Acta Pharmacologica Sinica最新文献

{"title":"Sirolimus potentiates oncolytic Virus M1 efficacy through tumor-selective augmentation of viral replication.","authors":"Jie-Hong Chen, Hong-Hui Li, Chao-Xin Chen, Cai-Xin Yan, Xuan-Ming Liang, Cui Guo, Yu Han, Yun-Hua Tang, Ying Liu, Jing Cai, Yuan Lin, Jian-Kai Liang, Jun Hu, Guang-Mei Yan, Jing-Jie Li, Wen-Bo Zhu","doi":"10.1038/s41401-026-01829-2","DOIUrl":"10.1038/s41401-026-01829-2","url":null,"abstract":"<p><p>Oncolytic virus M1 is a promising anticancer agent; however, its therapeutic efficacy is often limited by insufficient intratumoral viral replication and host antiviral immunity. Sirolimus, an mTOR inhibitor widely used in transplantation immunosuppression, has demonstrated potential to modulate antiviral responses. This study investigates whether sirolimus potentiates the efficacy of M1 virotherapy and elucidates the underlying mechanisms. Sirolimus significantly enhanced the antitumor efficacy of M1 virus in murine prostate cancer and liver cancer models, leading to reduced tumor growth. This synergistic effect remained evident in CD8⁺ T cell-depleted mice, indicating that the therapeutic benefit is independent of adaptive cytotoxic immunity. Mechanistically, sirolimus markedly increased M1 viral replication in tumor tissues, accompanied by enhanced tumor cell-cycle arrest and apoptosis. Notably, sirolimus selectively amplified viral load within tumors but not in normal organs, demonstrating tumor-specific viral enrichment and safety. Further analyses revealed that this increase in intratumoral virus was driven by mTOR pathway inhibition rather than alterations in macrophage or NK cell populations. Transcriptomic profiling and molecular validation indicated that sirolimus-mediated mTOR suppression downregulated key type I interferon-stimulated genes (Ifitm1, Stat1, Ifit3), thereby attenuating intrinsic antiviral defenses and facilitating viral amplification. In summary, sirolimus potentiates M1 oncolytic virotherapy by selectively enhancing viral replication in tumors via mTOR inhibition and suppression of type I interferon signaling, independent of CD8⁺ T cell-mediated immunity. These findings establish a mechanistic rationale for combining mTOR inhibitors with oncolytic viruses to achieve dual benefits of enhanced viral oncolysis and controlled immunosuppression, with translational relevance for cancer patients requiring long-term immunosuppressive therapy.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2668-2681"},"PeriodicalIF":10.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13487314/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148012993","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":"ApoE impairs microglial efferocytosis by targeting Gas6/MerTK in a mouse model of acute seizure.","authors":"Bo Gao, Si-Min Cheng, Yu-Yan Zhang, Hui-Xia Yang, Ming-Ming Hu, Yu Wang, Jian-Ming Han, Li Yu, Shun-Zhi Cao, Kun Dong, Hua Kong, Wen-Ning Wu","doi":"10.1038/s41401-026-01842-5","DOIUrl":"10.1038/s41401-026-01842-5","url":null,"abstract":"<p><p>Epilepsy, a neurological condition, is characterized by frequent, spontaneous seizures. Both apolipoprotein E (ApoE) and TAM (Tyro3, Axl and MerTK) receptors, the key efferocytosis receptors, have been associated with the pathological mechanisms underlying epilepsy. Nevertheless, little is known about how they interact or the molecular mechanisms. Here, we explored how ApoE and microglial efferocytosis interact in a mouse model of acute seizures caused by kainic acid (KA). KA exposure reduced microglial efferocytosis that is dependent on growth arrest-specific protein 6 (Gas6)/MER proto-oncogene tyrosine kinase (MerTK). Additionally, KA treatment increased microglial ApoE expression, whereas ApoE knockout restored Gas6/MerTK-mediated microglial efferocytosis and alleviated KA-induced seizures and neuronal injury. Furthermore, KA exposure promoted ApoE immunoprecipitation with nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3). ApoE knockout suppressed KA-induced NLRP3 inflammasome activation. Interestingly, KA-induced seizures and neuronal injury were lessened by hippocampal NLRP3 knockdown, which further preserved Gas6/MerTK-dependent microglial efferocytosis. Furthermore, exogenous delivery of recombinant Gas6 had anti-seizure and neuroprotective benefits in addition to restoring microglial efferocytosis function. Collectively, ApoE stimulates NLRP3 inflammasome activation and targets Gas6/MerTK in seizure-prone mice, thereby impairing microglial efferocytosis. For the treatment of seizures, the ApoE-NLRP3-Gas6/MerTK axis may represent a potential therapeutic target.