TOXICOLOGY
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2026
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IF 5.2
Huajie Yang,Haoyang Yuan,Yumeng Tai,Xi Chen,Xueli Yang,Chengzhi Chen,Liangpo Liu,Qiang Zhang,Naijun Tang
Arsenic is a widespread environmental pollutant associated with an increased risk of diabetes. However, the mechanisms by which N 6 -methyladenosine (m 6 A) RNA modification regulates insulin secretion following arsenic exposure remain largely unclear. In this study, MIN6 cells were exposed to 0–10 μmol·L⁻¹ sodium arsenite (NaAsO 2 ) for 36 h. Arsenic exposure reduced cellular metabolic activity and impaired glucose-stimulated insulin secretion (GSIS). Because S-adenosylmethionine (SAM) serves as a methyl donor for both arsenic methylation and m 6 A modification, we hypothesized that arsenic-induced SAM depletion may impair m 6 A methyltransferase activity, thereby disrupting m 6 A homeostasis and altering the expression of genes involved in insulin synthesis and secretion. Arsenic exposure significantly decreased intracellular SAM levels, global m 6 A abundance, and m 6 A methyltransferase activity. In addition, the mRNA expression of Mafa , Pdx1 , Foxa2 , and Glut2 was significantly reduced following arsenic exposure. SAM supplementation partially restored GSIS, global m 6 A abundance, total m 6 A methyltransferase activity in nuclear extracts, and attenuated the reduction in GLUT2 protein abundance. Moreover, arsenic exposure reduced m 6 A enrichment on Mafa and Pdx1 transcripts, whereas SAM supplementation attenuated these changes. Collectively, these findings suggest that arsenic exposure impairs insulin secretion in MIN6 cells, potentially through SAM depletion, disruption of m 6 A homeostasis, and altered m 6 A regulation of the MAFA–PDX1 regulatory network.
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Molecular Metabolism
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2026
·
IF 6.3
Weiyan Wang,Lingli Xie,Guilan Chen,Xin Zuo,Meiling Zhong,Tong Yang,Weihua Wu
Background Diabetic cardiomyopathy (DCM) is a prevalent and severe cardiovascular complication of diabetes mellitus, characterized by progressive cardiac dysfunction and pathological remodeling driven by myocardial metabolic disturbances. However, the underlying molecular mechanisms remain incompletely elucidated. Methods A type 2 DCM mouse model was established by feeding C57BL/6 mice a high-fat diet combined with streptozotocin injections. Cardiomyocyte-specific TRIM47 knockdown was achieved via AAV9-mediated delivery of a cardiomyocyte-specific cTnT promoter-driven shRNA. In vitro, primary neonatal mouse ventricular cardiomyocytes (NMCMs) were treated with palmitic acid (PA) to model cardiomyocyte injury. Results TRIM47 was significantly upregulated in diabetic hearts. Cardiomyocyte-specific TRIM47 knockdown improved left ventricular ejection fraction and fractional shortening, attenuated chamber dilation, and reduced heart weight-to-tibia length ratio. TRIM47 silencing attenuated cardiomyocyte hypertrophy, interstitial fibrosis, and cardiomyocyte apoptosis, alongside reduced myocardial inflammatory cytokine levels (TNF-α, IL-6, IL-1β). Furthermore, TRIM47 knockdown alleviated myocardial lipid accumulation and reduced triglyceride levels, accompanied by downregulation of the fatty acid translocase CD36. In vitro, PA-treated NMCMs exhibited elevated TRIM47 expression, and its knockdown mitigated PA-induced cardiomyocyte injury, inflammation, apoptosis, and lipid deposition. Mechanistically, the m6A reader YTHDF3 was upregulated under PA conditions and directly bound to m6A-modified TRIM47 mRNA, enhancing its stability. Rescue experiments demonstrated that YTHDF3 overexpression exacerbated PA-induced cardiomyocyte injury, whereas concurrent TRIM47 knockdown largely reversed these deleterious effects. Conclusions Our results revealed that TRIM47 may contribute to the progression of DCM by promoting abnormal cardiac lipid metabolism, exacerbating inflammation and apoptosis, and these effects are partially mediated through the upstream m6A reader YTHDF3.
