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Beyond classic receptor\u2010mediated recognition, this process drives phagocyte metabolic reprogramming to actively facilitate tissue repair. Consequently, defective efferocytosis serves as a core pathogenic mechanism across major human diseases. This review outlines the molecular and metabolic foundations of efferocytosis and defines four universal hallmarks of its dysfunction: senescence\u2010driven impairment, unresolved inflammation, loss of immune tolerance, and fibrotic tissue repair. Subsequent sections explore how these defects manifest in cardiovascular, autoimmune, and neurodegenerative conditions, as well as cancer. Because efferocytosis exhibits a dual pathophysiological nature, therapeutic interventions must be highly disease\u2010specific. Enhancing apoptotic clearance can effectively resolve chronic inflammatory and fibrotic conditions. Conversely, because tumors hijack these same pathways to build immunosuppressive microenvironments, inhibiting efferocytosis remains a critical strategy in oncology. The synthesis of these divergent roles informs a \u201ccontext\u2010dependent directionality\u201d framework to guide the clinical translation of efferocytosis\u2010targeted precision therapies.<\/jats:p>","DOI":"10.1002\/mco2.70764","type":"journal-article","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T07:26:33Z","timestamp":1778657193000},"source":"Crossref","is-referenced-by-count":0,"title":["Efferocytosis: Signaling Pathways and New Therapeutic Strategies for Diseases"],"prefix":"10.1002","volume":"7","author":[{"given":"Lei","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Oncology The First Affiliated Hospital of Zhengzhou University  Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Ge","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer Sun Yat\u2010sen University Cancer Center  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zehua","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Oncology The First Affiliated Hospital of Zhengzhou University  Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yihua","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Oncology The First Affiliated Hospital of Zhengzhou University  Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongxu","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Oncology The First Affiliated Hospital of Zhengzhou University  Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruyue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Oncology The First Affiliated Hospital of Zhengzhou University  Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2175-9617","authenticated-orcid":false,"given":"Yanru","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Oncology The First Affiliated Hospital of Zhengzhou University  Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,13]]},"reference":[{"key":"e_1_2_14_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0240-6"},{"key":"e_1_2_14_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-022-00470-y"},{"key":"e_1_2_14_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.70546"},{"key":"e_1_2_14_5_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pharmtox-032723-110507"},{"key":"e_1_2_14_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1485222"},{"key":"e_1_2_14_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/imr.13214"},{"key":"e_1_2_14_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2021.111776"},{"key":"e_1_2_14_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature08296"},{"key":"e_1_2_14_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2016.13"},{"key":"e_1_2_14_11_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-06-162404"},{"key":"e_1_2_14_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3607"},{"key":"e_1_2_14_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4400404"},{"key":"e_1_2_14_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature06307"},{"key":"e_1_2_14_15_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4837-11.2012"},{"key":"e_1_2_14_16_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01521"},{"key":"e_1_2_14_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.14467"},{"key":"e_1_2_14_18_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-09-528752"},{"key":"e_1_2_14_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature06329"},{"key":"e_1_2_14_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-020-0232-1"},{"key":"e_1_2_14_21_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13287-022-03174-7"},{"key":"e_1_2_14_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxy055"},{"key":"e_1_2_14_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.acvd.2023.07.007"},{"key":"e_1_2_14_24_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1504276112"},{"issue":"1","key":"e_1_2_14_25_1","first-page":"286","article-title":"Tryptophan Metabolism in Animals: Important Roles in Nutrition and Health","volume":"3","author":"Yao K.","year":"2011","journal-title":"Frontiers in Bioscience"},{"key":"e_1_2_14_26_1","doi-asserted-by":"crossref","DOI":"10.1177\/1178646917691938","article-title":"Kynurenine Pathway of Tryptophan Metabolism: Regulatory and Functional Aspects","volume":"10","author":"Badawy A. 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