Acta Pharmacologica Sinica最新文献

{"title":"TSG attenuated NAFLD and facilitated weight loss in HFD-fed mice via activating the RUNX1/FGF21 signaling axis.","authors":"Zhen-Lin Huang, Shao-Bo Zhang, Shang-Fu Xu, Xin-Nan Gu, Ze-Qi Wu, Yue Zhang, Jian Li, Li-Li Ji","doi":"10.1038/s41401-025-01568-w","DOIUrl":"10.1038/s41401-025-01568-w","url":null,"abstract":"<p><p>Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease characterized by steatosis in hepatocytes and is now becoming the major cause of liver-related mortality. Fibroblast growth factor 21 (FGF21) is an endocrine hormone mainly secreted by the liver, which can bind to its receptor (FGFR) and co-receptor beta klotho (KLB) to form a receptor complex, exerting its lipid-lowering function. 2,3,5,4'-Tetrahydroxy-stilbene-2-O-β-D-glucoside (TSG), a natural compound isolated from Polygonum multiflorum Thunb, has shown excellent activity in lowering lipid content and efficacy in improving NAFLD. In this study we investigated whether FGF21 was implicated in the therapeutic effect of TSG in NAFLD mice. NAFLD was induced in mice by feeding with a high-fat diet (HFD) for 12 weeks, and treated with TSG (20, 40 mg·kg^-1·d^-1, i.g.) during the last 4 weeks. We showed that TSG treatment significantly alleviated NAFLD in HFD-fed mice evidenced by reduced hepatic triglyceride (TG) and non-esterified fatty acids (NEFA), diminished lipid droplets and decreased NAFLD activity score (NAS) in liver tissues. We demonstrated that TSG treatment significantly increased the mRNA and protein levels of FGF21 in vitro and in vivo, and reduced lipid accumulation in both the liver and adipose tissues. Transcriptomics analysis revealed that TSG treatment significantly increased the nuclear translocation of a transcription factor RUNX1. Knockdown of Runx1 in HFD-fed mice eliminated the efficacy of TSG in alleviating NAFLD, reducing hepatic lipid accumulation and regulating FGF21 signaling pathway in liver and adipose tissues. In conclusion, TSG alleviates NAFLD by enhancing the FGF21-mediated lipid metabolism in a RUNX1-dependent manner.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2723-2733"},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12460612/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immune cells in systemic lupus erythematosus: biology and traditional Chinese medicine therapy.","authors":"Ya-Nan Liang, Luo Chen, Qing-Yu Huang, Yu-Ting Song, Yu-Juan Fan, Tong-Qing Chen, Jia-Hui Ni, Dong Wang, Xiao-Yan Shen, Yi-Ming Wang, Yan You","doi":"10.1038/s41401-025-01554-2","DOIUrl":"10.1038/s41401-025-01554-2","url":null,"abstract":"<p><p>Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterized by a progressive breakdown of immune tolerance to self-antigens, resulting in multiple tissue damage and clinical symptoms. Innate and adaptive immune cells including dendritic cells, macrophages, myeloid-derived suppressor cells (MDSCs), T cells and B cells are the key drivers in perpetuating and amplifying of this systemic disease. In this review we offer a comprehensive overview of recent advances in understanding the immune-pathogenesis of SLE with particular emphasis on regulatory immune cells exhibiting immunosuppressive properties, as well as newly identified factors influencing immune cell function and lineage differentiation. Furthermore, we discuss traditional Chinese medicine and natural extracts that have shown therapeutic effects on SLE by modulating immune cell differentiation and function, which may provide insights into their clinical applications.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2587-2596"},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12460875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Revisiting the role of GDF15 in atherosclerosis in mouse and human.","authors":"Mo-Nan Liu, Zheng-Hong Liu, Rui-Xue Leng, Hans Strijdom, Jian-Ping Weng, Suo-Wen Xu","doi":"10.1038/s41401-025-01561-3","DOIUrl":"10.1038/s41401-025-01561-3","url":null,"abstract":"<p><p>Growth differentiation factor 15 (GDF15) is a key regulator of food intake and energy metabolism. GDF15 mimetic drugs for the treatment of metabolic syndrome and obesity are under clinical development. While GDF15 presents a promising target for weight management, its potential cardiovascular actions remain elusive. In this study we investigated the role of GDF15 in macrophage function and atherosclerosis pathogenesis and whether