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FREE RADICAL BIOLOGY AND MEDICINE
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2026
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IF 8.2
Lili Hao,Wenjie Zhang,Xiaoting Peng,Yujia Bai,Cheng Tian,Yiwen Zhang,Di Li,Zhihui Feng,Baoshan Xu,Qiong Xu
Disordered osteogenic potential in bone marrow mesenchymal stem cells (BMSCs) is a hallmark of inflammatory jaw diseases. Recent studies suggest that inflammatory stimulating disrupts energy metabolism during BMSC osteogenesis. However, the impact of key metabolites on BMSC ossification remains unclear. In this study, a comprehensive targeted metabolomic analysis was performed during BMSC osteogenic differentiation, with and without inflammatory stimulation induced by lipopolysaccharide (LPS). We identified a significant downregulation of spermidine (SPD), along with methylated purines and pyrimidines, in the inflammatory environment. Exogenous SPD supplementation enhanced BMSC osteogenesis and increased N6-methyladenosine (m 6 A) methylation. Mechanistically, SPD elevated S-adenosylmethionine (SAM) levels and upregulated the methyltransferases METTL3 and METTL14. Similarly, betaine, a promoter of SAM synthesis, increased m 6 A methylation and improved BMSC osteogenic potential. In contrast, the METTL3/METTL14 inhibitor S-adenosylhomocysteine (SAH) reduced m 6 A methylation and negated SPD's osteogenic effects. This suggests that SPD enhances BMSC osteogenesis through m 6 A methylation regulation. Furthermore, SPD activated autophagy in BMSCs, while SAH inhibited SPD-induced autophagy. Notably, treatment with rapamycin (Rap), an autophagy inducer, restored both autophagy and osteogenic differentiation impaired by SAH. In vivo , SPD supplementation enhanced m 6 A methylation and facilitated bone regeneration in a rat model of inflammatory mandibular defects. In conclusion, this study demonstrates that SPD promotes the osteogenic potential of BMSCs through an m 6 A methylation–autophagy axis under inflammatory conditions, providing a novel therapeutic approach for inflammatory jaw diseases.
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Gut Microbes
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2025
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IF 11
Ruonan Chen,Xiaoqin Chai,Yunxiao Zhang,Tianxiu Zhou,Yinyin Xia,Xuejun Jiang,Bo Lv,Jun Zhang,Lixiao Zhou,Xin Tian,Ruonan Wang,Lejiao Mao,Feng Zhao,Hongyang Zhang,Jun Hu,Jingfu Qiu,Zhen Zou,Chengzhi Chen
Fat mass and obesity-associated protein (FTO) is the key demethylase that reverses the abnormally altered N6-methyladenosine (m6A) modification in eukaryotic cells under environmental pollutants exposure. Arsenic is an environmental metalloid and can cause severe symptoms in human mainly through drinking water. However, there is no specific treatment for its toxic effects due to the uncovered mechanisms. We previously revealed that exposure to arsenic increased the level of m6A via down-regulation of FTO, which might serve as a potential target for intervention against arsenic-related disorders. In this study, our results demonstrated that chronic exposure to arsenic significantly disrupted the intestinal barrier and microenvironment. Also, this administration resulted in the enhancement of m6A modification and the reduction of FTO expression in the intestine. By using both CRISPR/Cas9-based FTO knock-in strategy and adeno-associated virus (AAV)-mediated overexpression of FTO in the intestine, we established for the first time that up-regulation of FTO remarkably ameliorated arsenic-induced disruption of intestinal barriers and altered microenvironment of mice. We also firstly identified a dominant gut microbial species, Desulfovibrio fairfieldensis, which was sharply reduced in arsenic-exposed mice, was able to proceed arsenic-induced neurobehavioral impairments by declining the levels of its major metabolite hydrogen sulfide. Administration of Desulfovibrio fairfieldensis could significantly alleviate the neurotoxicity of arsenic. Intriguingly, the beneficial effects of FTO against arsenic neurotoxicity possibly occurred through a novel gut–brain communication via Desulfovibrio fairfieldensis and its produced hydrogen sulfide. Collectively, these findings will provide new ideas for understanding the mechanisms of arsenic-induced toxic effects from a gut–brain communication perspective, and will assist the development of explicit intervention strategy via regulation of a new potential target FTO for prevention and treatment against arsenic-related both intestinal and neurological disorders.