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2453-2466"},"PeriodicalIF":10.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13486699/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148161273","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":"Time-resolved proteomic and phosphoproteomic analysis reveals convergent and divergent biological perturbations induced by FDA-approved CDK4/6 inhibitors in hormone receptor-positive breast cancers.","authors":"Shi-Yu Duan, Lin-Hui Zhai, Wei Zhang, Luo-Yi Chen, Rui-Xi Zhao, Xun Zou, Jia-Hui Ni, Xing-Long Jia, Tian-Yu Liu, Hang Fu, Min Huang, Min-Jia Tan, Cheng-Yu Chu, Yi-Ting Jin","doi":"10.1038/s41401-026-01858-x","DOIUrl":"10.1038/s41401-026-01858-x","url":null,"abstract":"<p><p>Palbociclib, ribociclib, and abemaciclib, which are FDA-approved CDK4/6 inhibitors, constitute the standard first-line treatment for advanced hormone receptor-positive (HR⁺) breast cancers. Although these drugs share nominal targets and demonstrate comparable first-line efficacy, significant divergences exist in their cross-line therapeutic responses upon first-line progression, indicating distinct mechanisms of action. To systematically elucidate their similarities and differences, we employed quantitative proteomics and phosphoproteomics to investigate and compare the molecular expression characteristics induced by these drugs. As a result, the three CDK4/6 inhibitors exhibited distinct anti-proliferative potencies in HR⁺ breast cancer cells. Dynamic proteomic and phosphoproteomic profiling demonstrated cell cycle arrest and mTORC1 pathway downregulation by all inhibitors, with abemaciclib exerting the most potent suppression. Subsequent kinase activity analysis indicated an upregulation of AKT1 kinase activity following CDK4/6 inhibitor stimulation. Furthermore, acridine orange staining and flow cytometry indicated that abemaciclib elevated lysosomal proteins and acidification while increasing reactive oxygen species (ROS). Collectively, this study deepens the understanding of shared and drug-specific molecular characteristics and mechanisms of CDK4/6 inhibitors at multi-omic levels. Moreover, it provides an experimental basis and potential directions for customizing combination therapies based on pathway vulnerabilities, as well as exploration of novel therapeutic modes and drugs.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2653-2667"},"PeriodicalIF":10.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13487217/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148197056","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":"Serum/glucocorticoid-regulated kinase 1 regulates vascular inflammation in atherosclerosis.","authors":"Yang-Xian Li, Shu-Xiang Ding, Hui-Ling Hong, Xiao-Yun Cao, Yu-Meng Han, Jin-Wei Tian, Sin-Hang Fung, Stephen Kwok-Wing Tsui, Ya-Lan Wu, Xiao Yu Tian","doi":"10.1038/s41401-026-01825-6","DOIUrl":"10.1038/s41401-026-01825-6","url":null,"abstract":"<p><p>Endothelial and macrophage inflammation and sterol transport play an important role in atherogenesis. Serum/glucocorticoid-regulated kinase 1 (SGK1) is a member of the serine/threonine kinase family sharing approximately 54% identity with Akt. It has been implicated in smooth muscle cell calcification and macrophage inflammation during atherosclerosis; however, the role of SGK1 in endothelial dysfunction and endothelial or macrophage lipid metabolism is less characterized. In this study, we intraperitoneally injected high-cholesterol diet-fed male ApoE-knockout mice with the SGK1 inhibitor EMD638683 (10 mg/kg) every other day for 2 weeks, followed by histopathological and transcriptome analysis of the atherosclerotic lesion. To study the SGK1-associated mechanism in vascular inflammation in vitro, SGK1 silencing was performed in primary human umbilical vein endothelial cells (HUVECs), followed by treatment with pro-inflammatory cytokines. In THP-1-differentiated macrophages, SGK1 silencing followed by treatment with lipopolysaccharides was used. We showed