ZOOLOGICAL RESEARCH
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2025
·Vol. 46
·期 3
·722
·
IF 4.7
Chun-Xue Zhou,Si-Qi Wang,Ji-Yu Zhang,Xing Du,Qi-Fa Li
NORHA, a long non-coding RNA (lncRNA), serves as a key inducer of follicular atresia in sows by triggering granulosa cells (GCs) apoptosis. However, its regulation by N6-methyladenosine (m6A)—the most abundant RNA modification—remains unresolved. This study identified NORHA as a functional target of the m6A reader HNRNPA2B1 in sow GCs (sGCs). Transcriptome-wide mapping of RNA modification sites revealed extensive m6A enrichment on NORHA, with HNRNPA2B1 binding directly to the transcript and enhancing its stability via modification of multiple m6A sites, including A261, A441, and A919. HNRNPA2B1 suppressed 17β-estradiol (E2) biosynthesis and promoted sGC apoptosis by activating the NORHA-FoxO1 axis. FoxO1 subsequently repressed expression of cytochrome P450 family 19 subfamily A member 1 (CYP19A1), which encodes the enzyme essential for E2 biosynthesis. Additionally, HNRNPA2B1 functioned as a critical mediator of METTL3-dependent m6A modification, modulating NORHA expression and activity in sGCs. This study highlights an important m6A-dependent regulatory mechanism governing NORHA expression in sGCs.
研究领域:
生殖生物学
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RNA表观遗传学
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分子生殖学
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长非编码RNA
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卵巢生理学
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细胞凋亡
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高影响因子
Military Medical Research
·
2026
·Vol. 13
·期 1
·100054
·
IF 29
Xu-Ying Sun,Jing-Yue Su,Xin Chen,Yi-Xin Yang,Sheng-Wu Yang,Chun-Wu Zhang,Yu-Sheng Li,Jian Xu,Zhen-Han Deng
Background Osteoarthritis (OA) is currently the most common age-related degenerative joint disease, but there remains a lack of disease-modifying therapy for OA treatment. This study aimed to elucidate the critical roles and underlying mechanism of the fat mass and obesity associated gene (FTO) in OA pathogenesis induced by high fat diet (HFD) and HFD coupled with destabilized medial meniscus (DMM) surgery, and to ascertain the synergistic action of the two in OA pathogenesis. Methods Mouse models were established using solely HFD feeding and combined HFD feeding and DMM surgery. Primary mouse chondrocytes were treated with palmitic acid (PA) and interleukin-1β (IL-1β) to simulate lipotoxicity and inflammation. FTO expression was modulated via genetic, adenoviral, or pharmacological methods. Downstream pyruvate dehydrogenase phosphatases 2 (PDP2) and YTH N 6 -methyladenosine RNA binding protein 2 (YTHDF2) were similarly manipulated by siRNA or overexpression plasmids; adenovirus-mediated knockdown/overexpression of Pdp2 was applied in vivo . Mechanistic studies included RNA sequencing (RNA-Seq) and methylated RNA immunoprecipitation sequencing (MeRIP-Seq). Results The results revealed reduced FTO expression in the cartilage of both obese OA patients and mouse models. Genetically, adenovirus-induced or pharmacologically-induced FTO inhibition exacerbated OA progression in HFD-fed and HFD+DMM mice. Mechanistically, Fto knockdown downregulated the PDP2 level in an m 6 A-dependent manner via YTHDF2. Pdp2 knockdown exacerbated OA progression in HFD-fed and HFD+DMM mice, whereas PDP2 overexpression markedly alleviated cartilage degeneration. Moreover, YTHDF2 overexpression reversed the role of Fto knockdown in lipid deposition and cartilage degeneration. Conclusions Our study identifies that downregulation of FTO exerts a pivotal effect on OA with obesity. FTO drives disease progression by regulating PDP2 activity, and YTHDF2 mediates the m 6 A modification of FTO to PDP2. Targeting the FTO/YTHDF2/PDP2 axis offers promising therapeutic potential for OA treatment.
