International Journal of Biological Sciences最新文献

{"title":"Neutrophil Recruitment via Hepatocyte IL-1α Drives NETs-Mediated AIM2 Hepatocyte Apoptosis in Alcohol-associated steatohepatitis.","authors":"Yuan Zhang, Xueteng Meng, Yan Ding, Jinmao Yu, Yunyun Wan, Zhiying Yang, Zheyu Han, Qian Zhu, Rui Feng, Jun Li, Cheng Huang, Taotao Ma","doi":"10.7150/ijbs.121255","DOIUrl":"https://doi.org/10.7150/ijbs.121255","url":null,"abstract":"<p><p>Alcohol-associated steatohepatitis (ASH) represents a critical stage in the progression of Alcohol-associated liver disease (ALD), characterized by extensive hepatocellular steatosis, immune cell infiltration, and a poor therapeutic response. Neutrophils play a central role in the inflammatory landscape of ASH, with their hepatic accumulation strongly correlating with disease severity. Although studies have demonstrated that neutrophil depletion attenuates liver injury, the precise mechanisms underlying neutrophil-mediated hepatocellular damage remain poorly defined. Neutrophil extracellular traps (NETs), web-like DNA structures released during NETosis, have emerged as key effectors in sterile inflammation and may exacerbate liver injury beyond their antimicrobial functions. In this study, we employed the Binge-Gao mouse model to explore the involvement of NETs in ethanol-induced liver injury. Our findings revealed that ethanol exposure led to significant hepatic neutrophil infiltration and NET formation. Stressed hepatocytes released damage-associated molecular patterns (DAMPs), particularly interleukin-1 alpha (IL-1α), which activated Toll-like receptor 9 (TLR9) on neutrophils, thereby enhancing NET generation. NET components subsequently activated the cytosolic DNA sensor AIM2 (absent in melanoma 2) in hepatocytes, triggering apoptosis. This cascade illustrates a previously unrecognized immune axis linking ethanol-damaged hepatocytes, NET-producing neutrophils, and DNA-sensing death pathways.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 13","pages":"5762-5781"},"PeriodicalIF":10.0,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12509912/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145280004","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRAF2 Promotes Liver Fibrosis via Regulation of the HIF-1α/GLUT1-Mediated Glycolysis in Hepatic Stellate Cells.","authors":"Yina Zhang, Siduo Xu, Jiajia Shao, Yining Lu, Lingzhu Zhao, Xue Liang, Jiping Yao, Minwei Li, Yanning Liu, Min Zheng","doi":"10.7150/ijbs.99682","DOIUrl":"https://doi.org/10.7150/ijbs.99682","url":null,"abstract":"<p><p>Tumor necrosis factor receptor-associated factor 2 (TRAF2) is an intracellular aptamer protein with E3 ligase activity and has been reported to be involved in the pathogenesis of hepatitis and liver cancer. However, the specific mechanism for liver fibrosis mediated by TRAF2 is a still-unresolved issue. In this study, we uncovered high TRAF2 expression in activated hepatic stellate cells (HSCs) and fibrotic livers of both human and two mouse liver fibrosis models. TRAF2 in HSCs correlated positively with liver fibrosis and could directly prompt HSC activation, as evidenced by <i>in vitro</i> gain-of-function and loss-of-function models. <i>In vivo</i>, HSC-specific knockout of TRAF2 could alleviate liver injury and fibrosis in mice. Mechanistically, we demonstrated that TRAF2 in HSCs promoted the increase of hypoxia-inducible factor-1α (HIF-1α) levels by inhibiting von Hippel-Lindau (pVHL)-mediated HIF-1α degradation and inducing HIF-1α translation via activating mTORC1 pathway. Elevated HIF-1α expression predisposed to a rise in its transcriptional target glucose transporter 1 (GLUT1) expression and glycolytic activity in HSCs, eventually developing liver fibrosis. Thus, TRAF2 exerts a significant impact upon activating HSCs and may become a candidate molecule for anti-liver fibrosis therapy.