研究领域:
毒理学
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微生物学
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神经科学
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分子生物学
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胃肠病学
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BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
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2026
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IF 5
Guihong Li,Ting Lei,Erpeng Liu,Jing Shen,Dun Liu,Xuqiang Zhu
USP53 upregulation is identified as an independent risk factor for GBM progression. • USP53 upregulation is associated with poor prognosis of GBM patients. • USP53 promotes cell growth and the tumorigenicity of GBM cells. • USP53 removes ubiquitination from ALKBH5 and enhances its stability. • ALKBH5 removes the m6A modification of TERT and increases its RNA stability. Glioblastoma (GBM) is the most common malignant glioma, with a high recurrence rate and a poor prognosis. Deubiquitinating enzyme ubiquitin-specific peptidase 53 (USP53), known to enhance the stability of downstream proteins, exhibits distinct functions in different tumors. The function of USP53 in GBM progression remains unclear. Analysis of GSE104267 and GSE4290 datasets revealed significant USP53 upregulation in GBM tissues, a finding confirmed by TCGA data comparing GBM ( n = 163) with normal brain tissues ( n = 207). In univariate and multivariate cox regression analysis, USP53 was identified as an independent risk factor (univariate, hazard ratio (HR) =1.5357, p = 0.0229; multivariate, HR =1.4851, p = 0.0385) for GBM progression. Patients with high expression of USP53 had worse prognosis compared to those with low expression of USP53. Functionally, USP53 knockdown potently inhibited proliferation and induced apoptosis in LN229 and A172 cells in vitro and attenuated tumorigenicity of LN229 cells in vivo . Conversely, forced expression of USP53 had a carcinogenic effect. Mechanistically, USP53 targeted ALKB homolog 5 (ALKBH5) for deubiquitination, thereby stabilizing the protein and prolonging its half-life. Restoring ALKBH5 expression rescued the proliferative deficit in USP53-silenced LN229 cells. Telomerase catalytic subunit telomerase reverse transcriptase (TERT) was identified as a downstream effector of the USP53/ALKBH5 axis, where ALKBH5 upregulated TERT RNA expression by erasing m6A modifications at position 1989 bp on TERT mRNA. Collectively, those observations demonstrate that USP53/ALKBH5 axis drives GBM progression by targeting TERT, indicating that USP53/ALKBH5 axis may serve as a potential therapeutic target for GBM. Download: Download high-res image (229KB) Download: Download full-size image
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ANTIVIRAL RESEARCH
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2026
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IF 4.3
Ting Zhang,Zi-Ling Wang,Xi-Ya Li,Rong-Hua Luo,Lu-Xi Zhang,Hong-Yi Zheng,Si-Dong Xiong,Wen-Lan Yang,Yong-Tang Zheng
The continuous emergence of new SARS-CoV-2 variants limits the effectiveness of current vaccines and monoclonal antibodies, highlighting the urgent need for complementary antiviral strategies. Targeting host proteins that are exploited by the virus represents a promising approach to achieve broad-spectrum inhibition. Given the recently established proviral role of METTL3-dependent RNA m 6 A modification in SARS-CoV-2 replication, we conducted a structure-based virtual screening to repurpose compounds with acceptable safety profiles. Subsequent biochemical validation identified onvansertib and vilazodone as direct METTL3 binders and potent inhibitors of its methyltransferase activity. Notably, both compounds effectively suppressed the replication of ancestral SARS-CoV-2 and Omicron BA.2 variant in vitro . Mechanistically, each compound potentially enhanced the innate antiviral response of the host and repressed the expression of viral entry-associated host factors during infection; this observation is consistent with the established proviral role of METTL3. In summary, these findings not only substantiate METTL3 as a viable antiviral target but also lay the foundation for further research on the therapeutic potential of onvansertib and vilazodone against COVID-19.
