{"title":"Characterizing the immune landscape of tumor-infiltrating lymphocytes in non-small cell lung cancer","authors":"Jin-Guo Liu, Lin Yu, Xian-Ling Guo, Xue-Min He, Man Li, Ren-Yuan Gao, Bing-Hui Zhao, Qian-Yu Li, Wen-Jing Zhu, Ping Xu, Xiao-Hua Gu, Yong-An Chen, Xiao-Lan Yin, Yan Shang, Zhen-Hong Guo, Jia-Hao Mao, Yang-Xi Hu, Li-Ming Lu, Jian Hua, Hua Zhang, Yue Li","doi":"10.1038/s41435-025-00330-w","DOIUrl":"10.1038/s41435-025-00330-w","url":null,"abstract":"Tumor-Infiltrating Lymphocytes (TILs) immunotherapy is a highly promising treatment for Non-small Cell Lung Cancer (NSCLC), which is responsible for 18% of all cancer-related deaths. The heterogeneity of TILs remains poorly understood. Here, we utilized combined single-cell RNA (scRNA)/T cell receptor sequencing (scTCR-seq) data from lung adenocarcinoma (LUAD) patients. Naïve CD4+ and effector memory CD8+ T cells were increased in tumor tissue compared with circulating blood samples. Activated signaling pathways were detected, and GZMA was identified as a potential novel diagnostic biomarker. During the transitional phase, macrophages (FTL) and dendritic (AIF1) cells transported the most CD3 TCR clones to T cells, while cytotoxicity CD8+ T (NKG7) cells transported to terminal exhausted CD8+ T cells. In both transition and expansion phases, T helper cells (CXCL13) are transported to regulatory T cells (Tregs). Additionally, we investigated the expression profiles of key cytokines, checkpoint receptors, and their ligands. Cytotoxicity CD8+ T cells (CCL5 and IFNG), T helper cells (FTL, TNFRSF4, and TIGIT), and regulatory T cells (CTLA4, TIGIT and FTL) exhibited functional roles in both primary and metastatic tumor stages. Taken together, our study provides a single-cell resolution of the TIL immune landscape and suggests potential treatment strategies to overcome drug resistance.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"26 3","pages":"229-241"},"PeriodicalIF":4.5,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143983864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stanley I. Letovsky, Xia Cao, Jill A. Hollenbach, Steven J. Mack, Martin Maiers
{"title":"Association between HLA genetics and SARS-CoV-2 infection in a large real-world cohort","authors":"Stanley I. Letovsky, Xia Cao, Jill A. Hollenbach, Steven J. Mack, Martin Maiers","doi":"10.1038/s41435-025-00328-4","DOIUrl":"10.1038/s41435-025-00328-4","url":null,"abstract":"Genetic variation in the human leukocyte antigen (HLA) region is thought to influence susceptibility to and severity of a variety of infectious diseases. Several studies have explored a possible relationship between HLA genetics and SARS-CoV-2 infection, although mixed results, small sample sizes, and difficulty controlling for exposure risk have made it difficult to draw firm conclusions. Here, a dataset of 419,234 subjects with HLA genotype data and COVID-19 PCR test results was studied. A baseline analysis was performed to examine the association of non-HLA factors on COVID-19 positivity. Then, multivariate logistic regressions, incorporating single and paired HLA alleles, were performed and then corrected for significant factors from the baseline analysis. Proxies for socioeconomic status and exposure risk were significantly associated with COVID-19 positivity across all ancestry groups studied. Forty-one single HLA alleles displayed significant association with COVID-19 positivity; after controlling for socioeconomic status and exposure risk, only eight significant associations remained. Additionally, two HLA allele pairs were associated with test positivity after correction. Of all variables, socioeconomic status showed the greatest effect size. The results from this study suggest that many, if not all, of the reported associations between HLA alleles and SARS-CoV-2 infection may be spurious, owing to confounding factors.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"26 3","pages":"213-221"},"PeriodicalIF":4.5,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12170163/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144005552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marcio A. Almeida, Vincent P. Diego, Kevin R. Viel, Bernadette W. Luu, Karin Haack, Rajalingam Raja, Afshin Ameri, Meera Chitlur, Natalia Rydz, David Lillicrap, Raymond G. Watts, Craig M. Kessler, Christopher Ramsey, Long V. Dinh, Benjamin Kim, Jerry S. Powell, Eron G. Manusov, Juan M. Peralta, Ruayda Bouls, Shirley M. Abraham, Yu-Min Shen, Carlos M. Murillo, Henry Mead, Paul V. Lehmann, Eli J. Fine, Miguel A. Escobar, Satish Kumar, Barbara A. Konkle, Sarah Williams-Blangero, Carol K. Kasper, Laura Almasy, Shelley A. Cole, John Blangero, Tom E. Howard