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FREE RADICAL BIOLOGY AND MEDICINE
·
2026
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IF 8
Huanhuan Wang,Hanshu Zhao,Jiadi Gao,Sihan Liu,Yuanqi Xu,Xinyue Zhao,Shanshan Yang,Baozhi Gang,Zhongling Zhang
Vascular dementia (VaD) is a major cause of cognitive decline in the elderly, with chronic cerebral hypoperfusion (CCH) as its core pathogeny linked to neuroinflammation. Microglial M1 polarization drives CCH-related neuroinflammation, but its epigenetic regulation remains unclear. N6-methyladenosine (m6A) modification, centered on methyltransferase-like 14 (METTL14), is abundant in the brain, while CCAAT enhancer binding protein delta (CEBPD) is associated with central nervous system inflammation. This study explored METTL14’s role in microglial polarization and CCH pathology. In vitro , HMC3 cells induced by LPS/TNF-α (10 μg/mL, 50 ng/mL) showed upregulated METTL14 and CEBPD. METTL14 knockdown via short hairpin RNA inhibited the expression of M1 phenotypic markers (iNOS, CD86), reduced the release of pro-inflammatory factors (IL-1β, IL-6), and blocked NF-κB nuclear translocation, indicating that METTL14 silencing suppresses LPS/TNF-α-induced microglial M1 polarization and inflammatory response. In bilateral common carotid artery occlusion (BCCAo)-induced CCH rats, hippocampal METTL14/CEBPD was elevated. Adeno-associated virus-mediated METTL14 knockdown not only attenuated neuroinflammation and neuronal apoptosis in hippocampal CA1, but also significantly improved spatial learning memory and object recognition ability. Mechanistically, RIP-PCR and MeRIP-qPCR confirmed METTL14 enhances CEBPD mRNA stability via m6A modification. CEBPD overexpression reversed METTL14 knockdown’s effect, identifying it as a key downstream mediator. In conclusion, METTL14 knockdown impairs CEBPD mRNA stability via m6A, inhibits TLR4/MyD88/NF-κB pathway and microglial M1 polarization, alleviating CCH-related neuroinflammation and cognitive impairment, providing a potential epigenetic target for VaD.
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JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
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2026
·Vol. 45
·期 1
·118
·
IF 14.3
He Yuhui,Gong Yanqing,Wu Yucai,He Shiming,Wang Yang,Gao Wenzhi,Tian Tai,Xu Xinyu,Zhou Liqun,Shi Zhenduo,Han Conghui,Feng Ninghan,Wang Jianfeng,Li Xuesong
Background Bladder cancer (BC) presents a major clinical challenge due to high recurrence and progression rates, highlighting the need for novel therapeutic targets. While the N6-methyladenosine (m6A) writer complex is broadly implicated, the specific function and regulatory mechanism of its adaptor protein RNA binding motif protein 15 (RBM15) remain poorly defined in BC. This study reveals the oncogenic role of RBM15 in BC and its m6A-dependent regulatory axis, providing a new rationale for targeted intervention. Methods The clinical relevance of RBM15 was established by assessing its expression and prognostic significance in public datasets and a large clinical cohort. The biological function of RBM15 and its effect on global m6A methylation were subsequently investigated using a comprehensive suite of in vitro assays and in vivo models. We performed integrated multiomics analyses (RNA-seq, m6A-seq, and RIP-seq) and validated the underlying molecular mechanisms by performing additional targeted assays to elucidate the downstream regulatory network. Finally, the therapeutic potential of targeting this axis was validated in preclinical models using the METTL3 catalytic inhibitor STM2457. Results RBM15 was significantly upregulated in BC, and its elevated expression served as an independent predictor of a poor prognosis. Functionally, RBM15 increased global m6A levels and promoted the malignant progression of BC cells both in vitro and in vivo; these oncogenic effects were reversed upon RBM15 knockdown. Mechanistically, RBM15 bound Zona Occludens 2 (ZO2) mRNA and recruited the methyltransferase 3–methyltransferase 14–Wilms’ tumor 1-associating protein (METTL3-METTL14-WTAP) methyltransferase complex to increase the level of the m6A modification on the ZO2 mRNA. This modification was recognized by YTH N(6)-methyladenosine RNA binding protein 2 (YTHDF2) to accelerate ZO2 mRNA decay. Although ZO2 expression was globally reduced, its preferential nuclear accumulation was increased, which promoted Snail expression and accelerated malignant progression. The METTL3 catalytic inhibitor STM2457 suppressed BC growth and lung metastasis by targeting the METTL3/RBM15/ZO2 axis, with no observable toxicity. Conclusions RBM15 acts as an oncogenic driver in BC by facilitating the m6A-dependent degradation of ZO2 mRNA via the recruitment of the METTL3 complex and recognition by YTHDF2. Targeting this METTL3/RBM15/ZO2 axis with STM2457 represents a promising therapeutic strategy for BC.
