INFLAMMATION RESEARCH
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2026
·Vol. 75
·期 1
·79
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IF 6.2
Zhao Junyong,Luo Xiaolin,Wang Zelan,Luo Wenjian,Wu Shaofa,Ma Xingyu,Liu He,Chen Yang,Pi Shixian,Zhang Jiawen,Zhang Jihang,Liu Chuan,Bi Xianjin,Qin Zhexue
Aims Vascular calcification (VC) predicts cardiovascular risk in diabetes, chronic kidney disease (CKD) and atherosclerosis patients and is closely linked to the osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs). Our previous work revealed that cGAS-STING signalling pathway in VSMCs increases CKD-associated atherosclerotic plaque vulnerability and recent studies elucidated the involvement of STING in vascular calcification, but its upstream modulation mechanism remains to be elucidated. Methods and results DNA damage and robust upregulation of STING occurred in high phosphate (Pi)-stimulated VSMCs, calcified aortic tissues from 1,25(OH) 2 VitD 3 (VitD 3 )-overloaded mice and radial arteries from CKD patients, and these changes were accompanied by the activation of the cGAS‒STING signalling pathway. STING deficiency alleviated vascular calcification in CKD model mice. STING knockdown suppressed calcium deposition and the expression of osteogenic transdifferentiation markers in VSMCs, whereas the overexpression of STING or its agonist 2′,3′-cGAMP exacerbated VC. Mechanistically, Brd4 was identified as a critical epigenetic regulator of Pi-induced DNA damage, STING activation and VC. Furthermore, the N6-methyladenosine (m6A) modification of STING mRNA was significantly increased in Pi-stimulated VSMCs, increasing its stability. Brd4 depletion decreased the m6A modification of STING and accelerated its degradation. The m6A modification of STING was mediated by the core methyltransferase Mettl3, whose transcription was regulated by Brd4. Finally, C-176 showed translational potential by effectively suppressing vascular calcification and osteogenesis markers expression in both VitD 3 -overloaded mice and Pi-stimulated VSMCs. Conclusions Our study elucidated the interplay between Brd4-mediated epigenetic and Mettl3-dependent epitranscriptomic mechanisms governs STING m6A modification and STING may be a potential therapeutic target for vascular calcification.
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BIOCHEMICAL PHARMACOLOGY
·
2026
·
IF 5.6
Mingxing Sui,Shuying Wu,Qingqing Song,Siyao Chen,Yingli Lu
Polycystic ovary syndrome (PCOS) is characterized by a constellation of symptoms, including menstrual cycle irregularities, hyperandrogenism, and polycystic ovarian morphology. Despite extensive research efforts, a thorough understanding of the underlying pathophysiology and effective treatment options for PCOS remain elusive. In this study, ovarian tissues from dehydroepiandrosterone (DHEA)-induced PCOS mice and control mice underwent mRNA sequencing. Through a comprehensive bioinformatics analysis, we systematically examined the sequencing data, and one cut homeobox 2 (Onecut2), a significantly downregulated gene in PCOS mice, was identified and selected as the primary research target. Our findings determined that the overexpression of Onecut2 efficiently alleviated pathological changes and reduced mitochondrial dysfunction in DHEA-induced PCOS mice. Additionally, Onecut2 was found to be expressed at a low level in human ovarian granulosa KGN cells treated with dihydrotestosterone (DHT). Gain-of-function and loss-of-function experiments uncovered that Onecut2 played a role in inhibiting apoptosis and mitochondrial damage in DHT-treated KGN cells. Dual-luciferase reporter assays demonstrated that Onecut2 overexpression activated the transcriptional activity of the sirtuin 3 (SIRT3) promoter, thereby controlling the function of granulosa cells. Mechanistic investigation revealed that the mRNA stability of Onecut2 was regulated by methyltransferase-like 3 (METTL3) via m6A modification. Collectively, this study demonstrates that Onecut2 exerts an inhibitory role in PCOS progression by transcriptionally regulating SIRT3 expression and that this regulation is influenced by METTL3-mediated m6A methylation.
