{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T04:56:26Z","timestamp":1776056186135,"version":"3.50.1"},"reference-count":66,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T00:00:00Z","timestamp":1776038400000},"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>Fungal endophthalmitis (FE), although less common than bacterial endophthalmitis, carries a disproportionately high risk of irreversible blindness. Clinical observations show that some patients continue to experience progressive visual loss even after successful microbiological clearance, suggesting that disease outcomes are strongly influenced by excessive host immune\u2212inflammatory injury rather than pathogen burden alone. Focusing on the retinal pigment epithelium (RPE), a key component of the blood\u2013retinal barrier, this review summarizes recent advances in intraocular microenvironmental alterations, RPE immune responses, and the remodeling of cell death pathways during FE pathogenesis. We outline a conceptual framework centered on a \u201cmetabolism\u2013immunity\u2013death\u201d axis. In this model, fungal infection induces mitochondrial metabolic reprogramming and dynamic imbalance in RPE cells, which can be associated with cytosolic leakage of mitochondrial DNA (mtDNA). As a danger\u2212associated molecular pattern, mtDNA may activate the Z\u2212DNA binding protein 1 (ZBP1) sensor, promote PANoptosome assembly and coordinate inflammatory cell death programs including pyroptosis, apoptosis, and necroptosis. We further highlight the regulatory GSK3\u03b2\u2013MITF\u2013FBXW7 axis and discuss how its dysregulation may connect impaired metabolic adaptation with irreversible RPE PANoptosis. Finally, potential translational implications of host\u2212directed therapy (HDT) are discussed, including the use of cell\u2212free mtDNA as an early biomarker and therapeutic strategies that combine metabolic protection with antifungal treatment. Collectively, this review provides a mechanistic perspective on the poor visual outcomes of FE and identifies potential targets for retinoprotective intervention.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1826337","type":"journal-article","created":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T04:38:41Z","timestamp":1776055121000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Mitochondrial metabolic dysfunction drives PANoptosis in retinal pigment epithelium during fungal endophthalmitis: emerging roles of the MITF\u2013FBXW7 axis"],"prefix":"10.3389","volume":"17","author":[{"given":"Xiaohan","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Ningde Municipal Hospital, Ningde Clinical Medical College of Fujian Medical University","place":["Ningde, 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