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高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2025
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IF 4.7
Zeming Lei,Yansheng Wang,Liangzi Yin,Ziyuan Wang,Lunhao Bai
Wear particle-induced periprosthetic osteolysis (PPO) represents the primary reason for implant failure following joint replacement, driven by macrophage polarization and excessive osteoclastogenesis. While cell migration inducing hyaluronidase 1 (CEMIP) has been implicated in inflammation and bone metabolism, its role in wear particle-induced PPO remains unexplored. Here, we discover that CEMIP expression was upregulated in Ti particle-induced calvarial osteolysis model. Functional studies revealed that CEMIP knockdown could attenuate Ti particle-triggered bone resorption via suppressing macrophage M1 polarization, promoting M2 polarization, and inhibiting osteoclast differentiation, as evidenced by reduced M1 markers, increased M2 markers, decreased inflammatory cytokines, and osteoclast-specific gene expression. In vitro, CEMIP silencing suppressed IFNγ-induced M1 polarization, enhanced IL-4-induced M2 polarization, and RANKL/M-CSF-triggered osteoclastogenesis in bone marrow-derived macrophages (BMDMs). Mechanistically, wear particle exposure decreases N6-methyladenosine (m6A) modification of CEMIP mRNA, impairing m6A reader protein YTH N6-methyladenosine RNA binding protein F2 (YTHDF2)-mediated recognition and subsequent mRNA decay, thereby stabilizing CEMIP transcripts and enhancing their expression. Furthermore, CEMIP knockdown counteracted the enhancement of M1 macrophage polarization and osteoclast differentiation resulting from YTHDF2 silencing. Collectively, these findings highlight the critical role of the YTHDF2/CEMIP axis in regulating macrophage polarization and osteoclast differentiation, thus offering a promising therapeutic target for wear particle-induced PPO.
