.92; P = 0.01), and objective response rate (40.3% vs. 28.1%; P = 0.003). Moreover, we developed a nomogram to estimate the 12-month and 24-month survival probabilities after the initiation of immunotherapy. Further multi-omics analysis on both intrinsic and extrinsic immune landscapes revealed that MET mutation enhanced tumor immunogenicity, enriched infiltration of immune cells, and improved immune responses. In summary, MET mutation improves cancer immunity and is an independent biomarker for favorable outcomes in pan-cancer immunotherapy. These results may influence clinical practices, guide treatment decision-making, and develop immunotherapy for personalized care.

Bone morphogenetic protein 9 (BMP9) exhibits remarkable osteogenic potential. However, the intricate mechanisms driving this function of BMP9 remain elusive. This study endeavors to investigate the potential role of sirtuin 5 (SIRT5) in enhancing BMP9's osteogenic capacity and decipher the underlying molecular pathways. To achieve this aim, we employed real-time PCR, western blotting, histochemical staining, and a cranial defect repair model to assess the impact of SIRT5 on BMP9-mediated osteogenesis. We utilized real-time PCR, western blotting, immunofluorescent staining, and immunoprecipitation assay to explore the associated mechanisms. Our results revealed that SIRT5 significantly up-regulated BMP9-induced osteogenic markers, while SIRT5 knockdown reduced their expression. Concurrently, hypoxia-inducible factor 1 subunit alpha (HIF-1α) level was increased by SIRT5, but reduced by SIRT5 knockdown. Notably, HIF-1α potentiated the SIRT5's ability to strengthen BMP9's osteogenic potential, whereas HIF-1α silencing reduced this effect, which was confirmed by bone defect repair assay. The acetylation and malonylation levels of HIF-1α were reduced by SIRT5, which may enhance its stability to promote BMP9's osteogenic effect. Conversely, SIRT5 knockdown reversed these effects and promoted the degradation of HIF-1α. Collectively, our results demonstrated that the BMP9's osteogenic potential could be promoted by SIRT5, potentially through stabilizing HIF-1α by reducing its acetylation and malonylation modification. This discovery may offer a novel strategy to accelerate bone tissue engineering by enhancing osteogenic differentiation, and it also sheds light on the possible mechanisms underlying BMP9-mediated osteogenic differentiation.

Solute carrier family 27 member 5 (SLC27A5/FATP5) is a liver-specific metabolic enzyme that plays a crucial role in fatty acid transport and bile acid metabolism. Deficiency of SLC27A5 promotes the progression of hepatocellular carcinoma (HCC) and is strongly associated with a poor prognosis. SLC27A5 exhibits noncanonical functions beyond its metabolic role; however, its specific mechanisms in hepatocarcinogenesis remain elusive and are therefore investigated in this study. Immunoprecipitation-mass spectrometry analysis showed that SLC27A5-interacting proteins were significantly enriched in alternative polyadenylation (APA). RNA-sequencing data provided evidence that SLC27A5 plays a global role in regulating APA events in HCC. Mechanistically, SLC27A5 facilitates the usage of the proximal polyadenylation site of METTL14 by downregulating the expression of the APA-associated factor PABPC1, resulting in the shortening of the METTL14-3′UTR and the conversion of METTL14-UL to METTL14-US. In contrast to METTL14-UL, METTL14-US escapes the inhibitory effect of miRNA targeting, leading to increased METTL14 expression. METTL14-US upregulation by SLC27A5 suppressed the stemness of HCC. Therefore, low levels of SLC27A5 and METTL14 may serve as reliable biomarkers for identifying poor prognosis in patients with HCC. In conclusion, SLC27A5/PABPC1 inhibits HCC stemness via APA-regulated expression of METTL14, providing potential avenues for the development of novel therapeutic strategies.