that ApoE-knockout mice treated with EMD638683 show reduced atherosclerotic plaque area and attenuated endothelial and macrophage inflammation. Further transcriptome analysis of thoracic aortae showed that SGK1 inhibition downregulated inflammation and lipid metabolism-associated genes. In vitro, interleukin-1β treatment induces SGK1 phosphorylation. SGK1 inhibitor or siRNA reduced endothelial inflammation induced by pro-inflammatory cytokine treatments in HUVECs through nuclear factor κ light chain enhancer of activated B cell (NF-κB) signaling. In THP-1-differentiated macrophages, SGK1 inhibition or knockdown by siRNA is associated with reduced levels of pro-inflammatory cytokines, NF-κB, and sterol regulatory element binding protein 1 (SREBP1) pathway activation, following lipopolysaccharide treatment. SREBP1 inhibition by fatostatin or siRNA reduced p65 phosphorylation. In conclusion, the inhibition of SGK1 has been shown to reduce atherosclerotic plaque area and attenuate endothelial and macrophage inflammation in ApoE-knockout mice via NF-κB and SREBP1 signaling. These results not only contribute to our understanding of the complex interplay between vascular inflammation and lipid metabolism but also hold promise for the development of novel therapeutic strategies for atherosclerosis.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2539-2553"},"PeriodicalIF":10.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13486708/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148215836","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":"The solute carrier transporter SLCO5A1 as a novel therapeutic target for the treatment of myocardial infarction-induced heart failure.","authors":"Ke-Yu Liu, Ke Gong, Fang Fang, Qing-Hua Chen, Jin-Rong Xu, Liang-Qing Zhang, Wen-Liang Chen","doi":"10.1038/s41401-026-01827-4","DOIUrl":"10.1038/s41401-026-01827-4","url":null,"abstract":"<p><p>Heart failure (HF) following myocardial infarction (MI) remains a major threat to health worldwide. While transcriptomics has revealed numerous genes whose expression is altered in HF, distinguishing therapeutic targets remains challenging. In this study, we aimed to identify novel therapeutic targets for HF and explore potential pharmacological interventions. We integrated human HF datasets with weighted gene coexpression network analysis (WGCNA) and machine learning (LASSO/SVM-RFE) to screen for candidate genes and applied Mendelian randomization (MR) to assess causality. SLCO5A1 emerged as a prioritized candidate, as it showed a genetically supported protective association with HF and was consistently downregulated in the ischemic failing myocardium. In mice, cardiomyocyte-targeted SLCO5A1 overexpression attenuated post-MI systolic dysfunction and pathological remodeling. Using drug-gene signature mining followed by biophysical and cellular validation, we identified 3-iodothyronamine (T1AM) as a small molecule that directly binds to SLCO5A1 and increases SLCO5A1 protein levels. Pharmacological administration of T1AM increased post-MI survival, improved cardiac function and reduced fibrosis; these benefits were markedly weakened by cardiomyocyte-specific SLCO5A1 knockdown, supporting a functional requirement for SLCO5A1. Mechanistically, SLCO5A1 reduced cardiomyocyte transforming growth factor beta 1 (TGF‑β1) secretion, thereby limiting fibroblast Smad3 activation and myofibroblast marker expression in conditioned-medium assays. In conclusion, our findings demonstrate that SLCO5A1 is a cardioprotective regulator of cardiomyocyte-fibroblast communication in post-MI HF and support a pharmacological increase in SLCO5A1 levels as a potential therapeutic strategy. SLCO5A1 serves as a novel therapeutic target for heart failure. Enhancing SLCO5A1 expression protects against MI-induced HF by inhibiting TGF-β1/Smad3-mediated cardiomyocyte-fibroblast crosstalk.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2479-2492"},"PeriodicalIF":10.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13486707/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148040594","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":"Pulsatile FXR activation: Timing bile acid-targeted therapy to physiology.","authors":"Ting-Ying Jiao, Yang-Tai Li, Frank J Gonzalez, Cen Xie","doi":"10.1038/s41401-026-01889-4","DOIUrl":"10.1038/s41401-026-01889-4","url":null,"abstract":"","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2299-2302"},"PeriodicalIF":10.