{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T05:02:57Z","timestamp":1789448577471,"version":"build-2803163510"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"\n Background<\/jats:title>\n Heart failure (HF) and non-obstructive azoospermia (NOA) are high-burden diseases that share chronic inflammation and tissue injury. Macrophages are key regulators in both conditions, yet whether a common molecular basis exists remains unclear.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We analyzed HF and NOA expression profiles from the GEO database using WGCNA and machine learning to screen for core shared genes. Diagnostic performance was evaluated using AUC in independent validation sets. Single-cell RNA-seq mapped the cellular origin of core genes. Immune infiltration, pathway activity, and transcription factor networks were analyzed using xCell, PROGENy, and DoRothEA. To investigate functional roles, we applied single-cell in silico knockout to macrophages and designed\n in vitro<\/jats:italic>\n knockdown experiments for validation.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n SLAMF7<\/jats:italic>\n ,\n IL2RA<\/jats:italic>\n , and\n PRF1<\/jats:italic>\n were identified as core shared genes. The diagnostic model achieved AUCs of 0.782 (HF) and 0.724 (NOA) in validation sets. All three genes were highly expressed in macrophages, and their mean expression correlated with M2-like macrophages as well as\n JAK-STAT<\/jats:italic>\n and\n NF-\u03baB<\/jats:italic>\n pathway activities. Transcription factor network analysis revealed\n NFKB1<\/jats:italic>\n ,\n STAT1<\/jats:italic>\n ,\n STAT3<\/jats:italic>\n ,\n STAT4<\/jats:italic>\n and\n STAT5A\/B<\/jats:italic>\n as upstream regulators. Any gene loss upregulated C1q, scavenger receptors, the NLRP3 inflammasome, and inflammatory factors. Distinct context-specific changes were observed: in NOA macrophages,\n PRF1<\/jats:italic>\n loss caused ectopic expression of sperm protamine genes (\n PRM2<\/jats:italic>\n ,\n TNP1<\/jats:italic>\n );\n IL2RA<\/jats:italic>\n loss activated the\n IRF8\u2013TLR2<\/jats:italic>\n axis; and\n SLAMF7<\/jats:italic>\n loss enhanced MHC-II and interferon pathways. In HF macrophages,\n SLAMF7<\/jats:italic>\n loss activated the prostaglandin pathway;\n IL2RA<\/jats:italic>\n loss induced upregulation of M2-like markers\n FOLR2<\/jats:italic>\n and\n LYVE1<\/jats:italic>\n ; and\n PRF1<\/jats:italic>\n loss enhanced C1q expression.\n In vitro<\/jats:italic>\n knockdown experiments showed that, without antigen stimulation, knockdown of all three genes upregulated\n C1qa<\/jats:italic>\n ,\n Folr2<\/jats:italic>\n ,\n Il1b<\/jats:italic>\n ,\n Acod1<\/jats:italic>\n and\n Nlrp3<\/jats:italic>\n . Under sperm stimulation,\n PRF1<\/jats:italic>\n knockdown increased\n Prm2<\/jats:italic>\n and\n S100a8<\/jats:italic>\n , whereas\n IL2RA<\/jats:italic>\n knockdown increased\n Irf8<\/jats:italic>\n . Under cardiac lysate stimulation,\n PRF1<\/jats:italic>\n knockdown led to ectopic expression of the cardiac-specific genes\n Myh6<\/jats:italic>\n and\n Tnnt2<\/jats:italic>\n .\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n SLAMF7<\/jats:italic>\n ,\n IL2RA<\/jats:italic>\n and\n PRF1<\/jats:italic>\n form a negative immune regulatory hub in macrophages that links HF and NOA. Loss of these genes is associated with a conserved complement\u2013inflammation module, whereas the disease outcome is determined by organ-specific antigens. Targeting this shared hub may offer a potential therapeutic direction for future investigation.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1909437","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T04:26:55Z","timestamp":1789446415000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Impaired antigen clearance of macrophages associates with heart failure and non-obstructive azoospermia: insights from transcriptomics, in silico knockout, and in vitro validation"],"prefix":"10.3389","volume":"17","author":[{"given":"Zheng","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao University","place":["Qingdao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao University","place":["Qingdao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiology I, Qingdao Central Hospital, University of Health and Rehabilitation Sciences","place":["Qingdao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao University","place":["Qingdao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiawei","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao University","place":["Qingdao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Da","family":"Teng","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital)","place":["Qingdao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao University","place":["Qingdao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baoqi","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao University","place":["Qingdao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianmiao","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao University","place":["Qingdao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Xin","sequence":"additional","affiliation":[{"name":"Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao University","place":["Qingdao, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1097\/cd9.0000000000000180","article-title":"Introduction of heart failure: an increasing public health concern","volume":"5","author":"Zhang","year":"2025"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1002\/ejhf.2115","article-title":"Universal definition and classification of heart failure: a report of the Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology, Japanese Heart Failure Society and Writing Committee of the Universal Definition of Heart Failure: Endorsed by the Canadian Heart Failure 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