PLoS One
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2025
·Vol. 20
·期 4
·e0319605
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IF 2.6
Hong-Fei He,Shuang Hou,Xiao-Ya Ma,Song-song Huang,Bo Yang,Jun-Kang Wang,Yuan Xu,Lei Tan,Hai-Yang Li
As one of the major causes of acute kidney injury, renal ischemia-reperfusion is a common health problem in a series of clinical situations, including renal transplantation. Although the mechanisms of renal IRI have been widely investigated, effective strategies are still in lacking for its prevention and treatment. In previous study, we found that the down-regulation of taurine upregulated gene 1, a long non-coding RNA (lncRNA TUG1), markedly alleviated renal IRI through mitigating the cell inflammation and apoptosis. At meanwhile, YTHDF2, an RNA methylation reading protein, was identified as a vital player in IRI of distinct organs, however, not reported in kidney. We then conducted the current study on the function of YTHDF2 in renal IRI and its regulatory role to TUG1. Based on renal IRI models in vitro and in vivo, dramatical down-regulation of YTHDF2 was presented. Subsequently, exogenous perturbation of YTHDF2 was conducted and its protective effects on cell apoptosis were demonstrated in acute IRI exogenous. Furthermore, with the same model, it was indicated that YTHDF2 protein negative regulated TUG1 RNA via direction interaction. Since then, YTHDF2 was proved as a potential protector of renal IRI through restraining of TUG1. In further speculation, induction of YTHDF2 in IRI will possibly become a possible strategy to combat the pathological process post renal transplantation or other clinical conditions.
研究领域:
分子生物学
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肾脏病学
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医学
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PubMed
高影响因子
eLife
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2025
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IF 0
Chong Zhang,Zuoyan Zhang,Yueyi Wu,Yuchen Wu,Jing Cheng,Kaizhi Luo,Zhidi Li,Manman Zhang,Jian Wang,Xuesen Zhang,Yangling Li
Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer, and the prognosis is poor due to distant metastasis. Thus, there is an urgent need to discover novel therapeutic targets and strategies to overcome metastasis. A series of in vitro and in vivo phenotype experiments were performed to investigate the role of phosphodiesterase 1A (PDE1A) in NSCLC. The RNA binding protein immunoprecipitation (RIP) assay, messenger RNA (mRNA) stability assay, and LC-MS/MS were performed to investigate the molecular mechanisms of PDE1A in NSCLC progression. PDE1A has been shown to promote metastasis and epithelial-mesenchymal transition (EMT) progression of NSCLC. In addition, NSCLC cells overexpressing PDE1A promoted angiogenesis by regulating exosome release. IL-6/JAK/STAT3 signaling pathway was highly enriched in PDE1A-coexpressed genes, and PDE1A promoted NSCLC metastasis by activating the STAT3 pathway. GO enrichment analysis of PDE1A-interacting genes showed that PDE1A might interact with YTHDF2 and participate in m6A-containing RNA binding. The binding between PDE1A and YTHDF2 was verified, and PDE1A regulated the STAT3 pathway by interacting with YTHDF2. The mechanism of the YTHDF2/PDE1A complex in regulating the STAT3 pathway was predicted by overlapping YTHDF2-interacting RNAs and genes coexpressed with YTHDF2 and STAT3. The interactions between YTHDF2 and target mRNAs were predicted, and there were three predicted targets of YTHDF2 with high scores: NRF2, SOCS2, and MET. Indeed, PDE1A interacted with YTHDF2, destabilized SOCS2, and activated the STAT3 pathway. Mechanistic data uncover a novel PDE1A/YTHDF2/STAT3 axis driving NSCLC metastasis and suggest potential therapeutic strategies for metastatic disease.
