{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T05:14:53Z","timestamp":1778130893603,"version":"3.51.4"},"reference-count":158,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T00:00:00Z","timestamp":1778112000000},"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":"<jats:p>Efferocytosis\u2014the phagocytic clearance of apoptotic cells\u2014is central to tissue homeostasis and the active resolution of inflammation. Although its mechanistic basis and disease relevance have been studied in isolation, no review has comprehensively integrated neutrophil efferocytosis mechanisms, their pathophysiological roles across major chronic inflammatory gastrointestinal diseases, and natural product-based therapeutic strategies\u2014a gap this work addresses. We systematically describe the efferocytic recognition cascade, encompassing find-me signals, eat-me signals (including phosphatidylserine and the underappreciated plasminogen\/M6P-IGF2R axis), and don\u2019t-eat-me checkpoints (CD47-SIRP\u03b1). We clarify that efferocytosis is not restricted to M2-polarized macrophages\u2014M0 and M1 macrophages also participate\u2014but that polarization state critically determines the pro-resolving coupling of downstream signaling. We analyze shared and disease-specific efferocytic defect mechanisms in inflammatory bowel disease, chronic gastritis, NAFLD\/NASH, and pancreatitis, identifying IL-10R signaling failure, receptor shedding, CD47 upregulation, and SPM deficiency as convergent pathological nodes. Against this backdrop, we critically evaluate natural product strategies\u2014flavonoids, polyphenols, alkaloids, terpenoids, polysaccharides, and omega-3 fatty acids\u2014targeting these nodes, with explicit grading of evidence levels. Translational challenges and the potential of single-cell sequencing, spatial transcriptomics, and patient-derived organoid co-culture systems are also discussed. Restoring efferocytosis represents a mechanistically grounded therapeutic frontier for chronic gastrointestinal disease.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1835168","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T04:56:06Z","timestamp":1778129766000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Neutrophil efferocytosis in chronic inflammatory gastrointestinal diseases: mechanistic insights and therapeutic potential"],"prefix":"10.3389","volume":"17","author":[{"given":"Si-ying","family":"Ye","sequence":"first","affiliation":[{"name":"Liaoning University of Traditional Chinese Medicine","place":["Shenyang, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Qu","sequence":"additional","affiliation":[{"name":"Liaoning University of Traditional Chinese Medicine","place":["Shenyang, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jia-hao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Liaoning University of Traditional Chinese Medicine Affiliated Second Hospital","place":["Shenyang, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xi-han","family":"Wang","sequence":"additional","affiliation":[{"name":"Liaoning University of Traditional Chinese Medicine","place":["Shenyang, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian-bo","family":"Wang","sequence":"additional","affiliation":[{"name":"Liaoning University of Traditional Chinese Medicine","place":["Shenyang, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ya-nan","family":"Xue","sequence":"additional","affiliation":[{"name":"Liaoning University of Traditional Chinese Medicine","place":["Shenyang, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ji-dong","family":"Liu","sequence":"additional","affiliation":[{"name":"Liaoning University of Traditional Chinese Medicine","place":["Shenyang, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2514","article-title":"The neutrophil in vascular inflammation","volume":"17","author":"Phillipson","year":"2011","journal-title":"Nat Med"},{"key":"B2","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1053\/j.gastro.2016.09.046","article-title":"Management strategies to improve outcomes of patients with inflammatory bowel diseases","volume":"152","author":"Colombel","year":"2017","journal-title":"Gastroenterology"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1080\/00365521.2016.1235224","article-title":"Neutrophils in ulcerative colitis: a review of selected 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