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−inflammatory injury rather than pathogen burden alone. Focusing on the retinal pigment epithelium (RPE), a key component of the blood–retinal 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 “metabolism–immunity–death” 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−associated molecular pattern, mtDNA may activate the Z−DNA binding protein 1 (ZBP1) sensor, promote PANoptosome assembly and coordinate inflammatory cell death programs including pyroptosis, apoptosis, and necroptosis. We further highlight the regulatory GSK3β–MITF–FBXW7 axis and discuss how its dysregulation may connect impaired metabolic adaptation with irreversible RPE PANoptosis.
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−inflammatory injury rather than pathogen burden alone. Focusing on the retinal pigment epithelium (RPE), a key component of the blood–retinal 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 “metabolism–immunity–death” 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−associated molecular pattern, mtDNA may activate the Z−DNA binding protein 1 (ZBP1) sensor, promote PANoptosome assembly and coordinate inflammatory cell death programs including pyroptosis, apoptosis, and necroptosis. We further highlight the regulatory GSK3β–MITF–FBXW7 axis and discuss how its dysregulation may connect impaired metabolic adaptation with irreversible RPE PANoptosis. Finally, potential translational implications of host−directed therapy (HDT) are discussed, including the use of cell−free 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.