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Identifying key regulators of their activation is crucial for new therapies. This study aimed to identify novel regulators of pro\u2010inflammatory adipose tissue macrophage (ATM) activation and assess their therapeutic potential.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>\n                      We combined genome\u2010wide CRISPR\u2010Cas9 screening with scRNA\u2010seq data from human adipose tissue and identified long\u2010chain acyl\u2010CoA synthetase 4 (ACSL4) as critical for pro\u2010inflammatory ATM activation. Validation used myeloid\u2010specific\n                      <jats:italic>Acsl4<\/jats:italic>\n                      knockout mice (\n                      <jats:italic>Acsl4<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>fl\/fl<\/jats:italic>\n                      <\/jats:sup>\n                      <jats:italic>Lyz2<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>Cre<\/jats:italic>\n                      <\/jats:sup>\n                      ) and shRNA\u2010mediated knockdown in macrophage cell lines (RAW264.7, THP\u20101, and iBMDM). Mechanisms were explored via mutagenesis, immunostaining, co\u2010immunoprecipitation (co\u2010IP), bimolecular fluorescence complementation (BiFC), and transcriptional activity assays. A high\u2010throughput screen of 8,685 DrugBank compounds was performed to identify candidates targeting ACSL4.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      ACSL4 deficiency markedly reduced pro\u2010inflammatory factor expression (\n                      <jats:italic>Tnf\u03b1<\/jats:italic>\n                      ,\n                      <jats:italic>Il1\u03b2<\/jats:italic>\n                      , and\n                      <jats:italic>Il6<\/jats:italic>\n                      ). Myeloid ACSL4 deletion protected against high\u2010fat diet (HFD)\u2010induced obesity, correlated with reduced pro\u2010inflammatory ATMs and enhanced adipocyte lipolysis and thermogenesis, without affecting food intake, water intake, or locomotor activity in mice. However, glucose tolerance and insulin sensitivity were not significantly affected. Mechanistically, ACSL4 contributed to inflammation independent of its enzymatic\/ferroptotic functions (Thr328 mutation, troglitazone insensitivity). Instead, ACSL4 translocated to the nucleus in a karyopherin \u03b21 (KPNB1)\u2010dependent manner. DrugBank screening identified abemaciclib as a potential inhibitor of the ACSL4\u2010KPNB1 interaction. Notably, abemaciclib treatment reduced macrophage inflammation and attenuated HFD\u2010induced obesity in mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Implications<\/jats:title>\n                    <jats:p>ACSL4 promotes pro\u2010inflammatory macrophage activation through its KPNB1\u2010dependent nuclear translocation and cooperation with IRF5. Targeting the ACSL4\u2010KPNB1 interaction may represent a potential therapeutic strategy for metabolic inflammation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70681","type":"journal-article","created":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T03:27:16Z","timestamp":1792207636000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CRISPR screens identify ACSL4 as a key regulator in macrophage activation and metabolic inflammation"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6719-2815","authenticated-orcid":false,"given":"Yanting","family":"Lin","sequence":"first","affiliation":[{"name":"Institute of Translational Medicine China Pharmaceutical University  Nanjing Jiangsu China"},{"name":"State Key Laboratory of Natural Medicines China Pharmaceutical University  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-2501-1633","authenticated-orcid":false,"given":"Dongquan","family":"Jing","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine China Pharmaceutical University  Nanjing Jiangsu China"},{"name":"State Key Laboratory of Natural Medicines China Pharmaceutical University  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1776-6076","authenticated-orcid":false,"given":"Yiming","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine China Pharmaceutical University  Nanjing Jiangsu China"},{"name":"State Key Laboratory of Natural Medicines China Pharmaceutical University  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8221-0277","authenticated-orcid":false,"given":"Rui","family":"Gao","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine China Pharmaceutical University  Nanjing Jiangsu China"},{"name":"State Key Laboratory of Natural Medicines China Pharmaceutical University  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-0335-032X","authenticated-orcid":false,"given":"Qixiang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine China Pharmaceutical University  Nanjing Jiangsu China"},{"name":"State Key Laboratory of Natural Medicines China Pharmaceutical University  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6253-2191","authenticated-orcid":false,"given":"Xingyu","family":"Jiang","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine China Pharmaceutical University  Nanjing Jiangsu China"},{"name":"State Key Laboratory of Natural Medicines China Pharmaceutical University  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5061-1675","authenticated-orcid":false,"given":"Huijuan","family":"Da","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine China Pharmaceutical University  Nanjing Jiangsu China"},{"name":"State Key Laboratory of Natural Medicines China Pharmaceutical University  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9782-9074","authenticated-orcid":false,"given":"Yiming","family":"Ren","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine China Pharmaceutical University  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5974-2014","authenticated-orcid":false,"given":"Qiuhua","family":"Cao","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine China Pharmaceutical University  Nanjing Jiangsu China"},{"name":"Vaccine Center, School of Basic Medicine and Clinical Pharmacy China Pharmaceutical University  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9163-3633","authenticated-orcid":false,"given":"Jingwei","family":"Jiang","sequence":"additional","affiliation":[{"name":"ShuangYun BioMed Sci and Tech (Suzhou) Co., Ltd.  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