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13426063/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148617940","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":"Echoes in the powerhouse: mito-lncRNAs contribution to cardiac function and disease.","authors":"Abdallah Iddy Chaurembo, Na Xing, Zi-Feng Huang, Baraka Simon Mayamba, Francis Chanda, Yun-Tao Liang, Yong-Fang Lin, Wen-Hui Deng, Jian-Yuan Huang, Zeng-Yu He, Zheng Tan, Chi Shu, Han-Bin Lin","doi":"10.1038/s41401-026-01830-9","DOIUrl":"10.1038/s41401-026-01830-9","url":null,"abstract":"<p><p>Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide, and its progression is closely linked to mitochondrial dysfunction in cardiomyocytes. Given the high energy demands of the heart, precise regulation of mitochondrial homeostasis, including oxidative phosphorylation, reactive oxygen species balance, calcium handling, and mitophagy, is essential for maintaining cardiac function. Emerging evidence has identified mitochondrial-associated long non-coding RNAs (mito-lncRNAs) as important regulators of these processes. Mito-lncRNAs comprise both nuclear-encoded transcripts that translocate to mitochondria and mitochondrial genome-encoded lncRNAs that function within the organelle. These molecules modulate mitochondrial gene expression, respiratory chain stability, metabolic flux, and stress responses, thereby influencing the pathogenesis of acute myocardial infarction, heart failure, diabetic cardiomyopathy, pulmonary hypertension, and cardiac remodeling. In this review, we categorize mito-lncRNAs based on their genomic origin and mitochondrial localization and summarize their mechanistic roles in cardiovascular physiology and disease. Moreover, the review highlights context-dependent effects of key transcripts such as LIPCAR, MALAT1, RMRP, H19, and lncND5. We further discuss the emerging value of mito-lncRNAs as circulating biomarkers and examine the major challenges that currently limit therapeutic translation, including cardiac- and mitochondrial-specific delivery, mechanistic ambiguity, species conservation, and technical limitations in detection. A deeper understanding of mito-lncRNA biology may provide new insights into mitochondrial regulation in the heart and inform the development of novel diagnostic and therapeutic strategies for CVDs.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2341-2357"},"PeriodicalIF":10.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13486758/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148154775","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":"Nanoparticles for autoimmune diseases: advancing diagnostics and therapeutic solutions.","authors":"Elaine Xue Ning Ong, Chester Yan Jie Ng, Lu-Lei Cao, Xuexin Li, Pan P Li, Nguan Soon Tan, Zehuan Liao, Yan Zhao","doi":"10.1038/s41401-026-01794-w","DOIUrl":"10.1038/s41401-026-01794-w","url":null,"abstract":"<p><p>Autoimmune diseases pose a significant challenge to modern medicine due to their complicated and poorly understood mechanisms, which hinder effective diagnosis and treatment. The rising global incidence of autoimmune disorders is projected to place increasing strain on healthcare systems and financial resources. In response, nanotechnology has emerged as a promising avenue for both the diagnosis and treatment of these conditions. Among various nano-technological approaches, nanoparticles have garnered particular attention due to their advantageous properties including biocompatibility, enhanced drug bioavailability and efficient permeability across biological membranes. Furthermore, their unique characteristics such as magnetic responsiveness, anti-inflammatory, and antimicrobial capabilities, enable precise drug delivery and improved therapeutic outcomes, as well as the potential for earlier disease detection. Despite these promising developments, the clinical translation of nanoparticle-based strategies faces challenges including concerns regarding their stability in vivo and the need for further research to validate their safety and efficacy. While current diagnostic tools remain limited, certain nanoparticles have already received approval from the US Food and Drug Administration, demonstrating their potential for clinical application. This review aims to highlight the recent advances in use of nanoparticles for the diagnosis and treatment of autoimmune diseases, and to explore their prospective role in future clinical practice.