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 13","pages":"5645-5665"},"PeriodicalIF":10.0,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12509682/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145280103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GPX1 expression promotes stemness and aggressiveness in myxoid liposarcomas.","authors":"Carmen Huergo, Juan Tornín, Oscar Estupiñán, Paula Díez, Borja Gallego, Jun Gao, Marybeth Creskey, Gauri Muradia, M Victoria González, Dzohara Murillo, Verónica Rey, Lucia Martínez-Cruzado, Sofía T Menéndez, Mar Rodríguez-Santamaría, Verónica Blanco, Isabel Quirós, Rosa M Sáinz, Michael Rosu-Myles, Jessie R Lavoie, René Rodríguez","doi":"10.7150/ijbs.105217","DOIUrl":"https://doi.org/10.7150/ijbs.105217","url":null,"abstract":"<p><p>The sarcomagenic process initiates when mesenchymal stromal/stem cells (MSCs) or MSC-derived cells undergo tumoral transformation. Besides, sarcoma evolution is partly driven by the emergence of subpopulations of cancer stem cells (CSCs), which are strongly associated with more aggressive behaviors. Therefore, the characterization of CSC will contribute to the development of more effective therapies against sarcomas. Here, we compared the proteomes of adherent and CSC-enriched tumorsphere cultures in a tumor progression model of myxoid liposarcoma composed of three cell lines showing increasing aggressiveness after being serially transplanted in mice. We found that the expression of the antioxidant enzyme GPX1 increased constantly during the CSC-enrichment process in this model and other sarcoma lines. Depletion of GPX1 resulted in decreased proliferation and tumorsphere-forming potential and dramatically reduced tumor-formation ability <i>in vivo</i>. Conversely, GPX1 overexpression resulted in increased proliferation and tumorsphere formation. According to these findings, GPX1 expression in sarcoma patients was associated with aggressive phenotypes and worse prognosis. A proteomic analysis revealed that these effects were associated with the downregulation of interferon-mediated response, the IL6/JAK/STAT3 axis and the NFκB-mediated signaling in GPX1-silenced cells. Overall, these results suggest that GPX1 expression may serve as a functional marker of aggressive CSC subpopulations in sarcomas.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 13","pages":"5609-5627"},"PeriodicalIF":10.0,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12509692/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145279704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"O-GlcNAcylated Hsp47 as a predictive biomarker in colorectal cancer: Kaempferol targets OGT-collagen axis for therapeutic intervention.","authors":"Chishun Zhou, Jing Zheng, Zizheng Li, Yu Li, Xin Jin, Yukai Huang, Yuefang Lin, Xinyue Wen, Yin Wang, Jiarun Lin, Ying Wang, Wei Wang, Zhongqiu Liu, Linlin Lu","doi":"10.7150/ijbs.116513","DOIUrl":"10.7150/ijbs.116513","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is a highly lethal gastrointestinal malignancy, and its progression is closely related to abnormal protein O-GlcNAcylation modifications, especially during extracellular matrix (ECM) remodeling. Kaempferol is a natural flavonoid with medicinal value that can inhibit CRC progression through various pathways. However, it is unclear whether its mechanism of action involves O-GlcNAc-driven metabolic reprogramming. This study confirmed that kaempferol can significantly inhibit CRC growth both <i>in vitro</i> and <i>in vivo</i> and effectively reduce the overall protein O-GlcNAcylation levels. Mechanistic studies indicate that kaempferol reduces the levels of substrate uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) and downregulates the expression of O-GlcNAc transferase (OGT), thereby decreasing the O-GlcNAcylation levels of proteins. This leads to a reduction in the O-GlcNAc modification of downstream heat shock protein 47 (Hsp47), which in turn affects the expression and intracellular localization of Hsp47, ultimately inhibiting the maturation and secretion of type I collagen, thereby blocking CRC progression. This study reveals a new mechanism by which kaempferol inhibits CRC by targeting the O-GlcNAcylation pathway. The study results suggest that O-GlcNAc-modified Hsp47 could serve as a potential therapeutic target for CRC and propose a treatment strategy guided by flavonoid biomarkers based on the inhibition of the OGT-collagen axis.