研究领域:
分子生物学
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骨科
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免疫学
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骨代谢
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表观遗传学
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高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2022
·Vol. 23
·期 24
·15761
·
IF 6.208
Zixuan Zhou,Aijia Zhang,Xinyi Liu,Yang Yang,Ruqian Zhao,Yimin Jia
Excess fat deposition in broilers leads to great economic losses and is harmful to consumers’ health. Chronic stress in the life cycle of chickens could be an important trigger. However, the underlying mechanisms are still unclear. In this study, 30-day-old chickens were subcutaneously injected with 2 mg/kg corticosterone (CORT) twice a day for 14 days to simulate long-term stress. It was shown that chronic CORT exposure significantly increased plasma triglyceride concentrations and enlarged the adipocyte sizes in chickens. Meanwhile, chronic CORT administration significantly enlarged the adipocyte sizes, increased the protein contents of FASN and decreased HSL, ATGL, Beclin1 and PPARA protein levels. Moreover, global m6A methylations were significantly reduced and accompanied by downregulated METTL3 and YTHDF2 protein expression by CORT treatment. Interestingly, the significant differences of site-specific m6A demethylation were observed in exon7 ofPPARAmRNA. Additionally, a mutation of the m6A site in the PPARA gene fused GFP and revealed that demethylated RRACH in PPARA CDS impaired protein translation in vitro. In conclusion, these results indicated that m6A-mediated PPARA translational suppression contributes to CORT-induced visceral fat deposition in chickens, which may provide a new target for the treatment of Cushing’s syndrome.Keywords:adipose tissues;chicken;corticosterone;m6A;PPARA
研究领域:
动物科学
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分子生物学
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内分泌学
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高影响因子
JOURNAL OF CLINICAL INVESTIGATION
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2026
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IF 14.3
Sun Liu,Qihuan Ren,Guiling Mo,Zengguang Li,Huili Huang,Yuhao Zhou,Ziteng Miao,Xin Cao,Bilian Wu,Zhuoyu Xiao,Shihui Yu,Guangjin Wu,Linjian Xia,Jinru Cui,Junyuan Mo,Yuan Li,Laixin Xia,Juan Shen,Shan Xiao
Despite substantial progress in understanding the molecular pathology of Parkinson’s disease (PD), the underlying drivers of PD in many cases remain unknown. Here we investigate the role of RNA modification in PD, following observations of selective m6A hypomethylation in the substantia nigra (SN) of mouse PD models and dysregulated METTL3 and ALKBH5 expression in dopaminergic (DA) neurons from PD patients. We find preferential m6A deposition on transcripts of PD risk genes and a previously unreported heterozygous METTL3 p.K480R mutation in PD patients. Mettl3K480R/+ mice exhibit progressive METTL3 reduction and m6A hypomethylation in the SN, leading to progressive DA neuron loss, phospho-α-synuclein increase, and levodopa-responsive motor and non-motor deficits, mimicking PD progression. Dopamine transporter-specific METTL3 knockout mice recapitulate m6A hypomethylation, neurodegeneration and levodopa-responsive parkinsonism. Mechanistically, m6A deficiency disrupts mitochondrial biogenesis and function through regulating Tfam expression, while mitochondrial dysfunction reciprocally impairs m6A deposition, creating a pathogenic loop. Importantly, supplementation with S-adenosylmethionine (SAMe) enhances m6A modification, disrupts the pathogenic loop and alleviates parkinsonism in mouse models. Our findings reveal m6A dysregulation as an important contributor to PD pathogenesis, provide a valuable preclinical mouse model for PD progression, and highlight RNA methylation-targeted therapies as a promising strategy for PD intervention.
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高影响因子
FASEB JOURNAL
·
2026
·Vol. 40
·期 6
·e71640
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IF 4.3
Weijian Lun,Yongjia Liu,Canhua Luo,Huihuan Wu
Colorectal cancer (CRC) continues to be a significant global health concern. Emerging studies emphasize the tumor microenvironment (TME) as a key regulator of therapeutic response, particularly in its ability to suppress CD8 + T cell-mediated tumor clearance under chronic stimulation. However, the precise mechanisms responsible for this immunosuppressive effect remain unclear and require further exploration. Functional experiments evaluated CRC cell proliferation, migration, and invasion. CD8 + T cell infiltration and cytotoxicity were assessed using flow cytometry and LDH cytotoxicity assays. Mechanistic studies involved RNA immunoprecipitation (RIP), methylated RNA immunoprecipitation (MeRIP), chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assays to investigate the METTL5/YTHDF1-mediated regulation of COPS6 and the transcriptional activation of METTL5 by ZNF460. An in vivo CRC mouse model was established. The results indicated COPS6 was significantly upregulated in CRC and associated with poor prognosis. Knockdown of COPS6 suppressed CRC proliferation, migration, and invasion while enhancing CD8 + T cell infiltration and cytotoxicity. METTL5 was identified as an upstream regulator of COPS6, stabilizing its mRNA via m6A modification in a YTHDF1-dependent manner. ZNF460 bound to the METTL5 promoter, enhancing its transcription. In vivo, depletion of ZNF460 or METTL5 inhibited tumor growth and increased CD8 + T cell activity, whereas METTL5 overexpression reversed these effects. The ZNF460/METTL5/COPS6 axis promotes CRC progression and immune evasion by regulating COPS6 stability and CD8 + T cell infiltration. Targeting this pathway may offer new therapeutic strategies for CRC treatment. Graphical This study uncovers the ZNF460/METTL5/COPS6 regulatory axis in CRC, promoting tumor progression and immune escape. ZNF460 activates METTL5 transcription, enhancing COPS6 mRNA stability via m6A methylation in a YTHDF1-dependent manner. Elevated COPS6 impairs CD8⁺ T cell-mediated cytotoxicity. Disruption of this pathway reduces tumor growth and boosts immune infiltration. Targeting this mechanism may offer novel therapeutic strategies to restore antitumor immunity in CRC.