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Cancer Cell International
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2026
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IF 7
Siyi Liu,Lin Liang,Zihua Zhou,Chenyu Zhang,Shan Liao,Qian He,Yan Lei,Juan Xu,Gengqiu Luo,Yanling Li,Yanhong Zhou
As a cell surface glycoprotein, CD90 plays a significant role in the initiation and progression of malignancies such as gastric cancer (GC) by influencing tumor cell proliferation, migration, and angiogenesis. However, its specific role in immune evasion in GC and its potential therapeutic value have not been fully explored. In this study, we report that CD90 is highly expressed in GC tissues and is positively correlated with macrophage immune infiltration. Furthermore, we demonstrate that CD90 can mediate immune evasion in GC by affecting the phagocytic function of tumor-associated macrophages (TAMs). Mechanistically, CD90 functions as a scaffold protein, inhibiting the interaction between IGF2BP2 and TRIM21. This inhibition stabilizes the expression of the m6A methylation reader protein IGF2BP2. Subsequently, IGF2BP2 enhances the mRNA stability of the immune checkpoint molecule CD47 in an m6A-dependent manner, leading to the activation of the CD47/SIRPα axis. Ultimately, by inhibiting the phagocytic function of TAMs, CD90 mediates immune evasion in GC. In summary, our work highlights the critical role of the CD90-IGF2BP2-CD47 axis in immune evasion in GC. This finding is expected to provide significant experimental evidence for elucidating the pathogenesis of GC and discovering potential molecular targets for clinical treatment.
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Cell Death & Disease
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2025
·Vol. 16
·期 1
·1-18
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IF 9.6
Lu Qiutong,Wang Zhaopeng,Cao Shuixian,Wang Huan,Li Nianshuang,Hu Yi,Ding Wuhui,Zuo Wei,Hong Junbo
Helicobacter pylori (H. pylori) infection is a significant cause of gastric diseases, with its pathogenic mechanisms still not fully understood. This study investigates the role of METTL3, an enzyme involved in m6A methylation, in modulating the CXCL1/NF-κB signaling pathway in H. pylori-induced gastritis. Using both bioinformatics analysis of GEO database and experimental approaches including MeRIP, RIP assays, and immunostaining, this research highlights how METTL3 influences CXCL1 expression and NF-κB pathway activation. Results from both in vitro and in vivo models show that METTL3 increases inflammatory responses and apoptosis in gastric cells. Suppression of METTL3 resulted in decreased inflammation and apoptosis, suggesting its potential as a therapeutic target in gastritis management.