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 12","pages":"5586-5608"},"PeriodicalIF":10.0,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12435574/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FAM134B in Cellular Homeostasis: Bridging Endoplasmic Reticulum-Phagy to Human Diseases.","authors":"Ning Chen, Jia-Qi Yang, Sen Tong, Lu Xu, Ning Dong, Yao Wu, Yu-Xuan Li, Ren-Qi Yao, Yong-Ming Yao","doi":"10.7150/ijbs.113890","DOIUrl":"10.7150/ijbs.113890","url":null,"abstract":"<p><p>FAM134B, originally characterized as an oncogene in esophageal squamous carcinoma, has also been implicated in the pathogenesis of hereditary sensory and autonomic neuropathy type IIB (HSAN2B). It is recognized as the inaugural endoplasmic reticulum (ER)-phagy receptor in mammals containing an LC3-interacting region, which facilitates its interaction with LC3 and GABARAP proteins in the autophagosome. ER-phagy, a critical process involved in ER quality control, selectively degrades superfluous or damaged ER fragments in lysosomes, thereby maintaining ER and protein homeostasis. This review offers an in-depth analysis of FAM134B's structure, function, and regulation, emphasizing its role in infectious diseases, neuropathies, cancer, metabolic disorders, degenerative conditions, and cardiovascular diseases. The evidence presented highlights the need for further research on FAM134B as a potential therapeutic target in human diseases.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 12","pages":"5514-5530"},"PeriodicalIF":10.0,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12435581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DLGAP5 Promotes Acute Liver Injury via Hepatocyte Pyroptosis-Driven Macrophage Metabolic Reprogramming and M1 Polarization.","authors":"Xianzhi Liu, Zhiyuan Chen, Jun Lin, Yifan Lian, Wenxuan Gan, Huajie Liu, Xingxiang Huang, Jiaxin Mei, Tianrong Ma, Zhi Lu, Wei Zeng, Yihang Gong, Shuai Chen, Weiling He","doi":"10.7150/ijbs.118024","DOIUrl":"10.7150/ijbs.118024","url":null,"abstract":"<p><p>Pyroptosis is a novel programmed cell death that exists in inflammatory diseases and methyltransferase-like 3 (METTL3) is a core N6-methyladenosine (m6A) modified methyltransferase that has been shown to regulate cell fate. However, the role of pyroptosis in acute liver injury (ALI) is still unknown and whether it is regulated by m6A modification needs to be elucidated. Here, <i>Mettl3</i> mutant and <i>Nlrp3</i> knockout mouse were constructed, CCl₄- and TAA-induced ALI models were established and primary cells were isolated, and cell pyroptosis and m6A modification were evaluated. We found that hepatocyte pyroptosis is a key characteristic of ALI, and METTL3-mediated m6A modification was upregulated in hepatocytes during ALI. Inhibition of METTL3-mediated m6A modification alleviated hepatocyte pyroptosis and ALI. Through MeRIP-seq analysis and verification, <i>Dlgap5</i> was determined as the target of METTL3-mediated m6A modification, which was regulated in an IGF2BP2-dependent manner. Mechanistically, METTL3 can bind to DLGAP5, and then DLGAP5 promoted pyroptosis through NF-κB-dependent NLRP3 inflammasome activation and direct potentiation of inflammasome structure formation and assembly. <i>Mettl3</i> mutation or AT9283-mediated DLGAP5 inhibition alleviated pyroptosis and ALI. The effects of hepatocyte pyroptosis on cell interaction were then explored and we revealed that NLRP3 inflammasome and interleukin releasing by the GSDMD-N-dependent membrane pores from pyroptotic hepatocytes activated macrophage metabolic reprogramming and M1 polarization, further exacerbating ALI. <i>Nlrp3</i> deficiency alleviated ALI by suppressing hepatocyte pyroptosis and blocking communication between macrophages and hepatocytes. Our findings indicate the potential mechanisms of ALI from an intercellular communication perspective, and targeted-inhibition of DLGAP5 and -blockade of hepatocyte-macrophage interaction provide promising strategies for ALI treatment.