{"title":"A scan of pleiotropic immune mediated disease genes identifies novel determinants of baseline FVIII inhibitor status in hemophilia A","authors":"Marcio A. Almeida, Vincent P. Diego, Kevin R. Viel, Bernadette W. Luu, Karin Haack, Rajalingam Raja, Afshin Ameri, Meera Chitlur, Natalia Rydz, David Lillicrap, Raymond G. Watts, Craig M. Kessler, Christopher Ramsey, Long V. Dinh, Benjamin Kim, Jerry S. Powell, Eron G. Manusov, Juan M. Peralta, Ruayda Bouls, Shirley M. Abraham, Yu-Min Shen, Carlos M. Murillo, Henry Mead, Paul V. Lehmann, Eli J. Fine, Miguel A. Escobar, Satish Kumar, Barbara A. Konkle, Sarah Williams-Blangero, Carol K. Kasper, Laura Almasy, Shelley A. Cole, John Blangero, Tom E. Howard","doi":"10.1038/s41435-025-00325-7","DOIUrl":"10.1038/s41435-025-00325-7","url":null,"abstract":"Hemophilia-A (HA) is the X-linked bleeding disorder caused by heterogeneous factor (F)VIII gene (F8)-mutations and deficiencies in plasma-FVIII-activity that prevent intrinsic-pathway mediated coagulation-amplification. Severe-HA patients (HAPs) require life-long infusions of therapeutic-FVIII-proteins (tFVIIIs) but ~30% develop neutralizing-tFVIII-antibodies called “FVIII-inhibitors (FEIs)”. We investigated the genetics underlying the variable risk of FEI-development in 450 North American HAPs (206 and 244 respectively self-reporting black-African- or white-European-ancestry) by analyzing the genotypes of single-nucleotide-variations (SNVs) in candidate immune-mediated-disease (IMD)-genes using a binary linear-mixed model of genetic association with baseline-FEI-status, the dependent variable, while simultaneously accounting for their genetic relationships and heterogeneous-F8-mutations to prevent the statistical problem of non-independence. We a priori selected gene-centric-association-scans of pleiotropic-IMD-genes implicated in the development of either ≥2 autoimmune-/autoinflammatory-disorders (AADs) or FEIs and ≥1 AAD. We found that baseline-FEI-status was significantly associated with NOS2A (rs117382854; p = 3.2 × 10−6) and B3GNT2 (rs10176009; p = 5.1 × 10−6)—pleiotropic-IMD-genes known previously to function in anti-microbial-/-tumoral-immunity but not in the development of FEIs—and confirmed associations with CTLA4 (rs231780; p = 2.2 × 10−5). We also found that baseline-FEI-status has a substantial heritability (~55%) that involves (i) a F8-mutation-specific component of ~8%, (ii) an additive-genetic contribution from SNVs in IMD-genes of ~47%, and (iii) race, which is a significant determinant independent of F8-mutation-types and non-F8-genetics.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"26 3","pages":"179-189"},"PeriodicalIF":4.5,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143967698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Comprehensive analysis of heat shock proteins in glioma revealed the association with glioma-associated myeloid cells","authors":"Jiacheng Xu, Yuduo Guo, Weihai Ning, Jun Wang, Yujia Chen, Deshan Liu, Jingjing Yang, Yongmei Song, Hongwei Zhang","doi":"10.1038/s41435-025-00327-5","DOIUrl":"10.1038/s41435-025-00327-5","url":null,"abstract":"In the central nervous system, glioma stands as the predominant primary brain tumor. Heat shock proteins exerted a critical influence on tumor progression and tumor immune microenvironment. However, research on heat shock proteins in glioma remained ambiguous. We analyzed data from the CPTAC, TCGA, and GTEx databases, identifying seven heat shock protein genes critical to glioma prognosis. Subsequently, through Lasso regression, a model based on heat shock protein genes (DNAJC7, DNAJC12, HSPB2, HSP90B1, HSPA5) was constructed. And the risk score showed a positive correlation to the immune score. Further investigation into immune cells revealed that HSPA5 and HSP90B1 were expressed at higher levels in glioma and significantly linked to M2 