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Cell Reports
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2026
·Vol. 45
·期 2
·116933
·
IF 6.9
Chunyu Feng,Su-Ran Li,Xiaoshuai Xu,Zihan Dang,Zihan Jiang,Erhui Jiang,Zhengjun Shang
Summary The role of neurotransmitters in suppressing anti-tumor immunity has garnered increasing attention. While glutamate has been extensively studied in neurological diseases, its potential role in regulating anti-tumor immunity, particularly in the context of neoadjuvant immunochemotherapy, remains underexplored. In this study, we find that glutamate levels are elevated in the plasma of head and neck squamous cell carcinoma (HNSCC) patients. The METTL3/m6A/CD98 axis in cancer-associated fibroblasts (CAFs) is a key driver of glutamate secretion. Glutamate induces CD8 + T cell exhaustion through SLC1A3 and impairs the formation of immune memory in secondary lymphoid structures. Additionally, glutamate promotes ferroptosis resistance in HNSCC. Notably, glutamate depletion enhances the efficacy of neoadjuvant immunochemotherapy. Our findings provide insights into how the METTL3/m6A/CD98 axis-mediated regulation of glutamate efflux may sensitize HNSCC to neoadjuvant immunochemotherapy.
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Cell Death & Disease
·
2025
·Vol. 16
·期 1
·1-18
·
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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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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International Journal of Nanomedicine
·
2026
·
IF 8.7
Zhenglu Yin,Zhaoxiang Meng,Bo Chen,Junya Wang,Aihua Zhang,Yan Shen,Xiaojia Tang,Shunyan Lin
Purpose: The clinical application of small interfering RNA (siRNA) therapy is limited by instability, inefficient tumor targeting, and inadequate responsiveness to the hypoxic tumor microenvironment. Therefore, this study aimed to construct a hypoxia-sensitive polymer-based nanocarrier to improve siRNA delivery efficiency and enhance antitumor effects in colorectal cancer (CRC).Methods: A hypoxia-sensitive polymer (mPEG-Azo-PEI) was synthesized and its cytotoxicity was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The polymer was loaded with siRNA targeting the METTL3 gene to form nanoparticles, which were then optimized and characterized. Coumarin-loaded nanoparticles were also prepared to study the cellular uptake in HCT116 cells under hypoxic conditions. The Antitumor effects were evaluated via MTT and real-time polymerase chain reaction (RT-PCR) in vitro and in vivo, and a rectal cancer model was established using HCT116 cells in nude mice. Tumor size, weight, and histology (HE staining) were assessed, and RT-PCR analyzed METTL3 ex-pression.Results: The CMC of mPEG-Azo-PEI was 0.001687 mg/mL, indicating good self-assembly stability under dilution conditions. The optimized mPEG-Azo-PEI@siRNA2 nanoparticles exhibited a mean particle size of 141.34 ± 2.31 nm, a PDI of 0.213 ± 0.011, and a zeta potential of +21.76 ± 1.76 mV. Hypoxia-triggered release reached ~95% within 24 h, compared with ~10% under normoxic conditions. Coumarin uptake by HCT116 cells was enhanced under hypoxic conditions, indicating improved intracellular delivery. In vitro, the nanoparticles inhibited tumor cell proliferation, with IC50 values of 1.133 (normoxia) and 0.481 (hypoxia) nM. In vivo, mPEG-Azo-PEI@siRNA2 significantly suppressed tumor growth and improved body weight. RT-PCR confirmed the downregulation of METTL3, aligning with tumor suppression.Conclusion: These results demonstrated that hypoxia-sensitive mPEG-Azo-PEI@siRNA2 nanoparticles effectively delivered siRNA2 and inhibited HCT116 cell proliferation, offering a promising hypoxia-activated targeting strategy for colon cancer therapy. The graphical abstract illustrates the design and proposed mechanism of mPEG-Azo-PEI@siRNA nanoparticles for colorectal cancer treatment. In the upper section, mPEG-Azo-PEI is combined with siRNAs to form nanoparticles, with the particle size and surface charge indicated. In the lower section, HCT116 cells are used to establish a tumor-bearing mouse model. The magnified tumor schematic shows nanoparticles accumulating in the tumor microenvironment, where hypoxic conditions promote siRNA release from the carrier. The released siRNA is depicted as targeting METTL3 within tumor cells, illustrating the intended hypoxia-responsive gene-silencing strategy for antitumor therapy.Hypoxia-responsive mPEG-Azo-PEI nanoparticles for METTL3 siRNA delivery and antitumor therapy.