研究领域:
癌症生物学
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分子生物学
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细胞生物学
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生物化学
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信号转导
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RNA生物学
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肿瘤学
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PubMed
AMERICAN JOURNAL OF PATHOLOGY
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2024
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IF 4.7
N.I.N.G. HAN,N.A. YU,L.I. YU
Diabetic retinopathy (DR) is the major ocular complication of diabetes mellitus caused by chronic hyperglycemia, which leads to incurable blindness. Currently, the effectiveness of therapeutic interventions is limited. This study aimed to investigate the function of piezo-type mechanosensitive ion channel component 1 (PIEZO1) and its potential regulatory mechanism in DR progression. The results showed that PIEZO1 expression was upregulated in the retinal tissues of streptozotocin-induced diabetic mice and high glucose (HG)-triggered Müller cells. Functionally, the knockdown of PIEZO1 improves the abnormal retinal function of diabetic mice and impedes inflammatory cytokine secretion and gliosis of Müller cells under HG conditions. Mechanistic investigations utilizing RIP-qPCR, MeRIP-qPCR, and luciferase reporter assays demonstrated that PIEZO1 was a downstream target of methyltransferase-like 3 (METTL3). These studies revealed that METTL3-mediated N6-methyladenosine (m6A) modification within the coding sequence of PIEZO1 mRNA significantly shortened its half-life. In HG-stimulated cells, there was a negative regulatory relationship between PIEZO1 and YTH domain family 2 (YTHDF2), a recognized m6A reader. The loss of YTHDF2 resulted in an extended half-life of PIEZO1 in cells with overexpression of METTL3, indicating that the effect of METTL3 on the mRNA stability of PIEZO1 was dependent on YTHDF2. Taken together, this study demonstrated the protective role of the PIEZO1 silencing in DR development, and the degradation of PIEZO1 mRNA is accelerated by METTL3/YTHDF2-mediated m6A modification.
研究领域:
分子生物学
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细胞生物学
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神经科学
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糖尿病研究
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眼科学
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PubMed
高影响因子
ACTA BIOCHIMICA ET BIOPHYSICA SINICA
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2025
·Vol. 57
·期 9
·1529
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IF 3.4
Wenjuan Xia,Xin Wang,Jincheng Li,Ming Zhang,Jiafeng Lu,Hong Li,Quanze He,Qingxia Meng,Boxian Huang
Ovarian aging is a natural process characterized by a decline in both the quantity and quality of oocytes, which subsequently leads to diminished fertility, particularly in women over the age of 35. Given the societal trend toward postponing childbirth, it is imperative to understand the molecular mechanisms that underpin ovarian aging to address infertility issues. Melatonin (MT) is recognized for its therapeutic potential in mitigating ovarian aging; however, the specific epigenetic mechanisms involved, particularly concerning m 6 A methylation, remain inadequately defined. Our investigation demonstrates that MT mitigates ovarian aging in murine models, significantly decreasing m 6 A methylation levels. In vitro analyses of ovarian granulosa (KGN) cells reveals a marked increase in YTHDF2 expression, with differentially methylated genes being notably enriched in the polyubiquitination pathway. Further examination shows that YTHDF2 enhances the expression of the E3 ligase UBE3C by modulating the m 6 A methylation of UBE3C mRNA, thereby reducing the expression of the P53 senescence factor and alleviating the effects of ovarian aging.