Despite numerous studies suggesting that RNA m6A transferase core complex including METTL3 and METTL14 play essential roles in both the initiation and maintenance of acute myeloid leukemia (AML), effective pharmacological targeting of these two proteins remains elusive. Here, we report the development and evaluation of a novel METTL3 degrader, ZW27941, designed to induce METTL3 degradation via the VHL-mediated proteasomal degradation pathway. ZW27941 exhibited potent and selective degradation of METTL3 and its binding partner METTL14, leading to significant anti-leukemic activity in AML cell lines. Furthermore, ZW27941 demonstrated synergistic or additive effects when combined with standard AML therapeutics, such as cytarabine and venetoclax. Our findings suggest that selective METTL3 degraders, exemplified by ZW27941, hold promise as a novel therapeutic approach for AML, particularly when used in combination with existing treatments to enhance efficacy and overcome resistance mechanisms.

Amyloid precursor protein (APP), especially Swedish mutant APP (APPswe), is recognized as a significant pathogenic protein in Alzheimer's disease, but limited research has been conducted on the correlation between APPswe and the osteogenic differentiation of mesenchymal stem cells (MSCs). The effects of APPswe and its intracellular and extracellular segments on the osteogenic differentiation of bone morphogenetic protein 2 (BMP2)-induced MSCs were analyzed in this study. Our analysis of an existing database revealed that APP was positively correlated with the osteogenic differentiation of MSCs but negatively correlated with their proliferation and migration. Furthermore, APPswe promoted BMP2-induced osteogenic differentiation of MSCs, while APPswe-C (APPswe without an intracellular segment) had the opposite effect; thus, the intracellular domain of APPswe may be a key factor in promoting the osteogenic differentiation of MSCs. Additionally, both APPswe and APPswe-C inhibited the proliferation and migration of MSCs. Furthermore, the intracellular domain of APPswe inhibited the activity of the Notch pathway by regulating the expression of the Notch intracellular domain to promote the osteogenic differentiation of MSCs. Finally, APPswe-treated primary rat bone marrow MSCs exhibited the most favorable bone repair effect when a GelMA hydrogel loaded with BMP2 was used for in vivo experiments, while APPswe-C had the opposite effect. These findings demonstrate that APPswe promotes the osteogenic differentiation of MSCs by regulating the Notch pathway, but its extracellular segment blocks the self-renewal, proliferation, and migration of MSCs, ultimately leading to a gradual decrease in the storage capacity of MSCs and affecting long-term bone formation.

Primary testicular diffuse large B-cell lymphomas (PT-DLBCL) are a collection of 1%–9% of testicular tumors. However, the characterization of the tumor microenvironment and spatial organization of PT-DLBCL is poorly understood. We profiled the transcriptomes of 19,559 single cells derived from a PT-DLBCL patient via single-cell RNA sequencing. We found that the tumor microenvironment was majorly composed of three exhausted CD8+ T cell subpopulations and two B cell subpopulations, and the genetic heterogeneity was further analyzed. Then, transcription factors related to PT-DLBCL cell proliferation and development were identified. Our results demonstrated that inhibiting E2F and CREB could decrease cell proliferation, induce apoptosis in human B-lymphoma cells, and inhibit tumor growth in xenograft testicular DLBCL models. Subsequently, chromatin immunoprecipitation sequencing was performed to identify the enriched loci of E2F and CREB that regulate human B-lymphoma cell proliferation and apoptosis. To annotate the precise spatial cellular composition of testicular DLBCL, we performed spatial transcriptomics. The spatial organization of PT-DLBCL, especially the spatial location of exhausted CD8+ T and B cells, was identified. Concurrently, we delineated the expression patterns of key genes, including MALAT1, RPS3A, RPS7, RPS23, RPS27A, IGHM, HINT1, and HSPA8, across various regions. In this study, we unveiled the spatial architecture of the tumor microenvironment in DLBCL, where exhausted T cells were strategically positioned around tumor B cells, and macrophages, in turn, encircled the exhausted T cells. Inhibition of E2F and CREB in the tumor microenvironment may be a novel therapeutic option for testicular DLBCL patients.