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2024
·
IF 6.2
Biyun Chen,Lujiao Wang,Luyao Li,Mei Zhou,Shuya Pan,Qin Wang,Yaxuan Hou,Xue Zhou
Arsenic is a widespread carcinogen and an important etiological factor for lung cancer. Dysregulated miRNAs have been implicated in arsenic carcinogenesis and the mechanisms of arsenic-induced dysregulated miRNAs have not been fully elucidated. N 6 -methyladenosine (m 6 A) modification is known to modulate pri-miRNA processing. However, whether m 6 A-mediated pri-miRNA processing is involved in arsenic carcinogenesis is poorly understood. Here, we found that m 6 A modification was significantly increased in arsenite-transformed human bronchial epithelial BEAS-2B cells (0.5 µM arsenite, 16 weeks). Meanwhile, METTL3 was significantly upregulated at week 12 and 16 during cell transformation. The proliferation, migration, invasion, and anchorage-independent growth of arsenite-transformed cells were inhibited by the reduction of m 6 A levels through METTL3 knockdown. Further experiments suggest that the oncogene miR-106b-5p is a potentially essential m 6 A target mediating arsenic-induced lung cancer. miR-106b-5p was observed to be upregulated after exposure to arsenite for 12 and 16 weeks, and the reduction of m 6 A levels caused by METTL3 knockdown inhibited miR-106b-5p maturation in arsenite-transformed cells. What’s more, miR-106b-5p overexpression successfully rescued METTL3 knockdown-induced inhibition of the neoplastic phenotypes of transformed cells. Additionally, Basonuclin 2 (BNC2) was uncovered as a potential target of miR-106b-5p and downregulated by METTL3 via enhancing miR-106b-5p maturation. Additionally, the METTL3 inhibitor STM2457 suppressed neoplastic phenotypes of arsenite-transformed BEAS-2B cells by blocking pri-miR-106b methylation. These results demonstrate that m 6 A modification promotes the neoplastic phenotypes of arsenite-transformed BEAS-2B cells through METTL3/miR-106b-5p/BNC2 pathway, providing a new prospective for understanding arsenic carcinogenesis.
研究领域:
癌症生物学
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分子生物学
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毒理学
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表观遗传学
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Nature Communications
·
2022
·Vol. 13
·期 1
·1-23
·
IF 17.694
Hao WeiChao,Dian MeiJuan,Zhou Ying,Zhong QiuLing,Pang WenQian,Li ZiJian,Zhao YaYan,Ma JiaCheng,Lin XiaoLin,Luo RenRu,Li YongLong,Jia JunShuang,Shen HongFen,Huang ShiHao,Dai GuanQi,Wang JiaHong,Sun Yan,Xiao Dong
Autophagy is crucial for maintaining cellular energy homeostasis and for cells to adapt to nutrient deficiency, and nutrient sensors regulating autophagy have been reported previously. However, the role of eiptranscriptomic modifications such as m 6 A in the regulation of starvation-induced autophagy is unclear. Here, we show that the m 6 A reader YTHDF3 is essential for autophagy induction. m 6 A modification is up-regulated to promote autophagosome formation and lysosomal degradation upon nutrient deficiency. METTL3 depletion leads to a loss of functional m 6 A modification and inhibits YTHDF3-mediated autophagy flux. YTHDF3 promotes autophagy by recognizing m 6 A modification sites around the stop codon of FOXO3 mRNA. YTHDF3 also recruits eIF3a and eIF4B to facilitate FOXO3 translation, subsequently initiating autophagy. Overall, our study demonstrates that the epitranscriptome regulator YTHDF3 functions as a nutrient responder, providing a glimpse into the post-transcriptional RNA modifications that regulate metabolic homeostasis.