GDF15 acts both as a biomarker and mediator of atherosclerosis severity. ApoE^-/- mice were fed a high-cholesterol diet (HCD, 1.25% cholesterol) for 6, 12 or 18 weeks to establish atherosclerotic models. We showed that serum levels of GDF15 were elevated in ApoE^-/- mice with atheroprogression; increased serum levels of GDF15 were also observed in patients with coronary artery disease. Enlightened by this finding, we established atherosclerotic model in Gdf15^-/- mice by injecting with AAV8-PCSK9^D377Y virus and feeding HCD for 12 or 16 weeks. We showed that global Gdf15 knockout, whether in male or female mice, did not alter plaque size in en face aorta, lesion in aortic sinus, size of necrotic core or plaque composition. In macrophage-derived foam cells isolated from atherosclerotic mice, neither Gdf15 deletion nor the treatment with recombinant GDF15 protein (1, 10, 100 ng/mL) affected lipid deposition or macrophage polarization. To translate this finding into a clinically relevant scenario, we performed Mendelian randomization (MR) analysis, and found no significant causal association between circulating GDF15 levels and the incidence of cardiovascular diseases. Furthermore, MR studies suggest that genetic associations between GDF15 and factors such as BMI, ApoB, LDL and HDL were not significant in plasma data from the UK Biobank and the deCODE cohort. In summary, this study demonstrates that global Gdf15 deficiency does not affect the development of atherosclerosis in male or female mice despite the positive association between circulating GDF15 levels and disease progression in mice and human. Thus, GDF15 in circulation is a potential biomarker, but not a causal mediator, of atherosclerosis. Long-term cardiovascular safety of GDF15-targeted therapies warrants further investigation.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2663-2676"},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12460671/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Harnessing deep statistical potential for biophysical scoring of protein-peptide interactions.","authors":"De-Jun Jiang, Hui-Feng Zhao, Hong-Yan Du, Yu Kang, Pei-Chen Pan, Zhen-Xing Wu, Yun-Dian Zeng, O-Din Zhang, Xiao-Rui Wang, Ji-Ke Wang, Yuan-Sheng Huang, Yi-Hao Zhao, Chang-Yu Hsieh, Dong-Sheng Cao, Hui-Yong Sun, Ting-Jun Hou","doi":"10.1038/s41401-025-01659-8","DOIUrl":"https://doi.org/10.1038/s41401-025-01659-8","url":null,"abstract":"<p><p>Protein-peptide interactions (PpIs) play a critical role in major cellular processes. Recently, a number of machine learning (ML)-based methods have been developed to predict PpIs, but most of them rely heavily on sequence data, limiting their ability to capture the generalized molecular interactions in three-dimensional (3D) space, which is crucial for understanding protein-peptide binding mechanisms and advancing peptide therapeutics. Protein-peptide docking approaches provide a feasible way to generate the 3D models of PpIs, but they often suffer from low-precision scoring functions (SFs). To address this, we developed DeepPpIScore, a novel SF for PpIs that employs unsupervised geometric deep learning coupled with a physics-inspired statistical potential. Trained solely on curated experimental structures without binding affinity data or classification labels, DeepPpIScore exhibits broad generalization across multiple tasks. Our comprehensive evaluations in bound and unbound peptide bioactive conformation prediction, binding affinity prediction, and binding pair identification reveal that DeepPpIScore outperforms or matches state-of-the-art baselines, including popular protein-protein SFs, ML-based methods, and AlphaFold-Multimer 2.3 (AF-M 2.3). Notably, DeepPpIScore achieves superior results in peptide binding mode prediction compared to AF-M 2.3. More importantly, DeepPpIScore offers interpretability in terms of hotspot preferences at protein interfaces, physics-informed noncovalent interactions, and protein-peptide binding energies.