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 12","pages":"5563-5585"},"PeriodicalIF":10.0,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12435577/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activated B cells modulate the maturation of MDSCs via CD36-dependent MHC-II transfer to orchestrate CD4⁺ Th1-dominant antitumor immunity after cryo-thermal therapy.","authors":"Zelu Zhang, Shicheng Wang, Junjun Wang, Yichen Yao, Yuankai Hao, Yue Lou, Ping Liu, Lisa X Xu","doi":"10.7150/ijbs.115232","DOIUrl":"10.7150/ijbs.115232","url":null,"abstract":"<p><p>Immunotherapy, particularly immune checkpoint inhibitors (ICIs), has shown great success in treating various cancer types. However, the therapeutic efficacy of ICIs remains unsatisfactory because of the immunosuppressive tumor microenvironment. Cryo-thermal therapy (CTT), a novel tumor ablation approach developed by our laboratory, transforms the tumor immunosuppressive environment into an immunostimulatory environment by activating both innate and adaptive immunity. CTT promotes the differentiation of myeloid-derived suppressor cells (MDSCs) into mature dendritic cells and macrophages, activates antigen-presenting cells and natural killer (NK) cells, and induces Th1-dominant CD4⁺ T-cell-mediated antitumor immunity in numerous highly metastatic tumor models. However, the role of B cells in CTT-induced antitumor immunity remains unclear despite their critical function in adaptive immunity. Here, <i>in vivo</i> B-cell depletion with anti-CD20 monoclonal antibodies in multiple tumor models revealed that B cells play a crucial role in suppressing tumor metastasis and extending survival. More interestingly, CTT-activated B cells reprogram MDSCs to a mature phenotype through CD36-dependent major histocompatibility complex class II (MHC-II) transfer, resulting in enhanced Th1-dominant CD4⁺ T-cell responses and CD8⁺ T-cell cytotoxicity. These findings reveal a novel mechanism of B-cell-mediated modulation of the tumor microenvironment and provide insights into enhancing the efficacy of immunotherapy strategies.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 12","pages":"5547-5562"},"PeriodicalIF":10.0,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12435582/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Overcoming Ferroptosis-Induced Exhaustion of NK Cells through Inhibition of the ATF3-Mediated Integrated Stress Response in Ovarian Cancer.","authors":"Tian Chen, Shulin Zhou, Yashuang Zhang, Huangyang Meng, Huixian Miao, Mingming Feng, Yi Jiang, Yicong Wan, Lin Zhang, Wenjun Cheng","doi":"10.7150/ijbs.112615","DOIUrl":"10.7150/ijbs.112615","url":null,"abstract":"<p><p>The absence of cytotoxic effector cells, such as CD8⁺ T cells or Natural Killer (NK) cells, within tumors establishes an immune-cold tumor microenvironment (TME), contributing to poor immunotherapy responses, as observed in ovarian cancer. Although prior studies implicate NK cell exhaustion within the TME related to ferroptosis, the underlying mechanisms remain undefined. This study demonstrates that upon infiltrating the ovarian cancer TME, NK cells activate an integrated stress response (ISR) centered on ATF3. This ATF3-mediated ISR suppresses NRF2 expression, compromising their ability to counteract oxidative stress and ultimately triggering ferroptosis. Critically, we show that co-treatment with the ISR inhibitor ISRIB and NK cells not only prevents NK cell ferroptosis but also synergizes to enhance tumor cell killing. These findings provide novel insights into the mechanisms driving NK cell exhaustion within the TME and identify ISR inhibition as a promising therapeutic target and intervention strategy for developing NK cell-based therapies against ovarian cancer.