With the advancement of high-throughput sequencing and bioinformatics, an increasing number of overlooked small noncoding RNAs (sncRNAs) have emerged. These sncRNAs predominantly comprise transfer RNA-derived fragments (tsRNAs), PIWI-interacting RNAs (piRNAs), Ro-associated non-coding RNAs (RNYs or Y-RNAs), small nucleolar RNAs (snoRNAs), and small nuclear RNAs (snRNAs). Each of these RNA types possesses distinct biological properties and plays specific roles in both physiological and pathological processes. The differential expression of sncRNAs substantially affects the occurrence and progression of various systemic diseases. However, their roles in the cardiovascular system remain unclear. Therefore, understanding the functionality and mechanisms of sncRNAs in the cardiovascular system holds promise for identifying novel targets and strategies for the diagnosis, prevention, and treatment of cardiovascular diseases. This review examines the biological characteristics of sncRNAs and their potential roles in cardiovascular diseases.

R-loops, three-strand nucleic acid structures, have emerged as crucial players in various physiological processes, including the regulation of gene expression, DNA replication, and class switch recombination. However, their presence also poses a significant threat to genome stability. A particularly challenging aspect is understanding the dynamic balance between R-loops' “light” and “dark” sites, especially concerning maintaining genome integrity. The complex and multifaceted roles of R-loops in genome stability necessitate a deeper understanding. This review offers a comprehensive exploration of the formation, resolution, and implications of R-loops, particularly in the context of DNA damage and human disease. We delve into the dualistic nature of R-loops, highlighting their role in DNA damage response and repair, and discuss the therapeutic potential arising from our evolving understanding of these enigmatic entities. Emphasizing recent advancements and unresolved questions, this review aims to provide a cohesive overview of R-loops, inviting further inquiry and investigation into their complex biological significance.

Achondroplasia (ACH), is the prevailing type of genetic dwarfism in humans, caused by mutations in fibroblast growth factor receptor 3 (FGFR3) that are inherited in an autosomal dominant manner. FGFR3 is mainly expressed in condensed mesenchyme, chondrocytes, and mature osteoblasts and osteoclasts, in which it regulates the formation, development, growth, and remodeling of the skeletal system. Mutations in FGFR3 causing ACH result in enhanced FGFR3 signaling through combined mechanisms including enhancing FGF dimerization and tyrosine kinase activity and stabilizing FGF receptors. In ACH, suppression of the proliferation and maturation of chondrocytes in the growth plate leads to a notable reduction in growth plate size, trabecular bone volume, and bone elongation through a profound enhancement of FGFR3 signaling. This review aims to comprehensively outline the cellular and molecular mechanisms contributing to the pathological process of ACH and its potential therapeutic interventions.

Anaplastic thyroid cancer (ATC) stands as the most formidable form of thyroid malignancy, presenting a persistent challenge in clinical management. Recent years have witnessed a gradual unveiling of the intricate genetic underpinnings governing ATC through next-generation sequencing. The emergence of this genetic landscape has paved the way for the exploration of targeted therapies and immunotherapies in clinical trials. Despite these strides, the precise mechanisms governing ATC pathogenesis and the identification of efficacious treatments demand further investigation. Our comprehensive review stems from an extensive literature search focusing on the genetic implications, notably the pivotal MAPK and PI3K-AKT-mTOR signaling pathways, along with targeted therapies and immunotherapies in ATC. Moreover, we screen and summarize the advances and challenges in the current diagnostic approaches for ATC, including the invasive tissue sampling represented by fine needle aspiration and core needle biopsy, immunohistochemistry, and 18F-fluorodeoxyglucose positron emission tomography/computed tomography. We also investigate enormous studies on the prognosis of ATC and outline independent prognostic factors for future clinical assessment and therapy for ATC. By synthesizing this literature, we aim to encapsulate the evolving landscape of ATC oncology, potentially shedding light on novel pathogenic mechanisms and avenues for therapeutic exploration.