macrophage infiltration. Considering the limited research on HSP90B1 in glioma, we further revealed that HSP90B1 might have a connection with two crucial signaling pathways within tumors: PI3K/AKT and Wnt/β-catenin. Given that lactate could promote the M2 polarization of macrophages, we further found that HSP90B1 could enhance the transcription of glycolysis-related genes, including LDHA. Overall, our study demonstrated that heat shock protein genes were significantly linked to glioma patient prognosis. Additionally, we observed that HSP90B1 had a significant relationship with M2 macrophage infiltration and potentially regulated LDHA level in glioma.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"26 3","pages":"200-212"},"PeriodicalIF":4.5,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12170335/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143990073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zujian Xiong, Chaim T. Sneiderman, Chloe R. Kuminkoski, Jared Reinheimer, Lance Schwegman, ReidAnn E. Sever, Ahmed Habib, Baoli Hu, Sameer Agnihotri, Dhivyaa Rajasundaram, Pascal O. Zinn, Thomas G. Forsthuber, Ian F. Pollack, Xuejun Li, Itay Raphael, Gary Kohanbash
{"title":"Transcript-targeted antigen mapping reveals the potential of POSTN splicing junction epitopes in glioblastoma immunotherapy","authors":"Zujian Xiong, Chaim T. Sneiderman, Chloe R. Kuminkoski, Jared Reinheimer, Lance Schwegman, ReidAnn E. Sever, Ahmed Habib, Baoli Hu, Sameer Agnihotri, Dhivyaa Rajasundaram, Pascal O. Zinn, Thomas G. Forsthuber, Ian F. Pollack, Xuejun Li, Itay Raphael, Gary Kohanbash","doi":"10.1038/s41435-025-00326-6","DOIUrl":"10.1038/s41435-025-00326-6","url":null,"abstract":"Tumor antigens are crucial for T-cell mediated immunotherapy, but identified antigens for gliomas remain limited. Aberrant splicing variants are commonly expressed in tumors, resulting in unique tumor isoforms with potential antigenic properties. Herein, we analyzed multi-omics data from 587 glioma patients and assembled a library of putative tumor-enriched isoform antigens (TIA) and corresponding peptides presented on each HLA-I allele. We constructed an individual-specific TIA peptide candidate repertoire for each patient based on their TIA expression and HLA-I haplotypes. TIAs were highly expressed, enriched with glioma malignancy, and demonstrated strong HLA-binding affinity. We focused on periostin isoform-203 (POSTN-203), which was associated with poor survival of patients and contained multiple predicted HLA-restricted peptide epitopes. A selected HLA-A11-restricted peptide from POSTN-203 (POSTN-203A11) induced antigen-specific T-cell responses against both peptide-pulsed and POSTN-203-expressing glioma cells in an HLA-specific manner. Our findings highlight TIAs as a promising source of immunogenic antigens and POSTN-203 as a potential promising target for glioma immunotherapy.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"26 3","pages":"190-199"},"PeriodicalIF":4.5,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ivo Zeller, Andreas Weiss, Sandra Hummel, Anette-Gabriele Ziegler, Ezio Bonifacio
{"title":"Age-dependent gene expression trajectories during early childhood in children at increased risk for type 1 diabetes","authors":"Ivo Zeller, Andreas Weiss, Sandra Hummel, Anette-Gabriele Ziegler, Ezio Bonifacio","doi":"10.1038/s41435-025-00324-8","DOIUrl":"10.1038/s41435-025-00324-8","url":null,"abstract":"Early childhood is a period of rapid growth and immune system development. It is also critical for type 1 diabetes (T1D) autoimmunity, which has a peak incidence between 1 and 2 years of age. Here, we investigated age-related longitudinal gene expression changes in peripheral blood mononuclear cells from children aged 3 months to 3 years who had an increased genetic risk for T1D, aiming to delineate gene expression trajectories and identify patterns potentially linked to the development of islet autoimmunity. We found 2 432 genes (12.5% of analyzed genes) to exhibit significant temporal dynamics in the first 3 years of life. These genes were grouped into six major clusters each demonstrating distinct expression trajectories of consistent increase or decrease with age, as well as U-shaped, and inverted U-shaped age-related patterns. Notably, genes in clusters with U-shaped expression trajectories, which mirrored the incidence of islet autoantibodies, were enriched for T1D susceptibility genes, particularly within the Major Histocompatibility Complex (MHC) region. This study underscores the dynamic nature of gene expression in early childhood and its potential connection to T1D risk.