{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T13:27:15Z","timestamp":1787146035448,"version":"build-2736575974"},"reference-count":131,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"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>Diabetes mellitus and its complications are chronic inflammatory diseases driven by metabolic stress. PANoptosis is a recently defined inflammatory lytic cell death pathway that integrates key features of pyroptosis, apoptosis, and necroptosis, and is orchestrated by the PANoptosome complex. Emerging evidence indicates that PANoptosis plays a critical role in the pathogenesis of diabetic complications, prominently in diabetic kidney disease, retinopathy, neuropathy, and cardiomyopathy, with emerging indirect evidence from surrogate models suggesting its potential involvement in diabetic foot ulcers. In this review, we summarise the core molecular mechanisms of PANoptosis, with a focus on the crosstalk among the three programmed cell death pathways under diabetic conditions. We discuss how metabolic stressors such as hyperglycaemia, lipotoxicity, and endoplasmic reticulum stress activate distinct PANoptosome assemblies\u2014including those involving Z-DNA-binding protein 1 (ZBP1), absent in melanoma 2 (AIM2), receptor-interacting protein kinase 1 (RIPK1), NOD-like receptor family pyrin domain-containing protein 12 (NLRP12), NOD-like receptor family pyrin domain-containing protein 3 (NLRP3), and NOD-like receptor family CARD domain-containing protein 5 (NLRC5)\u2014thereby linking metabolic dysregulation to inflammatory cell death. Moreover, we highlight recent advances in targeting PANoptosis as a therapeutic strategy, emphasising interventions directed at upstream metabolic triggers, PANoptosome components, and downstream effector molecules. Finally, we identify key knowledge gaps and propose future research directions to facilitate clinical translation. A deeper understanding of PANoptosis in diabetic complications may pave the way for novel therapeutic approaches that simultaneously block multiple cell death pathways to ameliorate disease progression.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1902219","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T12:54:25Z","timestamp":1787144065000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The role of PANoptosis in diabetes and its complications: mechanisms and therapeutic prospects"],"prefix":"10.3389","volume":"17","author":[{"given":"Jinhong","family":"Yan","sequence":"first","affiliation":[{"name":"Department of Geriatrics, The First Hospital of China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuyue","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, The First Hospital of China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fenqin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Geriatrics, The First Hospital of China Medical University","place":["Shenyang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/s2213-8587(25)00299-2","article-title":"11th edition of the IDF Diabetes Atlas: global, regional, and national diabetes prevalence estimates for 2024 and projections for 2050","volume":"14","author":"Genitsaridi","year":"2026","journal-title":"Lancet Diabetes Endocrinol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2023.115734","article-title":"Diabetes mellitus: classification, mediators, and complications; a gate to identify potential targets for the development of new effective 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