研究领域:
微生物学
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分子生物学
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免疫学
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胃肠病学
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表观遗传学
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Communications Biology
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2026
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IF 5.1
Zheng Zhichao,Li Xingyang,Qin Wenguang,Yu Shuiqing,Xu Tianru,Cheng Haoyu,Xie Wei,Fu Zhihe,Pan Guokai,Zhang Yuhui,Huang Wenyan,Liu Fei,Jiang Yifan,Jaspers Richard T.,Pathak Janak L.,Wu Lihong
Non-coding RNAs, including piwi-interacting RNAs (piRNAs), are known to regulate osteogenic differentiation in bone marrow-derived mesenchymal stem cells (BMSCs); their role in mesenchymal stem cells (MSCs) from diverse origins remains unclear. In this study, we identified piR48444 as a key regulator that is downregulated during the osteogenic differentiation of stem cells from exfoliated deciduous teeth (SHED) but is upregulated in inflamed and aged BMSCs. Functionally, piR48444 inhibited, while its knockdown enhanced osteogenic differentiation across MSCs from multiple sources. Notably, piR48444-depleted MSCs exhibited superior bone defect repair capacity. PiR48444 antagomir promoted bone regeneration in LPS-induced osteolysis mice and aging mice. Mechanistically, we demonstrated that piR48444 targets METTL7A , suppressing BMP2 mRNA m 6 A methylation. Furthermore, we discovered that the METTL7A/eIF4E complex binds to BMP2 mRNA, thereby enhancing its translational efficiency. Our findings establish piR48444 as a negative regulator of MSC osteogenesis through METTL7A-mediated BMP2 m 6 A methylation, highlighting its potential as a therapeutic target to enhance MSC-based bone regeneration strategies.
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BRAIN RESEARCH
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2025
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IF 2.6
Shan Hui,Yi Long,Lemei Zhu,Wei Shi,Qing Zheng,Lihui Liang
Background Alzheimer’s disease (AD) is characterized by cognitive decline and neuronal loss, with cellular senescence emerging as a key driver. The insulin-like growth factor-1 receptor (IGF1R) pathway is implicated in aging and AD pathology. IGF2 mRNA binding protein 2 (IGF2BP2) can stabilize IGF1R mRNA, but its role in AD-associated neuronal senescence remains unclear. Methods We established AD mouse models and H 2 O 2 -induced senescent neuronal cell models to explore the impact of IGF2BP2 in neuronal senescence and cognitive deficits. RNA pull-down assays, methylated RNA immunoprecipitation (MeRIP)-qPCR, and behavioral tests were used to elucidate the molecular mechanisms and therapeutic potential of targeting IGF2BP2. Results IGF2BP2 was significantly up-regulated in the hippocampal neurons of AD mice. This upregulation correlated with increased β-amyloid (Aβ) deposition, neuronal damage, and cognitive impairments. In vitro , IGF2BP2 knockdown in H 2 O 2 -induced senescent neurons reduced IGF1R expression and alleviated neuronal senescence, as evidenced by decreased senescence-associated secretory phenotype factors and improved cell viability. Mechanistically, IGF2BP2 stabilized IGF1R mRNA through m6A modification, enhancing its expression. Knockdown of IGF2BP2 decreased IGF1R mRNA stability and expression, thereby mitigating neuronal senescence. In AD mice, IGF2BP2 knockdown improved cognitive function, reduced Aβ deposition, and delayed neuronal senescence. Conclusion IGF2BP2 contributes to neuronal senescence and cognitive deficits in AD by regulating IGF1R expression through m6A modification.
