{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T15:13:34Z","timestamp":1787238814725,"version":"build-2736575974"},"reference-count":182,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T00:00:00Z","timestamp":1781827200000},"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>Diabetic retinopathy (DR), a leading cause of blindness, is driven by hyperglycemia-induced neurovascular damage. Emerging evidence indicates that PANoptosis, an integrated inflammatory programmed cell death modality encompassing apoptosis, pyroptosis, and necroptosis, participates in the progression of diabetic retinal damage; however, the supporting evidence varies substantially across clinical specimens, diabetic animal models, high-glucose cultured retinal cells, and non-DR inflammatory disease models. This review systematically summarizes the latest advances in PANoptosis-associated mechanisms underlying DR pathogenesis, focusing on PANoptosome signaling networks, non-coding RNA-mediated regulation, and immune-metabolic crosstalk. We outline promising candidate biomarkers including PANoptosis-related gene signatures and inflammatory cell death molecules, and critically evaluate multiple translational therapeutic strategies covering small-molecule inhibitors, gene intervention, and nanomedicine delivery. Importantly, we further address context-dependent dual roles of PANoptosis, potential safety risks of non-selective PANoptosis blockade, challenges in blood\u2013retinal barrier penetration, systemic immune side effects, and pathological heterogeneity among DR subtypes and disease stages. Since PANoptosis also fundamentally contributes to host defense and retinal innate immune homeostasis, DR therapeutic strategies should prioritize biomarker-guided, local ocular delivery, time-dependent stage intervention, and cell-type-specific fine tuning, rather than generalized systemic suppression. By reconciling mechanistic progress with unresolved translational bottlenecks, this review proposes that PANoptosis serves as a dynamic and evolving conceptual framework for interpreting inflammatory neurovascular degeneration in DR, instead of an entirely confirmed clinical therapeutic target. We emphasize the urgent need for DR-specific mechanistic verification, longitudinal biomarker cohort studies, and well-designed multicenter clinical trials to advance safe and precise targeted interventions.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1668099","type":"journal-article","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T05:47:39Z","timestamp":1781848059000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["PANoptosis in diabetic retinopathy: immunological insights into mechanisms and translational therapies"],"prefix":"10.3389","volume":"17","author":[{"given":"Lingli","family":"Ma","sequence":"first","affiliation":[{"name":"Department of endocrinology and metabolism, China-Japan Union Hospital of Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of 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