研究领域:
细胞生物学
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分子生物学
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表观遗传学
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FASEB JOURNAL
·
2025
·Vol. 39
·期 20
·e71141
·
IF 4.2
Mingxing Sui,Shuying Wu,Qingqing Song,Siyao Chen,Yingli Lu
Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder with complex pathophysiology and limited therapeutic options. To elucidate potential biomarkers and molecular mechanisms underlying PCOS, we analyzed gene expression profiles in ovarian tissues from dehydroepiandrosterone (DHEA)-induced PCOS mice and control mice by conducting mRNA sequencing. Transcription factor forkhead box O6 (FOXO6) drew our focus, as it exhibited higher expression in PCOS ovarian tissues (fold change ≈1.71, p < 0.05). Functional validation revealed that FOXO6 knockdown alleviated ovarian dysfunction accompanied by attenuated mitochondrial damage and reduced apoptosis in the ovarian tissues of PCOS mice. Meanwhile, high expression of FOXO6 was also observed in dihydrotestosterone (DHT)-treated granulosa cells. Post-FOXO6 downregulation, DHT-induced apoptosis and mitochondrial dysfunction were suppressed. Notably, the RNA level of FOXO6 was upregulated by the methyltransferase METTL3, which inhibited the decay of FOXO6 RNA by increasing the m6A modification of FOXO6 RNA. The inhibitory effects of METTL3 knockdown on apoptosis and mitochondrial dysfunction in granulosa cells were weakened by FOXO6 overexpression. Furthermore, transcriptomic profiling of DHT-treated granulosa cells with or without FOXO6 overexpression was conducted. This analysis yielded 386 upregulated genes and 582 downregulated genes, among which thioredoxin-interacting protein (TXNIP) was prominently upregulated in FOXO6-overexpressing cells (fold change ≈4.5, p < 0.05). FOXO6 transcriptionally activated TXNIP by binding to its promoter, and TXNIP knockdown reversed the effects of FOXO6 overexpression. Collectively, our findings highlight the METTL3/FOXO6/TXNIP axis as a vital regulator of ovarian dysfunction in PCOS, offering novel insights for therapeutic intervention. Graphical To elucidate PCOS biomarkers and mechanisms, mRNA-sequencing of ovarian tissues from DHEA-induced PCOS and control mice identified highly expressed FOXO6 (FC ≈1.71, p < 0.05). FOXO6 knockdown alleviated PCOS ovarian dysfunction, mitochondrial damage, and apoptosis, and suppressed DHT-induced granulosa cell defects. METTL3 upregulated FOXO6 via m6A modification to inhibit its RNA decay. FOXO6 activated TXNIP transcription by binding its promoter. This highlights the METTL3/FOXO6/TXNIP axis as a key PCOS ovarian dysfunction regulator, offering new insights for PCOS therapy.
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BIOCHEMICAL PHARMACOLOGY
·
2026
·
IF 6.5
Guowei Zhu,Junqing Yang,Dongzhi Ran,Ying Luo,Yanyi Wang,Wenjia Guo,Xiaodan Tan,Xiaobing Zhao,Yuanhong Gan,Huafeng Yin,Hong Wang
Non-alcoholic fatty liver disease (NAFLD) has become the fastest-growing etiology of cirrhosis and hepatocellular carcinoma. No Food and Drug Administration (FDA)-approved pharmacotherapy currently exists, underscoring the urgent need for novel regulatory circuits that can be translated into druggable targets. Here we demonstrate that autophagic flux is severely impaired and lipid accumulation markedly exacerbated in livers of NAFLD mouse models and in hepatocytes challenged with free fatty acid (FFA). Knock-down of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) elevated miR-690 abundance, restored autophagic flux, and attenuated intracellular lipid deposition. Consistently, silencing methyltransferase-like 3 (METTL3) decreased MALAT1, thereby increasing miR-690 and producing the same protective phenotype, whereas METTL3 over-expression elicited the opposite effects. Mechanistically, METTL3 directly bound MALAT1 and installed N6-methyladenosine (m6A) modifications that enhanced MALAT1 stability and expression. Up-regulated MALAT1 subsequently sponged miR-690, leading to its functional depletion, autophagosome–lysosome fusion blockade, and aggravated lipid retention. Collectively, the METTL3-m6A/MALAT1/miR-690 axis orchestrates autophagy and lipid homeostasis, operationalizing an “m6A–long non-coding RNA (lncRNA)–microRNA (miRNA)” regulatory paradigm in NAFLD and offering an epitranscriptomic perspective on disease pathogenesis.