研究领域:
神经科学
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分子生物学
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表观遗传学
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衰老研究
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神经退行性疾病
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PubMed
高影响因子
CANCER GENE THERAPY
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2026
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IF 6.4
Shi Ruxue,Gu Kai,Li Haichuan,Sun Qingwei,Wu Xinyu,Huang Shuhong,Hu Qingxia
Castration-resistant prostate cancer (CRPC) is one of the most prevalent cancers in men. The new generation androgen receptor (AR) inhibitor enzalutamide can improve the therapeutic effectiveness of patients with CRPC. However, these patients eventually develop acquired enzalutamide resistance (ENZR), and the mechanisms underlying resistance are not well understood. Wilms’ tumor 1-associating protein (WTAP) plays an important role in m 6 A modification and has been reported as an oncogene in various cancers. Here, we utilized a tissue microarray and collected tissues from prostate cancer (PCa) patients to detect WTAP expression, and found that WTAP is upregulated in PCa. Meanwhile, WTAP overexpression promotes cell proliferation and accelerates tumor growth through colony formation assays and the establishment of a subcutaneous xenograft model in vivo. These findings establish the tumor promoter role of WTAP in prostatic tumorigenesis. Furthermore, we verified that WTAP is a novel responsive gene of AR via promoter activity and chromatin immunoprecipitation (ChIP) assays. Importantly, we uncovered that WTAP is upregulated in ENZR cells, and WTAP knockdown inhibited the proliferation of ENZR cells. Mechanistically, ubiquitin-specific protease (USP7) enhanced the stability of WTAP by the ubiquitin-proteasome pathway in ENZR cells, thereby WTAP increases promote AKT signaling through an m 6 A-mediated way, and an AKT inhibitor can abolish the pro-resistance phenotype mediated by WTAP. Together, these findings suggest that WTAP plays a key role in ENZR development of PCa cells, and WTAP may be a potential treatment target for ENZR tumors. The alternative text for this image may have been generated using AI. In this manuscript, we utilized a tissue microarray and collected tissues from prostate cancer (PCa) patients to detect WTAP expression, and found that WTAP is upregulated in PCa. Meanwhile, WTAP overexpression promotes cell proliferation and accelerates tumor growth through colony formation assays and the establishment of a subcutaneous xenograft model in vivo. These findings establish the tumor promoter role of WTAP in prostatic tumorigenesis. Furthermore, we verified that WTAP is a novel responsive gene of AR via promoter activity and chromatin immunoprecipitation (ChIP) assays. Importantly, we uncovered that WTAP is upregulated in ENZR cells, and WTAP knockdown inhibited the proliferation of ENZR cells. Mechanistically, ubiquitin-specific protease (USP7) enhanced the stability of WTAP by the ubiquitin-proteasome pathway in ENZR cells, thereby WTAP increases promote AKT signaling through an m 6 A-mediated way, and an AKT inhibitor can abolish the pro-resistance phenotype mediated by WTAP. Together, these findings suggest that WTAP plays a key role in ENZR development of PCa cells, and WTAP may be a potential treatment target for ENZR tumors.
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Molecular & Cellular Toxicology
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2025
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IF 1.4
He Chaojie,Fan Hongyan,Zhu Chunyan,Huang Yueqing
Background Ischemia–reperfusion (I/R) injury is a severe disorder during revascularization therapy against acute myocardial infarction. Objective Our study aims to investigate the role and regulation mechanism of Annexin A1 (ANXA1) against I/R injury. Results Western blotting analysis showed that ANXA1 expression in rat cardiomyocytes (H9C2 cells) was notably decreased by oxygen–glucose deprivation/reperfusion (OGD/R) treatment. Meanwhile, the NLRP3 inflammasome activation accompanied by pyroptosis and inflammation was observed in H9c2 cells under OGD/R induction. Besides, overexpression or knockdown of ANXA1 dramatically inhibited or aggravated NLRP3-mediated pyroptosis and inflammation. Further investigations found that the m 6 A level of ANXA1 was upregulated by OGD/R, thus leading to decreased mRNA stability in H9C2 cells. FTO, a N6-methyladenosine (m 6 A) “eraser”, was downregulated in H9C2 cells by OGD/R and shown to increase the ANXA1 protein expression by demethylating mRNA in H9c2 cells under OGD/R induction. Moreover, knockdown FTO reversed the protection of ANXA1 against NLRP3-mediated pyroptosis and inflammation in OGD/R-induced H9C2 cells. Conclusion ANXA1 protects cardiomyocytes against I/R injury by alleviating NLRP3-mediated pyroptosis and inflammation via FTO-mediate demethylation. These findings innovatively suggest the therapeutic potential of ANXA1 for myocardial I/R injury.
研究领域:
分子生物学
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心脏病学
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表观遗传学
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