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Cell and Bioscience
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2021
·Vol. 11
·期 1
·1-16
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IF 7.133
Xu Hongfei,Wang Zhen,Chen Miao,Zhao Wenting,Tao Tingting,Ma Liang,Ni Yiming,Li Weidong
Background Pathological cardiac hypertrophy is a major contributor of heart failure (HF), which seriously threatens human’s health world widely. Deregulation of m6A RNA methylation, and m6A methyltransferases and de-methyltransferases have been demonstrated to act essential roles in cardiac hypertrophy and HF. Here, we studied the potential roles and its underlying mechanisms of m6A Reader YTHDF proteins in HF. In this study, we constructed HF mouse model by transverse aortic constriction surgery. Primary cardiomyocytes were isolated and stimulated with isoproterenol (ISO) or phenylephrine (PHE) to induce myocardial hypertrophy.Results Through single-cell RNA-seq analysis, immunofluorescent staining, HE staining, Western blotting, and real time-PCR detections, we found that YTHDF2 mRNA and protein level, but not YTHDF1 or YTHDF3, was significantly increased during HF development. YTHDF2 overexpression could efficiently alleviate cardiac hypertrophy. Furthermore, through immunoprecipitation accompanied with mass spectrometry analysis, Gene Ontology (GO) analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, we found that ISO stimulation did not evidently affect YTHDF2-interacting proteins. However, ISO or PHE stimulation significantly increased YTHDF2 protein interacting with Myh7 (beta-myosin heavy chain) mRNA, an important cardiac hypertrophy marker, in an m6A-dependent manner. Knockdown of Myh7 or deletion of the YTH domain of YTHDF2 reversed the protective effects of YTHDF2 on cardiac hypertrophy. Finally, we found that ISO or PHE stimulation promoted YTHDF2 protein expression through enhancing Ythdf2 mRNA stability in an m6A-dependent manner in cardiomyocytes.Conclusion sOverall, our results indicate that the m6A Reader YTHDF2 suppresses cardiac hypertrophy via Myh7 mRNA decoy in an m6A-dependent manner. This study highlights the functional importance of YTHDF2-dependent cardiac m6A mRNA regulation during cardiac hypertrophy, and provides a novel mechanistic insight into the therapeutic mechanisms of YTHDF2.
研究领域:
心脏病学
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分子生物学
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表观遗传学
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RNA生物学
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PubMed
高影响因子
CANCER LETTERS
·
2023
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IF 9.7
Jiaoshun Chen,Haoxiang Zhang,Chaoyang Xiu,Chenggang Gao,Shihong Wu,Jianwei Bai,Qiang Shen,Tao Yin
In eukaryotes, N 6 -methyladenosine (m6A) is the most prevalent epigenetic alteration. Methyltransferase-like 3 (METTL3) is a key player in the control of m6A, although its function in pancreatic cancer is incompletely understood. In this study, we examined the role that METTL3 plays in pancreatic cancer cell proliferation and stemness. We discovered that in pancreatic cancer cells, METTL3-mediated m6A alterations regulate ID2 as a downstream target. The stability of ID2 mRNA was decreased and m6A modification was effectively eliminated by METTL3 knockdown in pancreatic cancer cells. We also demonstrate that m6a-YTHDF2 is necessary for the METTL3-mediated stabilization of ID2 mRNA. Additionally, we show that ID2 controls the stemness molecules NANOG and SOX2 via the PI3K-AKT pathway to support pancreatic cancer growth and stemness maintenance. Our data suggest that METTL3 may post-transcriptionally upregulate ID2 expression in an m6A-YTHDF2-dependent manner to further promote the stabilization of ID2 mRNA, which may be a new target for pancreatic cancer treatment.
研究领域:
癌症生物学
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分子生物学
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表观遗传学
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PubMed
高影响因子
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
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2026
·Vol. 45
·期 1
·118
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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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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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PubMed
高影响因子
ONCOGENE
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2024
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IF 6.9
Du Kaixuan,Luo Yongbo,Zhang Lei,Zeng Youmiao,Dai Yiheng,Ren Mengda,Pan Wenbang,Liu Yuanhao,Tian Fengyan,Zhou Lijie,Gu Chaohui
Cuproptosis, a cell death process caused by copper ions, is mediated by protein lipidation related to lipoic acid metabolism. There is a close connection between cuproptosis and the progression and prognosis of various tumors. Here, we identified lipoyltransferase 1 (LIPT1), a key gene related to cuproptosis, was downregulated in bladder cancer (BLCA) and was associated with unfavorable patient prognosis. Restoring the LIPT1 expression in BLCA cells suppressed the proliferation and promoted cuproptosis. Moreover, the consequences of RNA sequencing and Bodipy staining showed that the metabolic pathway mediated by LIPT1 inhibited the accumulation of lipid droplets in cells, disrupted endoplasmic reticulum (ER) homeostasis, and promoted cell apoptosis. Additionally, overexpression of LIPT1 not only repressed the proliferation rate of BLCA cells in vitro but also in vivo. Mechanistically, YTH N6-Methyladenosine RNA Binding Protein F2 (YTHDF2) promoted the degradation of LIPT1 mRNA in a m 6 A-dependent manner. In summary, these conclusions reveal that LIPT1 promotes cuprotosis and ER stress to inhibit the progression of BLCA, indicating that LIPT1 will provide a powerful treatment direction and drug target for treating BLCA.
