BIOCHEMICAL PHARMACOLOGY
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2024
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IF 5.3
Lingli Jiang,Rui Liang,Qing Luo,Zhe Chen,Guanbin Song
Fat mass and obesity-associated protein (FTO) is an N6-methyladenosine (m6A) demethylase and plays critical oncogenic roles in multiple cancers. Here we show that FTO is an effective target in hepatocellular carcinoma (HCC). FTO is highly expressed in patients with HCC. Genetic depletion of Fto dramatically attenuated HCC progression in mice. Pharmacological inhibition of FTO by FB23/FB23-2 markedly suppressed the proliferation and migration of HCC cell lines in vitro and inhibited HCC tumorigenicity in xeno-transplanted mice. Mechanistically, FB23-2 suppressed the expression of Erb-b2 receptor tyrosine kinase 3 (ERBB3) and human tubulin beta class Iva (TUBB4A) by increasing the m6A level in these mRNA transcripts. The decrease in ERBB3 expression resulted in the inhibition of Akt-mTOR signaling, which subsequently impaired the proliferation and survival of HCC cells. Moreover, FB23-2 disturbed the stability of the tubulin cytoskeleton, whereas overexpression of TUBB4A rescued the migration of HCC cells. Collectively, our study demonstrates that FTO plays a critical role in HCC by maintaining the proliferation and migration of cells and highlights the potential of FTO inhibitors for targeting HCC.
研究领域:
癌症生物学
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分子生物学
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药理学
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Frontiers in Cell and Developmental Biology
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2026
·
IF 5.3
Xiaoying Chen,Guanyi Zheng,Kailong Fu,Minglong Yao,Kan Lin
Objective This study was designed to elucidate the molecular pathways responsible for anti-atherosclerotic effects of the traditional Chinese medicine formula Yishen Huoxue Huatan, with a focus on its key active component sesamin. Methods Network pharmacology was applied to predict potential targets and pathways associated with the anti-atherosclerotic activity of Yishen Huoxue Huatan. An atherosclerosis model was constructed in ApoE −/− mice treated with sesamin (50 or 100 mg/kg), and endothelial injury was induced in human umbilical vein endothelial cells (HUVECs) using oxidized low-density lipoprotein (ox-LDL). Aortic pathology, lipid profiles, m 6 A RNA methylation levels, iron accumulation, oxidative stress, and ferroptosis-related markers were assessed. Ferrostatin-1 (Fer-1) was used to verify the involvement of ferroptosis in sesamin-mediated endothelial protection. The involvement of the METTL3/SREBF1 axis was further investigated using RT–qPCR, MeRIP–qPCR, mRNA stability assays, and gene-silencing approaches. Results Network pharmacology identified sesamin as a major bioactive constituent associated with atherosclerosis-related and epigenetic regulatory pathways. In ApoE −/− mice, sesamin reduced aortic lipid deposition, alleviated vascular injury, and improved dyslipidemia. In HUVECs, sesamin attenuated ox-LDL–induced endothelial injury, iron overload, lipid peroxidation, and oxidative stress. Fer-1 produced protective effects similar to those of sesamin, supporting the involvement of ferroptosis inhibition in sesamin-mediated endothelial protection. Mechanistically, sesamin downregulated METTL3 expression and reduced m 6 A modification of SREBF1 mRNA, thereby increasing SREBF1 mRNA stability and protein expression. SREBF1 silencing markedly weakened the anti-ferroptotic effects of sesamin, whereas concurrent METTL3 knockdown partially restored this protective phenotype. Conclusion Sesamin upregulates SREBF1 expression by inhibiting METTL3-mediated m 6 A methylation, thereby alleviating ferroptosis-related alterations in vascular endothelial cells and ultimately delaying the progression of atherosclerosis.