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PRL-3: unveiling a new horizon in cancer therapy.","authors":"Zi-Tong Cao, Jia-Luo Mao, Chang-Ying Huang, Han-Lin Wang, Ming-Zhi Wang, Wen-Long Wang, Yu-Bo Zhou, Jia Li","doi":"10.1038/s41401-025-01563-1","DOIUrl":"10.1038/s41401-025-01563-1","url":null,"abstract":"<p><p>PRL-3, a protein tyrosine phosphatase (PTP), has a significant influence on the pathogenesis of various cancers with its overexpression significantly correlating with tumor invasion, metastasis and poor prognosis. It significantly affects tumor cell behavior through its involvement in cell proliferation, migration and metabolic processes. Furthermore, the interaction between PRL-3 and the tumor microenvironment characterized by its adaptability to stress and its role in metabolic reprogramming enhances tumor cell survival and dissemination. Targeted therapies against PRL-3, encompassing small molecule inhibitors and the monoclonal antibody PRL-3-zumab, have shown promise in clinical and preclinical studies, presenting new avenues for cancer treatment. In addition, innovative approaches such as CAAX motif-targeting agents and PRL-3 degradation strategies hold promise for developing more precise and effective interventions. This review explores PRL-3's multifaceted roles across different tumor types and microenvironments, while discussing current and emerging therapeutic strategies aimed at exploiting its oncogenic potential.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2597-2607"},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12460878/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Celastrol inhibits the DPYSL2-JAK/STAT pathway by targeting mito-IDHs mediated mitochondrial metabolism to exhaust breast cancer.","authors":"Qiao-Li Shi, Chen-Ran Feng, Hui-Ying Li, Pei-Li Wang, Peng Chen, Xu Wei, Wen-Hua Kuang, Guan-Jun Li, Shi-Jie Qin, Rui Liu, Rui-Xing Chen, Jun-Zhe Zhang, Ping Song, Yuan Yuan, Ji-Gang Wang, Ling Huang","doi":"10.1038/s41401-025-01548-0","DOIUrl":"10.1038/s41401-025-01548-0","url":null,"abstract":"<p><p>Targeting mitochondrial metabolism represents a novel approach in the discovery and development of anti-tumor drugs. Celastrol (Cel) is a naturally-derived small molecule from Tripterygium wilfordii with significant anticancer activities. In this study, we investigated the anti-tumor mechanisms involving mitochondrial metabolic reprogramming regulated by Cel in breast cancer (BRCA). We showed that Cel potently inhibited the proliferation of triple-negative breast cancer cells (MDA-MB-231) and ER⁺ breast cancer cells (MCF-7) with IC₅₀ values of 2.15 μM and 2.29 μM, respectively. Administration of Cel (5, 2, 2 mg/kg, i.p. for three times after tumor formation) significantly suppressed the tumor growth in syngeneic allograft and CDX breast cancer mouse models. Using activity-based protein profiling (ABPP) technology, we identified mitochondrial isocitrate dehydrogenases (including IDH2 and IDH3A, collectively referred to as mito-IDHs) as direct targets of Cel. We demonstrated that Cel significantly inhibited mito-IDHs mediated mitochondrial metabolism to induce the accumulation of metabolites α-ketoglutaric acid, and that Cel enhanced the interaction between DPYSL2 with IDH3A while promoting the accumulation of DPYSL2 within mitochondria of BRCA cells resulting in inactivation of JAK/STAT pathway and ultimately induced ferroptosis and apoptosis in cancer cells. Collectively, this study elucidates a pharmacological mechanism by which Cel exerts its tumor-inhibiting effects through modulation of mitochondrial metabolism. Furthermore, it provides compelling evidence supporting Cel as a promising candidate for development as a small-molecule inhibitor targeting mitochondrial metabolism.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2765-2778"},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12460889/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"OTUD1 positively regulates microglia neuroinflammation and promotes the pathogenesis of Alzheimer's disease by deubiquitinating C/EBPβ.","authors":"Ling-Yu She, Lu-Yao Li, Hao Tang, Qin Yu, Feng-Yi Gao, Yu-Qing Zeng, Lin-Jie Chen, Li Xiong, Li-Wei Li, Fan Chen, Jin-Feng Sun, Wen-Hua Zheng, Xia Zhao, Guang Liang","doi":"10.1038/s41401-025-01566-y","DOIUrl":"10.1038/s41401-025-01566-y","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide. Microglia-mediated neuroinflammation is closely associated with AD pathogenesis. Abnormal deubiquitinating enzyme (DUB) expression is associated with neuroinflammation. Identification of functional DUBs in microglia may provide novel targets for AD treatment. Here, we found that the levels of DUB, ovarian tumor deubiquitinase 1 (OTUD1), were upregulated in AD model mice and amyloid-beta-induced microglia. OTUD1 knockdown in microglia significantly