Protein citrullination involves the deimination of arginine or methylarginine residues in peptide chains to form citrulline by peptidyl arginine deiminases. This process is an important protein post-translational modification that affects molecular structure and function of various proteins, including histones. In recent years, protein citrullination has attracted widespread attention for its influence on gene transcription. Studies on the impact of protein citrullination modification on chromatin structure remodeling and the establishment of gene regulatory networks have made rapid progress. In this review, we briefly summarize the physiological functions of protein citrullination modification. Specifically, we comprehensively outline the latest progress in the study of the role of protein citrullination modification in gene transcription regulation, focusing on the interaction of protein citrullination with other post-translational modifications.

Hepatocellular carcinoma (HCC) is the most prevalent type of malignant liver tumor with high morbidity and mortality and severely threatens human health and life quality. Thus, it is of great significance to investigate the molecular mechanism underlying the pathogenesis of HCC and seek biomarkers for early diagnosis. Neddylation, one of the most conserved post-translational modification types in eukaryotes, plays vital roles in the progression of HCC. During the process of neddylation, NEDD8 is covalently conjugated to its substrate proteins, thereby modulating multiple necessary biological processes. Currently, increasing evidence shows that the aberrant activation of neddylation is positively correlated with the occurrence and development of tumors and the poor clinical prognosis of HCC patients. Based on the current investigations, neddylation modification has been reported to target both the cullins and non-cullin substrates and subsequently affect HCC progression, including the virus infection, malignant transformation, tumor cell proliferation, migration and invasion ability, and tumor microenvironment. Therefore, inhibitors targeting the neddylation cascade have been developed and entered clinical trials, indicating satisfactory anti-HCC treatment effects. This review aims to summarize the latest progress in the molecular mechanism of pathologically aberrant neddylation in HCC, as well as the advances of neddylation-targeted inhibitors as potential drugs for HCC treatment.

Fatty acid oxidation (FAO) denotes the mitochondrial aerobic process responsible for breaking down fatty acids (FAs) into acetyl-CoA units. This process holds a central position in the cancer metabolic landscape, with certain tumor cells relying primarily on FAO for energy production. Over the past decade, mounting evidence has underscored the critical role of FAO in various cellular processes such as cell growth, epigenetic modifications, tissue-immune homeostasis, cell signal transduction, and more. FAO is tightly regulated by multiple evolutionarily conserved mechanisms, and any dysregulation can predispose to cancer development. In this view, we summarize recent findings to provide an updated understanding of the multifaceted roles of FAO in tumor development, metastasis, and the response to cancer therapy. Additionally, we explore the regulatory mechanisms of FAO, laying the groundwork for potential therapeutic interventions targeting FAO in cancers within the metabolic landscape.

The expression and function of the receptor are controlled by epigenetic changes, such as DNA methylation, histone modification, and noncoding RNAs. These modifications play a pivotal role in receptor activity and can lead to or exacerbate endocrine-related diseases. This review examines the epigenetic alterations of nuclear receptors and their significant impact on conditions such as diabetes, thyroid disorders, and endocrine-related tumors. It highlights current therapies targeting these epigenetic mechanisms, including gene editing, epigenetic drugs, and various other therapeutic approaches. This review offers fresh insight into the mechanisms of endocrine-associated disorders, highlighting the latest progress in the development of novel epigenetic therapies that can be used to address receptor–endocrine interactions.

RNA-binding proteins (RBPs) regulate the generation of circular RNAs (circRNAs) by participating in the reverse splicing of circRNA and thereby influencing circRNA function in cells and diseases, including cancer. Increasing evidence has demonstrated that the circRNA-RBP network plays a complex and multifaceted role in tumor progression. Thus, a better understanding of this network may provide new insights for the discovery of cancer drugs. In this review, we discuss the characteristics of RBPs and circRNAs and how the circRNA-RBP network regulates tumor cell phenotypes such as proliferation, metastasis, apoptosis, metabolism, immunity, drug resistance, and the tumor environment. Moreover, we investigate the factors that influence circRNA-RBP interactions and the regulation of downstream pathways related to tumor development, such as the tumor microenvironment and N6-methyladenosine modification. Furthermore, we discuss new ideas for targeting circRNA-RBP interactions using various RNA technologies.