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BMC Veterinary Research
·
2026
·
IF 3.1
Yao Lulu,Kang Yunzhe,Zhao Xuyang,Wang Lucai,Lv Lijie,Zhu Wenhui,Yang Xiuwen,Zhuang Guoqing,Sun Aijun
Background N6-methyladenosine, the most prevalent post-transcriptional modification in eukaryotes, plays a critical role in regulating gene expression and disease pathogenesis. Concurrently, G-quadruplex structures are implicated in key biological processes, including the regulation of transcription and post-transcriptional events. Emerging evidence suggests that m 6 A modifications and G4 structures colocalize within viral genomes and human pre-mRNAs; however, their functional interplay remains poorly understood. Results Using existing MeRIP-seq data from Marek’s disease virus (MDV)-infected samples, we investigated the colocalization pattern and its potential role in viral infection. Our bioinformatic analyses revealed that the predicted G4 structures were predominantly two G-tetrad G-quadruplexes. Genes with m 6 A-G4 colocalization were significantly enriched in pathways related to immune response and tumorigenesis. Then we verified the presence of co-localization on the CCL4 , which inhibited CCL4 expression. Co-localization also affected viral replication and regulated ICP4 expression. Conclusions We systematically characterized the features of G4 structures co-localized with m 6 A modifications during MDV infection, investigated the role in viral replication and gene regulation, and provided experimental evidence for m 6 A-G4 co-localization. These findings shed new light on the epitranscriptomic regulatory mechanisms employed by an oncogenic virus and may inform the development of novel antiviral and anti-tumor therapeutic strategies.
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CARBOHYDRATE RESEARCH
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2026
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IF 3.4
Yupeng Zhang,Haihan Pei,Jing Zhou,Kan Ding,Can Jin
The structure of homogeneous polysaccharide FM02 was characterized for the first time, and it was identified as arabinogalactan with a molecular weight of 12.1 kDa. • The interaction between FM02 and YTHDF2 was discovered through protein fishing assay, and the binding was further validated by surface plasmon resonance (SPR). • These findings reveal that FM02 directly targets YTHDF2, providing a new polysaccharide-based ligand for YTHDF2-related functional studies. Polygonum multiflorum Thunb. ( P. multiflorum ) is a traditional Chinese medicinal herb with a long history of use, and its polysaccharide constituents have been reported to possess a range of biological activities. Nevertheless, most existing studies have focused on crude polysaccharide fractions or preliminary bioactivity evaluations, leaving the fine structural features and molecular targets of these polysaccharides insufficiently defined. Here, a homogeneous polysaccharide, FM02 ( Mw 12.1 kDa), was isolated from P. multiflorum . Structural characterisation indicated that FM02 is a novel arabinogalactoglucan with a backbone of alternating →4)-α-Glc p -(1→ and →4, 6)-α-Glc p -(1→ residues. Branches at the O-6 position of 1, 4, 6-linked glucosyl residues comprise three distinct types: a terminal T-α-Glc p cap, a trisaccharide branch →1)-α-Glc p -(4 → 1)-β-Gal p -(3 → 1)-α-Ara f , and a longer chain →1)-α-Glc p -(4→[1)-Gal p -(4] 3 →[1)-α-Glc p -(4] 4 → 1)-α-Glc p . Affinity pull-down of LX-2 hepatic stellate cell lysates combined with mass spectrometry identified YTHDF2 as a candidate binding protein. Surface plasmon resonance (SPR) detected a concentration-dependent interaction between FM02 and YTHDF2 (K D 5.47 × 10 −7 M). Neither the acid-hydrolysis-resistant fraction FM02I nor the released degradation fragment FM02E showed detectable binding to YTHDF2, suggesting that the intact primary structure of the polysaccharide may be required to sustain this interaction. In summary, this study reports for the first time a novel arabinogalactoglucan, FM02, isolated from P. multiflorum , and reveals its potential direct interaction with the m 6 A reader protein YTHDF2, thereby providing foundational data for further activity screening, mechanistic studies, and related drug development of this polysaccharide. Download: Download high-res image (356KB) Download: Download full-size image
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FASEB JOURNAL
·
2025
·Vol. 39
·期 20
·e71141
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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
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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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TISSUE & CELL
·
2025
·
IF 2.5
Xiaoxue Zhao,Bingyu Zhang,Sining Duan,Tengfei Wu,Xiaojiao Yang,Yuxiang Liu