inhibited neuroinflammation, thereby improving cognitive impairment in AD model mice. Liquid chromatography-tandem mass spectrometry analysis coupled with co-immunoprecipitation revealed the CCAAT/enhancer-binding protein β (C/EBPβ), a key transcription factor regulating microglial inflammation, as an OTUD1-interacting protein. Mechanistically, OTUD1 bound to C/EBPβ and maintained its stability by removing the K48 ubiquitin chain at K253 of C/EBPβ, thereby activating the C/EBPβ-nuclear factor-κB-mediated inflammatory responses in microglia. Overall, our results revealed the roles of the OTUD1-C/EBPβ axis in mediating the microglial inflammatory responses and AD pathology, facilitating the development of new strategies targeting microglial neuroinflammation for AD treatment.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2608-2621"},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12460882/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Norcantharidin promotes M1 macrophage polarization and suppresses colorectal cancer growth.","authors":"Xiao-Man Wei, Si-Cheng Lu, Liu Li, Ying-Jie Gao, Jun-Yi Wang, Song-Yang Xi, Ling-Yu Linda Ye, Wei-Xing Shen, Mian-Hua Wu, Dayue Darrel Duan, Hai-Bo Cheng","doi":"10.1038/s41401-025-01578-8","DOIUrl":"10.1038/s41401-025-01578-8","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is characterized by an immunosuppressive and inflammatory microenvironment, thus responds poorly to therapy. Previous studies show that norcantharidin (NCTD), a demethylated cantharidin (CTD) derived from Mylabris, exerts high efficacy in treating various cancers. In this study we investigated the antitumor effects of NCTD against CRC and the underlying mechanisms. Subcutaneous CRC models were established in balb/c mice using mouse colorectal cancer cell line CT26 and in balb/c nude mice using human colorectal cancer cell line HCT116. The mice were administered NCTD (2 or 4 mg·kg^-1·d^-1, i.p.) for 14 days. We showed that NCTD dose-dependently reduced the tumor growth in both the CRC models. Furthermore, NCTD markedly increased M1 macrophage infiltration in tumor tissue in both the CRC models. NCTD-induced macrophage M1 polarization was confirmed by flow cytometry and qPCR assays in both THP-1 cell-derived and RAW264.7 macrophage models in vitro. We demonstrated that NCTD (20, 40 μM) dose-dependently increased CSF2 secretion from CRC cells and macrophages, and suppressed the JAK2/STAT3 signaling pathway in CRC cells. Concurrently, NCTD (10-40 μM) dose-dependently inhibited CRC cell proliferation, invasion and migration in vitro. In conclusion, this study provides new evidence for the effects of NCTD against CRC and elucidates its antitumor mechanisms through remodeling the inflammatory microenvironment via CSF2-mediated macrophage M1 polarization and inhibiting JAK2/STAT3 phosphorylation in CRC cells.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2820-2834"},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12460879/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GPR40 activation alleviates pulmonary fibrosis by repressing M2 macrophage polarization through the PKD1/CD36/TGF-β1 pathway.","authors":"Hui-Qi Wan, Ling-Feng Xie, Hong-Lin Li, Yan Ma, Qiu-Hui Li, Meng-Qing Dai, Yuan-Dong Fu, Wen-Jun Li, Jin-Pei Zhou, Min-Yi Qian, Xu Shen","doi":"10.1038/s41401-025-01558-y","DOIUrl":"10.1038/s41401-025-01558-y","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterized by complex aetiologies involving the accumulation of inflammatory cells, such as macrophages, in the alveoli. This process is driven by uncontrolled extracellular matrix (ECM) deposition and the development of fibrous connective tissues. Here, we observed that the mRNA expression of Ffar1, the gene encoding G protein-coupled receptor 40 (GPR40), is repressed, while Cd36 is increased in the bronchoalveolar lavage fluid (BALF), which is predominantly composed of alveolar macrophages, of IPF patients. Furthermore, the GPR40 protein was found to be largely adhered to macrophages and was pathologically downregulated in the lungs of bleomycin (BLM)-induced PF model mice (PF mice) compared with those of control mice. Specific knockdown of GPR40 in pulmonary macrophages by adeno-associated virus 9-F4/80-shGPR40 (AAV9-shGPR40) exacerbated the fibrotic phenotype in the PF mice, and activation of GPR40 by its determined agonist compound SC (1,3-dihydroxy-8-methoxy-9H-xanthen-9-one) effectively protected the PF mice from pathological exacerbation. Moreover, Ffar1 or Cd36 gene knockout mouse-based assays were performed to explore the mechanism underlying the regulation of GPR40 activation in pulmonary macrophages with compound SC as a probe. We found that compound SC mitigated pulmonary fibrosis progression by preventing M2 macrophage polarization from exerting profibrotic effects through the GPR40/PKD1/CD36 axis. Our results strongly support the therapeutic potential of targeting intrinsic GPR40 activation in pulmonary macrophages for IPF and highlight the potential of compound SC in treating this disease.