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"26 2","pages":"173-177"},"PeriodicalIF":4.5,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12006016/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143669636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Multi-omics clustering analysis carries out the molecular-specific subtypes of thyroid carcinoma: implicating for the precise treatment strategies","authors":"Zhenglin Wang, Qijun Han, Xianyu Hu, Xu Wang, Rui Sun, Siwei Huang, Wei Chen","doi":"10.1038/s41435-025-00322-w","DOIUrl":"10.1038/s41435-025-00322-w","url":null,"abstract":"Thyroid cancer (TC) is the most prevalent endocrine malignancy worldwide. This study aimed to explore the molecular subtypes and improve the selection of targeted therapies. We used multi-omics data from 539 patients with DNA methylation, gene mutations, mRNA, lncRNA, and miRNA expressions. This study employed consensus clustering algorithms to identify molecular subtypes and used various bioinformatics tools to analyze genetic alterations, signaling pathways, immune infiltration, and responses to chemotherapy and immunotherapy. Two prognostically relevant TC subtypes, CS1 and CS2, were identified. CS2 was associated with a poorer prognosis of shorter progression-free survival times (P < 0.001). CS1 exhibited higher copy number alterations but a lower tumor mutation burden than CS2. CS2 exhibited activation in cell proliferation and immune-related pathways. Drug sensitivity analysis indicated CS2’s higher sensitivity to cisplatin, doxorubicin, paclitaxel, and sunitinib, whereas CS1 was more sensitive to bicalutamide and FH535. The different activated pathways and sensitivity to drugs for the subtypes were further validated in an external cohort. Twenty-four paired tumors and adjacent normal tissues by immunohistochemical staining further demonstrated the prognostic value of CXCL17. In conclusion, we identified two distinct molecular subtypes of TC with significant implications for prognosis, genetic alterations, pathway activation, and treatment response.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"26 2","pages":"137-150"},"PeriodicalIF":4.5,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Annexin A1 regulates inflammatory-immune response and reduces pancreatic and extra- pancreatic injury during severe acute pancreatitis","authors":"Shizhao Lin, Feihong Liang, Changgan Chen, Jiajing Lin, Yuwei Wu, Zelin Hou, Heguang Huang, Haizong Fang, Yu Pan","doi":"10.1038/s41435-025-00321-x","DOIUrl":"10.1038/s41435-025-00321-x","url":null,"abstract":"Severe acute pancreatitis (SAP) poses significant challenges due to its complex pathophysiology, which includes inflammatory-immune responses that cause considerable damage to both the pancreas and other tissues. In this study, we explored the role of Annexin A1 (Anxa1), a glucocorticoid-regulated protein recognized for its anti-inflammatory properties, in regulating inflammation during acute pancreatitis. Using flow cytometry, single-cell RNA sequencing, and gene expression analysis, we examined how Anxa1 expression is regulated in myeloid cells throughout acute pancreatitis, employing various animal models to evaluate the consequences of modulating Anxa1 on injuries induced by SAP. Our findings revealed dynamic regulation of Anxa1 expression in myeloid cells, with mice lacking Anxa1 exhibiting worsened pancreatic injury and heightened systemic inflammation, resulting in significant damage to extra-pancreatic organs such as the lungs, liver, and kidneys. In contrast, treatment with Ac2-26, a synthetic peptide derived from Anxa1, effectively mitigated both pancreatic and extra-pancreatic inflammation and tissue damage. Overall, this study highlights the critical role of Anxa1 in modulating inflammatory responses during acute pancreatitis. Targeting Anxa1 presents a promising therapeutic strategy to mitigate pancreatic injury and prevent systemic complications associated with severe acute pancreatitis.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"26 2","pages":"124-136"},"PeriodicalIF":4.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Raza Ali Naqvi, Araceli Valverde, Deepak Shukla, Afsar Naqvi