In recent years, the incidence and mortality rates of pancreatic cancer have been steadily increasing, and conventional therapies have shown a high degree of tolerance. Therefore, the search for new therapeutic targets remains a key issue in current research. Mitochondrial glutamic-oxaloacetic transaminase 2 (GOT2) is an important component of the malate-aspartate shuttle system, which plays an important role in the maintenance of cellular redox balance and amino acid metabolism, and has the potential to become a promising target for anti-cancer therapy. In this paper, we will elaborate on the metabolic and immune effects of GOT2 in pancreatic cancer based on existing studies, with a view to opening up new avenues for the treatment of pancreatic cancer.

HER3, formally referred to as ERB-B2 receptor tyrosine kinase 3, is a member of the ErbB receptor tyrosine kinases (also known as EGFR) family. HER3 plays a significant pro-cancer role in various types of cancer due to its overexpression and abnormal activation, which initiates downstream signaling pathways crucial in cancer cell survival and progression. As a result, numerous monoclonal antibodies have been developed to block HER3 activation and subsequent signaling pathways. While pre-clinical investigations have effectively showcased significant anti-cancer effects of HER3-targeted therapies, these therapies have had little impact on cancer patient outcomes in the clinic, except for patients with rare NRG1 fusion mutations. This review offers a comprehensive description of the oncogenic functions of HER3, encompassing its structure and mediating signaling pathways. More importantly, it provides an in-depth exploration of past and ongoing clinical trials investigating HER3-targeted therapies for distinct types of cancer and discusses the tumor microenvironment and other critical determinants that may contribute to the observed suboptimal outcomes in most clinical studies using HER3-targeted therapies. Lastly, we suggest alternative approaches and the exploration of novel strategies to potentially improve the efficacy of targeting the pivotal oncogenic HER3 signaling pathway in future translational investigations.

Breast cancer is the most common malignant tumor threatening women's health. Alteration in lipid metabolism plays an important role in the occurrence and development of many diseases, including breast cancer. The uptake, synthesis, and catabolism of lipids in breast cancer cells are significantly altered, among which the metabolism of fatty acids, cholesterols, sphingolipids, and glycolipids are most significantly changed. The growth, progression, metastasis, and drug resistance of breast cancer cells are tightly correlated with the increased uptake and biosynthesis of fatty acids and cholesterols and the up-regulation of fatty acid oxidation. Cholesterol and its metabolite 27-hydroxycholesterol promote the progression of breast cancer in a variety of ways. The alteration of lipid metabolism could promote the epithelial–mesenchymal transition of breast cancer cells and lead to changes in the tumor immune microenvironment that are conducive to the survival of cancer cells. While the accumulation of ceramide in cancer cells shows an inhibitory effect on breast cancer. This review focuses on lipid metabolism and elaborates on the research progress of the correlation between different lipid metabolism and the growth, progression, and drug resistance of breast cancer.

Adipose tissue fibrosis, characterized by abnormal extracellular matrix deposition within adipose tissue, signifies a crucial indicator of adipose tissue malfunction, potentially leading to organ tissue dysfunction. Various factors, including a high-fat diet, non-alcoholic fatty liver disease, and insulin resistance, coincide with adipose tissue fibrosis. MicroRNAs (miRNAs) represent a class of small non-coding RNAs with significant influence on tissue fibrosis through diverse signaling pathways. For instance, in response to a high-fat diet, miRNAs can modulate signaling pathways such as TGF-β/Smad, PI3K/AKT, and PPAR-γ to impact adipose tissue fibrosis. Furthermore, miRNAs play roles in inhibiting fibrosis in different contexts: suppressing corneal fibrosis via the TGF-β/Smad pathway, mitigating cardiac fibrosis through the VEGF signaling pathway, reducing wound fibrosis via regulation of the MAPK signaling pathway, and diminishing fibrosis post-fat transplantation via involvement in the PDGFR-β signaling pathway. Notably, the secretome released by miRNA-transfected adipose-derived stem cells facilitates targeted delivery of miRNAs to evade host immune rejection, enhancing their anti-fibrotic efficacy. Hence, this study endeavors to elucidate the role and mechanism of miRNAs in adipose tissue fibrosis and explore the mechanisms and advantages of the secretome released by miRNA-transfected adipose-derived stem cells in combating fibrotic diseases.

