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Mitochondrial Metabolic Dysfunction Drives PANoptosis in Retinal Pigment Epithelium During Funga

Review of metabolic and immune alterations in retinal pigment epithelium during fungal endophthalmitis, highlighting PANoptosis and the GSK3β–MITF–FBXW7 axis and potential host-dir

GIST

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.

Clinical Editorial

Unfolding Mechanisms in Fungal Endophthalmitis: A Metabolism–Immunity–Death Framework Context and scope: - The article reviews intraocular microenvironmental changes, retinal pigment epithelium (RPE) immune responses, and cell death remodeling in fungal endophthalmitis (FE), focusing on how host factors contribute to irreversible visual impairment beyond pathogen clearance. Study design and conceptual model: - The authors advance a framework labeled “metabolism–immunity–death,” linking fungal infection–driven mitochondrial metabolic reprogramming in RPE to downstream inflammatory and cell death pathways. - They describe a scenario in which metabolic disturbances correlate with cytosolic leakage of mitochondrial DNA (mtDNA), a danger-associated molecular pattern that may engage innate sensing. Molecular pathways and death modalities: - mtDNA is proposed to activate the ZBP1 sensor, promoting PANoptosome assembly and coordinating multiple programmed cell death pathways. - The core death processes implicated include pyroptosis, apoptosis, and necroptosis, collectively termed PANoptosis, within RPE during FE. Regulatory axis and potential dysregulation: - A GSK3β–MITF–FBXW7 signaling axis is highlighted as a regulatory node that may link defective metabolic adaptation to sustained RPE PANoptosis. - Dysregulation of this axis is proposed to connect metabolic imbalances with progressive retinal injury. Translational and clinical implications: - The concept supports exploring host-directed therapies (HDT) that address metabolic protection alongside antifungal treatment. - Potential biomarkers discussed include cell-free mtDNA as an early indicator of inflammatory risk. - The review considers retinoprotective strategies aimed at stabilizing metabolism and mitigating inflammatory cell death. Limitations and uncertainties: - The synthesis emphasizes mechanistic connections based on current literature; the direct causal relationships and clinical efficacy of proposed interventions remain to be validated in future studies.

Original source: https://www.frontiersin.org/articles/10.3389/fimmu.2026.1826337