{"title":"Long noncoding RNA PARAL1 regulates myeloid dendritic cell differentiation and TLR signaling","authors":"Raza Ali Naqvi, Araceli Valverde, Deepak Shukla, Afsar Naqvi","doi":"10.1038/s41435-025-00323-9","DOIUrl":"10.1038/s41435-025-00323-9","url":null,"abstract":"Dendritic cells (DCs) are professional antigen presentation cells (APCs) that bridge innate and adaptive immune functions to contain pathogenic threats. Long noncoding RNAs (lncRNAs) are implicated in regulating biological processes, including inflammation and immunity. However, the knowledge of myeloid DC-expressed lncRNA repertoire and their regulatory functions is limited. Here we profiled lncRNA expression kinetics during monocyte-to-DC (moDC) differentiation and characterized their functional roles. Our RNA-seq data identified a repertoire of differentially expressed lncRNAs associated with moDC differentiation and a large subset of these lncRNAs are distinct from M1 or M2 macrophages. We selected two DC-enriched lncRNAs and observed that PARAL1 silencing, or overexpression modulates DC surface markers expression. Importantly, PARAL1 RNAi significantly reduced, while its overexpression upregulated the levels of multiple TLRs. Upon treatment with TLR agonists PARAL1 knockdown cells exhibit reduced NF-κB, IRF3 and IRF7 phosphorylation substantiating its role in potentiating TLR signaling. Mechanistically, PARAL1 silencing showed significant downregulation of multiple NF-κB-induced genes and time-dependent inhibition of proinflammatory cytokine secretion upon challenge with TLR agonists. Finally, PARAL1 RNAi in DCs significantly impaired antigen processing and presentation to T cells. Overall, this study characterized novel functions of PARAL1 in regulating DC differentiation, TLR-dependent innate immunity and activation of adaptive immune response.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"26 2","pages":"151-165"},"PeriodicalIF":4.5,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143500543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Comprehensive analysis of autophagy status and its relationship with immunity and inflammation in ischemic stroke through integrated transcriptomic and single-cell sequencing","authors":"Xiaole Zhu, Zhongman Zhang, Yi Zhu, Yanlong Chen, Wei Li, Huae Xu, Xufeng Chen","doi":"10.1038/s41435-025-00320-y","DOIUrl":"10.1038/s41435-025-00320-y","url":null,"abstract":"Ischemic stroke (IS) significantly impacts patients’ health and quality of life, with the roles of autophagy and autophagy-related genes in IS still not fully understood. In this study, IS datasets were retrieved from the GEO database. Autophagy-related genes(ARGs) were identified and screened for differential expression. A prediction model was constructed using machine learning algorithm. WGCNA was employed to analyze differential regulation modules among different clusters of stroke patients. The analysis results were validated using single-cell sequencing data. Finally, autophagy hub genes were validated in an external cohort and an IS mouse model. We observed suppressed autophagy states in IS patients. A diagnostic model with good clinical efficacy for stroke diagnosis was constructed based on the selected key genes (AUC = 0.87). Consensus clustering identified two IS subtypes with distinct gene expression patterns and immune cell infiltration. scRNA-seq data analysis confirmed downregulation of pexophagy in IS. CellChat analysis identified key signaling pathways and intercellular interactions related to pexophagy. Validation in an external cohort and IS mouse model confirmed differential gene expression, supporting the involvement of pexophagy in IS pathogenesis. The identified key genes, molecular subtypes, and cellular interactions provide a foundation for further research into targeted therapies and precision medicine approaches for IS patients.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"26 2","pages":"111-123"},"PeriodicalIF":4.5,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}