研究领域:
癌症生物学
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分子生物学
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细胞生物学
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生物化学
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PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2025
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IF 4.7
Xinyi Li,Hui Song,Yiwen Yuan,Na Jiang,Wei Duan,Tianzhao Xu,Chang Liu,Xinghui Liu
Cardiovascular diseases have long posed a significant threat to public health. Among them, myocarditis is a major category of cardiovascular disorders that is characterized by high mortality during its acute phase, necessitating urgent medical attention. This study aims to explore the therapeutic effects and underlying mechanisms of Spi1-mediated gene regulation in chemotherapy induced cardiomyopathy. To validate our findings, we employed bioinformatics analysis methods and established myocarditis models using the chemotherapeutic drug doxorubicin in both cellular and animal models. Our results demonstrated that the inhibition of Spi1 significantly suppressed inflammatory factor expression in H9C2 rat cardiomyocytes. Furthermore, in C57BL/6 mouse model, Spi1 inhibition was shown to improve cardiac function and alleviate both myocardial inflammation and fibrosis in mice with doxorubicin-induced myocarditis. Mechanistic investigations revealed that Spi1 suppression altered the expression of genes associated with immune response, cell differentiation and proliferation. Notably, Spi1 modulates the expression of YTHDF2, thereby influencing the PI3K/AKT/mTOR signaling pathway and subsequently regulating the inflammatory response. Collectively, these findings suggest that Spi1 plays a pivotal role in doxorubicin-induced myocarditis by mitigating inflammatory responses and myocardial injury through the regulation of YTHDF2 and the PI3K/AKT/mTOR signaling pathways, offering a promising therapeutic target for the treatment of myocarditis.
研究领域:
心血管研究
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分子生物学
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药理学
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肿瘤学
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信号转导
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PubMed
高影响因子
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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高影响因子
MOLECULAR AND CELLULAR BIOCHEMISTRY
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2026
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IF 4.7
Li Qianyu,Wang Huiyue,Chen Nan,Liu Xue,Li Yongle,Chen Lei,Gan Lu,Luan Yong
Postoperative cognitive dysfunction (POCD) is a common complication following surgery, particularly in elderly patients, and is closely linked to neuroinflammation driven by microglial activation. While dexmedetomidine (Dex) has shown neuroprotective potential in clinical settings, the molecular mechanisms underlying its beneficial effects—particularly in relation to RNA epigenetic regulation and metabolic reprogramming in microglia—remain poorly understood. Here, we uncover a novel mechanism by which Dex alleviates POCD through modulation of N6-methyladenosine (m 6 A)–dependent post-transcriptional regulation of pyruvate kinase M2 (PKM2). We demonstrate that Dex enhances the expression of the m 6 A reader protein YTHDF2, which recognizes m 6 A-modified PKM2 mRNA and promotes its degradation, thereby suppressing microglial glycolysis and neuroinflammation. In both in vitro and in vivo models, Dex treatment reversed surgery- or LPS-induced cognitive deficits, reduced pro-inflammatory cytokine production, and normalized metabolic shifts in microglia—effects that were dependent on YTHDF2-mediated PKM2 downregulation. Our findings uncovered a novel epigenetic mechanism by which Dex exerts neuroprotection and highlight YTHDF2-mediated PKM2 regulation as a potential therapeutic target for POCD.
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高影响因子
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