Neuronal death is associated with mitochondrial dysfunction caused by mutations in mitochondrial DNA. Mitochondrial DNA becomes damaged when processes such as replication, repair, and nucleotide synthesis are compromised. This extensive accumulation of damaged mitochondrial DNA subsequently disrupts the normal function of mitochondria, leading to aging, degeneration, or even death of neurons. Mitochondrial dysfunction stands as a pivotal factor in the development of neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Recognizing the intricate nature of their pathogenesis, there is an urgent need for more effective therapeutic interventions. In recent years, mitochondrial DNA editing tools such as zinc finger nucleases, double-stranded DNA deaminase toxin A-derived cytosine base editors, and transcription activator-like effector ligand deaminases have emerged. Their emergence will revolutionize the research and treatment of mitochondrial diseases. In this review, we summarize the advancements in mitochondrial base editing technology and anticipate its utilization in neurodegenerative diseases, offering insights that may inform preventive strategies and therapeutic interventions for disease phenotypes.

Osteosarcoma (OS), frequently observed in children and adolescents, is one of the most common primary malignant tumors of the bone known to be associated with a high capacity for invasion and metastasis. The incidence of osteosarcoma in children and adolescents is growing annually, although improvements in survival remain limited. With the clinical application of neoadjuvant chemotherapy, chemotherapy combined with limb-preserving surgery has gained momentum as a major intervention. However, certain patients with OS experience treatment failure owing to chemoradiotherapy resistance or metastasis. Nuclear factor E2-related factor 2 (Nrf2), a key antioxidant factor in organisms, plays a crucial role in maintaining cellular physiological homeostasis; however, its overactivation in cancer cells restricts reactive oxygen species production, promotes DNA repair and drug efflux, and ultimately leads to chemoradiotherapy resistance. Recent studies have also identified the functions of Nrf2 beyond its antioxidative function, including the promotion of proliferation, metastasis, and regulation of metabolism. The current review describes the multiple mechanisms of chemoradiotherapy resistance in OS and the substantial role of Nrf2 in the signaling regulatory network to elucidate the function of Nrf2 in promoting OS chemoradiotherapy resistance and formulating relevant therapeutic strategies.

The growing interest in post-translational protein modification, particularly in SUMOylation, is driven by its crucial role in cell cycle regulation. SUMOylation affects various cell cycle regulators, including oncogenes, suggesting its relevance in cancer. SUMO E3 ligases are pivotal in this process, exhibiting diverse functionalities through structural domains and subcellular localizations. A less-explored SUMO E3 ligase, RANBP2, a component of the vertebrate nuclear pore complex, emerges as a central player in cellular cycle processes, as well as in tumorigenesis. The current studies illuminate the importance of RANBP2 and underscore the need for more extensive studies to validate its clinical applicability in neoplastic interventions. Our review elucidates the significance of RANBP2 across various types of malignancies. Additionally, it delves into exploring RANBP2 as a prospective therapeutic target for cancer treatment, offering insights into the avenues that scholars should pursue in their subsequent research endeavors. Thus, further investigation into RANBP2's role in solid tumorigenesis is eagerly awaited.