Growing evidence demonstrated the involvement of ferroptosis in the pathogenesis of myocardial ischemia/reperfusion injury (MIRI). The nature compound Wedelolactone (Wed) exhibits anti-ferroptosis effects. The current study aims to explore the impact of Wed on MIRI and reveal whether Wed could protect cardiomyocytes from ferroptosis. Rats underwent cardiac IR operation, and H9c2 cardiomyocytes were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). Rats or cell in Wed-treated group were subdivided into 2 different dose regimens: low and high. Wed intervention alleviated myocardial infarction and left ventricle dysfunction, and diminished the levels of biochemical markers for cardiac injury caused by cardiac IR. The content of Fe 2+ and MDA, 4-HNE expression, and ROS production were increased in infarct zone, as well as GSH content, GSH-Px activity, and the levels of ferroptosis-related proteins were reduced. Treatment with Wed reversed the aforementioned changes. Similar results were observed in vitro experiments. Molecular docking analysis showed good binding affinity between Wed and the target protein METTL3. In OGD/R-induced H9c2 cells, Wed downregulated METTL3 protein expression and further blocked METTL3-mediated m 6 A modification of BRD4 mRNA. Overexpression of METTL3 reversed the antagonistic effect of Wed on cardiomyocyte ferroptosis. Collectively, our findings uncovered that Wed showed anti-ferroptosis effects in cardiomyocytes through downregulating the METTL3/BRD4 axis, thereby ameliorating MIRI.
研究领域:
药理学
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心脏病学
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分子生物学
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生物化学
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生物医学研究
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Cell Death & Disease
·
2025
·Vol. 16
·期 1
·1-15
·
IF 9.6
Cen Junjie,Zhao Dongliang,Shi Xin,Chen Jinlong,Zhou Hang,Liang Yanping,Gui Chengpeng,Chen Wei,Luo Junhang,Chen Xu
Renal cell carcinoma (RCC) remains a significant clinical challenge due to its increasing incidence and resistance to conventional therapy. This study identifies an unprecedented mechanism by which mesencephalic astrocyte-derived neurotrophic factor (MANF) contributes to RCC progression. From single-cell transcriptome, we observed a significant upregulation of MANF in RCC compared to its progenitor cells, the proximal tubular cells. Mechanistically, decreased N6-methyladenosine (m6A) modification on MANF mRNA, mediated by the upregulation of the m6A demethylase ALKBH5, led to reduced RNA degradation and increased MANF protein expression. Furthermore, while the common von Hippel-Lindau (VHL) deletion in RCC results in the accumulation of misfolded proteins and endoplasmic reticulum (ER) stress, increased MANF efficiently mitigated ER stress by binding to phosphorylated inositol-requiring enzyme-1 alpha (IRE1α) and inhibited its phosphorylation, indicating that MANF-mediated ER stress resistance compensates for the negative effects of VHL depletion and contributes to the survival of RCC. Our findings highlight a potential therapeutic strategy for RCC by targeting the m6A-mediated regulation, directly degrading MANF protein or inhibiting its function.
研究领域:
分子生物学
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癌症研究
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生物化学
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细胞生物学
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转化医学
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MOLECULES
·
2024
·Vol. 29
·期 19
·4718
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IF 4.2
Jingyi Guo,Mei Zhao,Xia Kuang,Zilin Chen,Fang Wang
Laser-induced graphene (LIG) possesses characteristics of easy handling, miniaturization, and unique electrical properties. We modified the surface of LIG by electropolymerizing β-cyclodextrin (β-CD), which was used to immobilize antibodies on the electrode surface for highly sensitive detection of targets.N6-methyladenosine (m6A) is the most prevalent reversible modification in mammalian messenger RNA and noncoding RNA, influencing the development of various cancers. Here, β-CD was electropolymerized to immobilize the anti-m6A antibody, which subsequently recognized the target m6A. This was integrated into the catalytic hydrogen peroxide–hydroquinone (H2O2-HQ) redox system using phos-tag-biotin to generate electrochemical signals from streptavidin-modified horseradish peroxidase (SA-HRP). Under optimal conditions, the biosensor exhibited a linear range from 0.1 to 100 nM with a minimum detection limit of 96 pM. The method was successfully applied to the recovery analysis of m6A from HeLa cells through spiking experiments and aims to inspire strategies for point-of-care testing (POCT).