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高影响因子
Nature Communications
·
2023
·Vol. 14
·期 1
·1-20
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IF 16.6
Han Xiao,Liu Lijuan,Huang Saihua,Xiao Wenfeng,Gao Yajing,Zhou Weitao,Zhang Caiyan,Zheng Hongmei,Yang Lan,Xie Xueru,Liang Qiuyan,Tu Zikun,Yu Hongmiao,Fu Jinrong,Wang Libo,Zhang Xiaobo,Qian Liling,Zhou Yufeng
N 6 -methyladenosine (m 6 A), the most prevalent mRNA modification, has an important function in diverse biological processes. However, the involvement of m 6 A in allergic asthma and macrophage homeostasis remains largely unknown. Here we show that m 6 A methyltransferases METTL3 is expressed at a low level in monocyte-derived macrophages from childhood allergic asthma patients. Conditional knockout of Mettl3 in myeloid cells enhances Th2 cell response and aggravates allergic airway inflammation by facilitating M2 macrophage activation. Loss and gain functional studies confirm that METTL3 suppresses M2 macrophage activation partly through PI3K/AKT and JAK/STAT6 signaling. Mechanistically, m 6 A-sequencing shows that loss of METTL3 impairs the m 6 A-YTHDF3-dependent degradation of PTX3 mRNA, while higher PTX3 expression positively correlates with asthma severity through promoting M2 macrophage activation. Furthermore, the METTL3/YTHDF3-m 6 A/PTX3 interactions contribute to autophagy maturation in macrophages by modulating STX17 expression. Collectively, this study highlights the function of m 6 A in regulating macrophage homeostasis and identifies potential targets in controlling allergic asthma.
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高影响因子
CYTOKINE
·
2023
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IF 3.8
Wei Liu,Hui Zeng
Background Ulcerative colitis (UC) is a chronic and uncontrolled inflammatory bowel disease. N 6 -methyladenine (m 6 A) is a reversible mRNA modification method. IGF2BP2 is an RNA-binding protein regulated by m 6 A methylation. However, understanding of m 6 A-related proteins in UC is limited. This study was to analyze the function and related mechanism of IGF2BP2 in UC. Methods The UC models were established by dextran sulfate sodium (DSS) in NCM460 cells and mice. The expression of IGF2BP2 and GPX4 in UC were detected by qPCR and western blot. The effects of IGF2BP2 on inflammation, ferroptosis and colon injury were measured by gain- and loss-of-function experiments. This study conducted a clinical evaluation of mice using the Disease Activity Index score. The molecular mechanism of IGF2BP2 in ferroptosis were analyzed by m 6 A RNA methylation quantification kit, RNA immunoprecipitation-qPCR analysis, and RNA stability assay. Results IGF2BP2 and GPX4 were under-expressed in DSS-treated UC. IGF2BP2 enhanced the stability of GPX4 mRNA modified by m 6 A. IGF2BP2 overexpression repressed the ROS, MDA, and iron levels but enhanced the GSH and GPX4 levels in DSS-triggered NCM460 cells, which were partially reversed by GPX4 silencing. In UC mice, IGF2BP2 high-expression ameliorated symptoms, Disease Activity Index score, pathological changes, inflammatory reaction, and ferroptosis, which were also partly neutralized by GPX4 inhibition. Conclusions IGF2BP2 augmented the GPX4 expression by the m 6 A modification to weaken UC progression via suppressing ferroptosis.