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Cell Death & Disease
·
2023
·Vol. 14
·期 2
·1-14
·
IF 9
Zhang Shouyi,Lv Chengcheng,Niu Yichen,Li Changqi,Li Xiuming,Shang Yu,Zhang Yunchao,Zhang Yue,Zhang Yong,Zeng Yu
Bone metastasis is the most happened metastatic event in prostate cancer (PCa) and needs a large effort in treatment. When PCa metastasizes to the bone, the new microenvironment can induce the epigenome reprogramming and stemness remodeling of cancer cells, thereby increasing the adaptability of cancer cells to the bone microenvironment, and this even leads to the occurrence of secondary tumor metastasis. Our group has previously found that RNA binding motif 3 (RBM3) affects the stem cell-like properties of PCa by interfering with alternative splicing of CD44. However, whether RBM3, as a stress-response protein, can resist microenvironmental remodeling of PCa particularly in bone metastasis remains unknown. By co-culturing PCa cells with osteoblasts to mimic PCa bone metastases, we found that RBM3 upregulates the N6-methyladenosine (m 6 A) methylation on the mRNA of catenin beta 1 (CTNNB1) in a manner dependent on methyltransferase 3 (METTL3), an N6-adenosine-methyltransferase complex catalytic subunit. Consequently, this modification results in a decreased stability of CTNNB1 mRNA and a followed inactivation of Wnt signaling, which ultimately inhibits the stemness remodeling of PCa cells by osteoblasts. Thus, the present study may extend our understanding of the inhibitory role of RBM3 on particularly bone metastasis of PCa.
研究领域:
肿瘤学
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分子生物学
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癌症生物学
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Cell Reports
·
2026
·Vol. 45
·期 1
·116808
·
IF 6.9
Jie Fu,Xin Zong,Hong Zhang,Luoyi Zhu,Tao Gong,Yuanzhi Cheng,Fengqin Wang,Zeqing Lu,Caiqiao Zhang,Mingliang Jin,Yizhen Wang
Summary NLRP3 inflammasome activation requires both transcriptional priming and complex assembly, but how RNA m 6 A methylation coordinates these steps remains unclear. Here, we show that m 6 A levels increase during macrophage NLRP3 inflammasome activation and that METTL3 loss suppresses this activation. Myeloid-specific Mettl3 knockout mice display reduced inflammation and improved metabolic outcomes in lipopolysaccharide (LPS)-induced sepsis, monosodium urate (MSU)-induced arthritis, and diet-induced obesity. Integrated chromatin-associated RNA sequencing (chrRNA-seq), kethoxal-assisted single-stranded DNA sequencing (KAS-seq), and chrRNA-methylated RNA immunoprecipitation (MeRIP)-seq analyses show that METTL3 installs m 6 A co-transcriptionally on nascent Jak1 , Nlrp3 , and Il1β RNAs and that METTL3 regulates dynamic transcription and chromatin accessibility while selectively maintaining Nlrp3 / Il1β transcription. YTHDF1-driven translation of Jak1 activates the JAK1-STAT3-C/EBPβ axis to initiate Nlrp3 / Il1β transcription, and m 6 A-YTHDF1 translation of Nlrp3 / Il1β amplifies protein output, forming a coupled transcriptional-translational circuit. Pharmacologic STAT3 inhibition and METTL3 catalytic rescue validate this pathway and identify METTL3-mediated m 6 A as a therapeutic target for inflammasome-driven diseases.
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