MYC is dysregulated in approximately 70% of human cancers, strongly suggesting its essential function in cancer. MYC regulates many biological processes, such as cell cycle, metabolism, cellular senescence, apoptosis, angiogenesis, and immune escape. MYC plays a central role in carcinogenesis and is a key regulator of tumor development and drug resistance. Therefore, MYC is one of the most alluring therapeutic targets for developing cancer drugs. Although the search for direct inhibitors of MYC is challenging, MYC cannot simply be assumed to be undruggable. Targeting the MYC-MAX complex has been an effective method for directly targeting MYC. Alternatively, indirect targeting of MYC represents a more pragmatic therapeutic approach, mainly including inhibition of the transcriptional or translational processes of MYC, destabilization of the MYC protein, and blocking genes that are synthetically lethal with MYC overexpression. In this review, we delineate the multifaceted roles of MYC in cancer progression, highlighting a spectrum of therapeutic strategies and inhibitors for cancer therapy that target MYC, either directly or indirectly.

Glutathione S-transferases (GSTs) are a family of enzymes detoxifying various harmful compounds by conjugating them with glutathione. While primarily beneficial, dysregulation of GST activity or specific isoforms can contribute to disease pathogenesis. The intricate balance of detoxification processes regulated by GSTs is pivotal in cellular homeostasis, whereby dysregulation in these mechanisms can have profound implications for human health. Certain GSTs neutralize carcinogens, shielding cells and potentially preventing tumorigenesis. Polymorphisms in specific GSTs may result in the accumulation of toxic metabolites, exacerbating oxidative stress, inflammation, and DNA damage, notably observed in neurodegenerative diseases like Parkinson's disease. They can also modulate signaling pathways involved in cell proliferation, survival, and apoptosis, with aberrant activity potentially contributing to uncontrolled cell growth and resistance to cell death, thus promoting cancer development. They may also contribute to autoimmune diseases and chronic inflammatory conditions. This knowledge is useful for designing therapeutic interventions and understanding chemoresistance due to GST polymorphisms. A variety of GST inhibitors have been developed and investigated, with researchers actively working on new inhibitors aimed at preventing off-target effects. By leveraging knowledge of the involvement of specific GST isoforms in disease pathogenesis across different populations, more effective and targeted therapeutics can be designed to enhance patient care and improve treatment outcomes.

Regulator of G protein signaling 12 (RGS12) belongs to the superfamily of RGS proteins defined by a conserved RGS domain that canonically binds and deactivates heterotrimeric G-proteins. As the largest family member, RGS12 is widely expressed in many cells and tissues. In the past few decades, it has been found that RGS12 affects the activity of various cells in the human body, participates in many physiological and pathological processes, and plays an important role in the pathogenesis of many diseases. Here, we set out to comprehensively review the role of RGS12 in human diseases and its mechanisms, highlighting the possibility of RGS12 as a therapeutic target for the treatment of human diseases.

RNA-binding proteins (RBPs) act as crucial regulators of gene expression within cells, exerting precise control over processes such as RNA splicing, transport, localization, stability, and translation through their specific binding to RNA molecules. The diversity and complexity of RBPs are particularly significant in cancer biology, as they directly impact a multitude of RNA metabolic events closely associated with tumor initiation and progression. The fragile X mental retardation protein (FMRP), as a member of the RBP family, is central to the neurodevelopmental disorder fragile X syndrome and increasingly recognized in the modulation of cancer biology through its influence on RNA metabolism. The protein's versatility, stemming from its diverse RNA-binding domains, enables it to govern a wide array of transcript processing events. Modifications in FMRP's expression or localization have been associated with the regulation of mRNAs linked to various processes pertinent to cancer, including tumor proliferation, metastasis, epithelial–mesenchymal transition, cellular senescence, chemotherapy/radiotherapy resistance, and immunotherapy evasion. In this review, we emphasize recent findings and analyses that suggest contrasting functions of this protein family in tumorigenesis. Our knowledge of the proteins that are regulated by FMRP is rapidly growing, and this has led to the identification of multiple targets for therapeutic intervention of cancer, some of which have already moved into clinical trials or clinical practice.