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2303-2322"},"PeriodicalIF":10.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13487202/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832108","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":"PGK1 epigenetically silences STING via DNMT1 and its knockdown synergizes with STING agonists in pancreatic cancer.","authors":"Wan-Mei Liu, Jia-Hui Xu, Chun-Yong Ding, Ao Zhang","doi":"10.1038/s41401-026-01809-6","DOIUrl":"10.1038/s41401-026-01809-6","url":null,"abstract":"<p><p>The highly immunosuppressive tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) severely limits the efficacy of current immunotherapies. Identifying key molecular drivers of this immunosuppressive niche is therefore essential for developing new treatment strategies. In this study, through comprehensive bioinformatic analysis of PDAC clinical datasets and systematic experimental validation, we demonstrate that PGK1 is upregulated in PDAC and is associated with poor immune infiltration. Genetic knockdown of PGK1 upregulated STING expression, promoted the recruitment of antitumor immune cells into the tumor microenvironment, and significantly enhanced the in vivo efficacy of STING agonist treatment. Mechanistically, PGK1 stabilizes DNMT1 by blocking its ubiquitination-mediated degradation, which in turn promotes methylation of the STING promoter and suppresses its transcription. Our findings reveal a non-metabolic role of PGK1 in promoting an immunosuppressive microenvironment and propose a promising combination strategy targeting the PGK1-STING axis for the treatment of PDAC.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2603-2618"},"PeriodicalIF":10.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13487145/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147961824","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":"Few-shot learning-driven discovery of Lutein suppresses Th1-mediated inflammation via glucose metabolism.","authors":"Li-Jun Yang, Zong-Hui Wei, Pei-Jian Cao, Zhi-Bin Li, Xiang Li, Jun-Wei Zhao, Yi-Wen Du, Ke-Han Wang, Qiao-Hong Zheng, Qiao-Jun He, Bo Yang, Jia-Jia Wang, Qin-Jie Weng","doi":"10.1038/s41401-026-01822-9","DOIUrl":"10.1038/s41401-026-01822-9","url":null,"abstract":"<p><p>The discovery of selective immunosuppressants for T cell-mediated diseases like Ulcerative Colitis (UC) is a significant challenge. While traditional screening is inefficient, Artificial intelligence (AI)-driven approaches are often hindered by the scarcity of high-quality labeled data, challenging the accurate identification of functional molecules. In this study, we leveraged a transfer learning strategy to compensate for the lack of high-quality data, establishing a screening platform to identify potential T cell inhibitors. Using this approach, we identified Lutein as a novel, specific immunomodulatory candidate from a natural product library. Integrated multi-omics analyses revealed that Lutein activates peroxisome proliferator-activated receptor gamma (PPARγ), suppressing glucose uptake and glycolysis, thereby selectively inhibiting Th1 cell differentiation. In a dextran sulfate sodium (DSS)-induced mouse model of ulcerative colitis, Lutein treatment significantly restored Th1-mediated immune balance and alleviated pathological tissue damage. Our findings highlight the feasibility of using a few-shot learning strategy based on transfer learning to screen for specific immunosuppressants and indicate that Lutein is a promising therapeutic candidate for ulcerative colitis. An AI screening platform leveraging the Uni-Mol model identifies Lutein as a selective Th1 immunomodulator, which targets PPARγ-mediated glucose metabolism to inhibit Th1 differentiation and ameliorate colitis.</p>","PeriodicalId":6942,"journal":{"name":"Acta Pharmacologica Sinica","volume":" ","pages":"2569-2584"},"PeriodicalIF":10.4,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13486481/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147961830","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}