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 12","pages":"5531-5546"},"PeriodicalIF":10.0,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12435575/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PGK1 Regulates Oxidative Stress in Gestational Diabetes Mellitus through the Estradiol-Keap1-Nrf2 Pathway.","authors":"You Peng, Hengli Zhao, Jun Chen, Chi Chiu Wang, Tao Zhang, Tsz Ching Yeung, Haotong Ouyang, Jiayu Zhu, Xiangli Chen, Meng Li, Haoyue Hu, Mei Zhong","doi":"10.7150/ijbs.113728","DOIUrl":"10.7150/ijbs.113728","url":null,"abstract":"<p><p>Gestational diabetes mellitus (GDM), the most common pregnancy-related metabolic disorder, is characterized by exacerbated oxidative stress (OS). The inhibition of phosphoglycerate kinase 1 (PGK1), the first ATP-generating enzyme in the glycolytic pathway, activates Keap1-Nrf2 antioxidant pathways and reduces OS. However, the detailed roles of PGK1 in GDM remain unexplored. Disruption of pro-oxidant/antioxidant homeostasis was observed in the placentas of GDM patients. PGK1 was significantly upregulated in both human GDM placentas and streptozotocin (STZ)-induced model mice. Pharmacological inhibition of PGK1 <i>in vivo</i> ameliorated placental dysfunction, attenuated excessive ROS production, and improved pregnancy outcomes. Lentivirus-mediated PGK1 knockdown in HTR8/SVneo trophoblasts increased Nrf2-dependent antioxidant protein expression while reducing ROS generation. Mechanistically, PGK1 inhibition elevated estradiol levels, facilitating Keap1 dimerization, and this dimerization destabilized the Keap1-Nrf2 complex, enabling Nrf2 accumulation and antioxidant activation. Exogenous estradiol supplementation recapitulated the effect of inhibiting PGK1 by enhancing Keap1 dimer formation, effectively mitigating placental OS and adverse pregnancy phenotypes in GDM models. This study elucidates the critical role of PGK1 in restoring redox homeostasis through the estradiol-Keap1-Nrf2 axis in the pathogenesis of GDM. PGK1/estradiol crosstalk represents a druggable target, and pharmacological PGK1 inhibition has translational potential for mitigating oxidative stress-related pregnancy complications.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 12","pages":"5496-5513"},"PeriodicalIF":10.0,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12435576/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WTAP Maintains Alternative Activation of Macrophages by Promoting IDH1-Mediated α-ketoglutarate Production.","authors":"Qianqian Xu, Jing Zhang, Yuan Zou, Longmin Chen, Fei Sun, Xi Luo, Ting Wang, Yang Li, Shu Zhang, Fei Xiong, Qilin Yu, Ping Yang, Quan Gong, Shi-Wei Liu, Cong-Yi Wang","doi":"10.7150/ijbs.115672","DOIUrl":"10.7150/ijbs.115672","url":null,"abstract":"<p><p><b>Background</b>: <i>N</i> ⁶-methyladenosine (m⁶A) modification plays a crucial role in various physiological processes by regulating mRNA biology. However, the exact impact of m⁶A modification on macrophages in adipose tissues under obese settings remains to be further elucidated. <b>Methods</b>: We established macrophage-specific <i>Wtap</i>-deficient mice to explore the effects of <i>Wtap</i> on obesity and metabolic disorders induced by high-fat diet (HFD) in mice. The molecular targets were explored by MeRIP-qPCR, and the metabolomic assays were performed to detect the alteration of relevant metabolites. <b>Results</b>: Wilms tumor 1-associated protein (WTAP), one of the m⁶A \"writers\", was downregulated in adipose tissue macrophages (ATMs) from obese individuals and negatively correlated with clinical metabolic traits. Depletion of <i>Wtap</i> in mouse macrophages exacerbated the metabolic consequences of high-fat diet (HFD) induced obesity. Additionally, energy expenditure and adipose beiging were considerably lower in <i>Wtap</i>-deficient mice in response to cold exposure. Mechanistic study revealed that WTAP-mediated m⁶A modification of isocitrate dehydrogenase 1 (<i>Idh1</i>) transcripts enhanced its stability and translation in macrophages leading to α-ketoglutarate (α-KG) production. Alpha-KG further supported alternative activation of macrophages by metabolic reprogramming. <b>Conclusions</b>: Our data support that <i>Wtap</i> modulates HFD-induced macrophages through interfering with the IDH1-α-KG axis, and highlight the importance of WTAP-mediated m⁶A modification in maintaining alternative macrophage activation, proposing potential targets for the regulation of obesity and related metabolic diseases.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 12","pages":"5428-5443"},"PeriodicalIF":10.0,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12435483/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}