研究领域:
生物化学
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分析化学
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生物医学工程
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癌症研究
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FASEB JOURNAL
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2026
·Vol. 40
·期 13
·e72115
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IF 4.3
Hanjing Song,Jiani Zhang,Suman Huo,Xian Xu,Caiyan Huang,Lin Chen,Xueqin Yang,Yeqing Qian,Xiao-Jing Zhu
The transcription factor p63 is indispensable for epithelial stem cell proliferation/differentiation and epidermal development, with alterations in the p63 pathway underlying a subset of ectodermal dysplasias. Despite its critical role, the mechanisms regulating p63 expression remain poorly understood. Here, we identify an m 6 A-mediated posttranscriptional mechanism controlling the expression of ΔNp63 , the predominant functional p63 isoform in epidermal basal cells. We found that Cre-mediated conditional deletion of Mettl16 , encoding a conserved m 6 A methyltransferase, in mouse epithelial basal cells caused severe skin developmental abnormalities, reminiscent of human ectodermal dysplasias. RNA sequencing revealed significant downregulation of ΔNp63 and its target genes in Mettl16- deficient skin, which linked METTL16 to p63 pathways. Mechanistically, we demonstrated that METTL16 directly binds to ΔNp63 mRNA to mediate its m 6 A modification; this modified ΔNp63 mRNA is subsequently recognized by the m 6 A reader IGF2BP2, which stabilizes ΔNp63 mRNA and thereby modulates its protein levels. Critically, restoration of ΔNp63 expression mitigated the epidermal defects in Mettl16 -deficient mice. Collectively, our findings uncover a novel METTL16-m 6 A-IGF2BP2- ΔNp63 regulatory axis governing epidermal development, providing insights into the etiology of ectodermal dysplasias. Graphical p63 is essential for epithelial stem cell proliferation, differentiation, and epidermal development, and alterations in its pathway are associated with human ectodermal dysplasias. This study identifies a posttranscriptional mechanism whereby METTL16 directly binds to p63 mRNA and adds m6A modifications. The m6A reader IGF2BP2 recognizes these modifications, stabilizes p63 mRNA, and controls p63 protein levels. Together, these findings uncover a METTL16-m6A-IGF2BP2-p63 regulatory axis governing epidermal development, offering new insights into the etiology of human ectodermal dysplasias.
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International Journal of Biological Sciences
·
2026
·Vol. 22
·期 5
·2302
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IF 11.7
Jiaoshun Chen,Gengqiao Wang,Haoxiang Zhang,Qingyi Hu,Jun Zhao,Qiang Shen,Qingke Duan,Tao Yin
Pancreatic cancer is a highly aggressive malignancy characterized by a progressively stiffened extracellular matrix, which promotes mechanical memory acquisition in cancer cells and facilitates malignant progression and metastasis. Despite its clinical significance, the mechanisms underlying matrix stiffening and mechanical memory formation remain poorly defined. This study demonstrates that a high-stiffness microenvironment induces mechanical memory in pancreatic tumor cells, which in further aggravates stromal remodeling and adversely affects prognosis. Under mechanically stiff conditions, pancreatic cancer cells exhibit pronounced enrichment of RNA modification-related and metabolic pathways, along with significantly increased m6A levels. Mechanistically, METTL14 enhances YAP1 expression through YTHDF3-mediated m6A-dependent translational regulation, while YAP1 in turn transcriptionally upregulates METTL14 via TEAD1, establishing a positive feedback loop that sustains mechanical memory. This METTL14-YAP1 axis activates CD166-EGFR-LOXL2 signaling, leading to enhanced collagen cross-linking and deposition, increased stromal stiffness, and maintenance of tumor stemness. These results identify the METTL14-YAP1 feedback loop as a core regulator of mechanical memory in pancreatic ductal adenocarcinoma, which drives stromal dysfunction and tumor progression through CD166-LOXL2 axis, and suggest targeting this loop as a potential therapeutic strategy to disrupt mechanical memory and ameliorate stiffness-induced remodeling.
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Cell Reports
·
2026
·Vol. 45
·期 1
·116808
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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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