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2707-2722"},"PeriodicalIF":8.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12460884/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HDAC3 mediates retinal endothelial cell metabolic reprogramming and angiogenesis.","authors":"Christian D Mitchell, Carol A Morris, Melissa Wild, Ashlynn Cunningham, Piyanan Chuesiang, Aya A Mohammed, Bolni Marius Nagalo, Nancy J Rusch, Abdelrahman Y Fouda, Esraa Shosha","doi":"10.1038/s41401-025-01642-3","DOIUrl":"https://doi.org/10.1038/s41401-025-01642-3","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Pathological retinal neovascularization (NV) contributes to vision loss in diabetic retinopathy (DR) and retinopathy of prematurity, which are the leading causes of blindness in working-age adults and children, respectively. Retinal hypoxia is a key driver of pathological neovascularization that results in uncontrolled vessel sprouting and the formation of immature and leaky blood vessels. Anti-vascular endothelial growth factor and laser therapies are the standard of care to mitigate vision loss, but their limited effectiveness underlies the need to identify new therapeutic targets. The goal of the current study was to define the role of the enzyme histone deacetylase 3 (HDAC3) in the pathogenesis of experimental NV. Pathological neovascularization was induced by subjecting C57BL/6 J mouse pups to oxygen-induced retinopathy (OIR). Retinal tissues were analyzed by Western blotting and immunofluorescent labeling was conducted on mouse retinal flatmounts and human retinal sections from patients with DR. In vitro studies used cultured bovine retinal endothelial cells (REC) subjected to oxygen-glucose deprivation (OGD) followed by reoxygenation (R). Cells were treated with the HDAC3 inhibitor, RGFP966, the mitochondrial fission inhibitor, Mdivi-1 or DMSO as a control. Endpoints included assays of cell migration, untargeted proteomic analysis, Seahorse analysis of glycolysis, and mitochondrial morphology using MitoTracker dye. Using the methods described above, we found that HDAC3 expression was increased in retinal vessels of OIR mice and human DR retinal samples. HDAC3 also was upregulated in REC following OGD/R. Treatment with RGFP966 (2, 8 μM) attenuated OGD/R-induced angiogenesis as determined by cell migration. In confirmation, siRNA-mediated HDAC3 knockdown attenuated REC migration whereas HDAC3 overexpression increased it. OGD/R induced a strong upregulation of the rate-limiting glycolysis enzyme, hexokinase 2 (HK2), as determined by untargeted proteomic analysis, which correlated with increased glycolysis and mitochondrial fission. Treatment with RGFP966 or Mdivi-1 (5 μM), blocked HK2 upregulation, suppressed glycolytic flux, and reduced mitochondrial fission. Our findings indicate that HDAC3 plays a crucial role in pathological neovascularization by driving endothelial cell metabolic reprogramming toward glycolysis via the induction of mitochondrial fission and HK2 signaling. Targeting HDAC3 or its downstream metabolic pathways may offer a promising therapeutic strategy for mitigating pathological NV. Retinal endothelial cells (REC) respond to oxygen glucose deprivation/reperfusion (OGD/R) injury by increasing the expression of HDAC3 which, in turn, upregulates hexokinase 2 (HK2) and mitochondrial fission. These then go on to metabolically reprogram the REC toward a more glycolytic phenotype and promote the process of pathological angiogenesis of the retina. Inhibiting HDAC3 by RGFP966 protects against the OGD/R-induced metabolic chang","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":""},"PeriodicalIF":8.4,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145190631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}