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CHEMOSPHERE
·
2023
·
IF 8.8
Lin Han,Jingyu Wang,Lei Zhang,Jiaru Jing,Wei Zhang,Ziyan Liu,Ai Gao
Benzene is a universal ambient pollutant. Population-based studies have shown that benzene exposure affects male fertility. However, the mechanism of benzene-induced reproductive toxicity is unknown. Here, we established a dynamic inhalation model and exposed C57BL/6J mice to 0, 10, and 50 ppm benzene (6 h/day, 6 days/week, 7 weeks). Our study revealed that benzene exposure caused testicular injury, including structural damage to spermatogenic tubules, reduced semen quality, and decreased testosterone levels. In addition, the decrease in the global level of N 6 -Methyladenosine (m 6 A) and the change of m 6 A important regulatory enzymes in mice testes suggested that m 6 A was involved in the benzene-induced testicular injury. Further genome-wide m 6 A methylation analysis showed that 1469 differential m 6 A peaks were present in the testes of control and benzene groups, indicating that benzene exposure modulated m 6 A methylation in testes. Furthermore, the comprehensive analysis of m 6 A-sequencing and transcriptome revealed that hypermethylated Rara and its consequent reduced expression impaired the sperm production process. In particular, melatonin alleviated benzene-induced testicular injury by modulating m 6 A-related genes. Overall, our research provides a new idea and fundamental knowledge into the possible mechanisms of m 6 A modifications in benzene-induced testicular impairment, as well as a new experimental basis for benzene-induced male fertility therapy.
研究领域:
毒理学
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生殖生物学
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表观遗传学
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高影响因子
REPRODUCTION
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2022
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IF 3.923
Luchun Zhang,Meng Yuan,Xingwei Huang,Qianzi Cao,Shaogang Huang,Ruizhen Sun,Lei Lei
In brief: Several factors affect the reprogramming efficiency of nuclear transfer embryos. This study shows that inhibiting 18S rRNA m6A methyltransferase METTL5 during nuclear transfer can improve the developmental rate of nuclear transfer embryos. Abstract: N6-methyladenosine (m6A) is one of the most important epigenetic modifications in eukaryotic RNAs, which regulates development and diseases. It is identified by several proteins. Methyltransferase-like 5 (METTL5), an enzyme that methylates 18S rRNA m6A, controls the translation of proteins and regulates pluripotency in embryonic stem cells. However, the functions of METTL5 in embryonic development have not been explored. Here, we found that Mettl5 was upregulated in somatic cell nuclear transfer (SCNT) embryos compared with normal fertilized embryos. Therefore, we hypothesized that METTL5 knockdown during the early stage of SCNT would improve the developmental rate of SCNT embryos. Notably, injection of Mettl5 siRNA (si-Mettl5) into enucleated oocytes during nuclear transfer increased the rate of development and the number of cells in blastocysts. Moreover, inhibition of METTL5 reduced the activity of phosphorylated ribosomal protein S6, decreased the levels of the repressive histone modification H3K27me3 and increased the expression of activating histone modifications H3K27ac and H3K4me3 and mRNA levels of some 2-cell-specific genes. These results expand our understanding of the role of METTL5 in early embryonic development and provide a novel idea for improving the efficiency of nuclear transfer cloning.
研究领域:
分子生物学
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生殖生物学
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表观遗传学
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高影响因子
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