Jul 2026· Journal of Photochemistry and Photobiology. B: Biology· Vol 282, pp.
113524
· 0 citations· 61 references
Medicine
TL;DR
It is found that intense light exposure caused photoreceptor loss, accompanied by features of ferroptosis and autophagy, including disrupted iron homeostasis, lipid peroxidation, mitochondrial impairment, autophagosome accumulation, and dysregulated expression of key molecular mediators.
Abstract
Retinal photochemical damage is associated with the development of ocular diseases, yet its underlying mechanisms are incompletely defined, and therapeutic strategies are limited. Delphinidin, an anthocyanidin with broad pharmacological activities, has been demonstrated to protect against retinal damage. However, the molecular basis of this effect remains unclear. Here, we investigated the pathogenic mechanisms of light-induced retinal damage and evaluated the therapeutic potential of delphinidin. We found that intense light exposure caused photoreceptor loss, accompanied by features of ferroptosis and autophagy, including disrupted iron homeostasis, lipid peroxidation, mitochondrial impairment, autophagosome accumulation, and dysregulated expression of key molecular mediators. Co-immunoprecipitation assays of FTH1 and NCOA4, together with confocal microscopy analyses of FTH1 and LAMP1 colocalization, demonstrated that light exposure exacerbates NCOA4-mediated ferritinophagy in retinal cells, whereas delphinidin attenuated this process. RNA-seq identified abnormal STING expression, and silencing STING with siRNA effectively inhibited NCOA4-mediated ferritinophagy induced by light exposure. Delphinidin modulated the cGAS-STING pathway by reducing light-induced DNA damage. Molecular docking further suggested that delphinidin may occupy the ATP-binding pocket of cGAS, indicating a potential competitive inhibitory interaction. These findings, for the first time in the context of photochemical retinal damage, identify STING activation and NCOA4-mediated ferritinophagy as contributors to retinal ferroptosis, and highlight delphinidin as a therapeutic candidate that acts by inhibiting cGAS-STING signaling, with molecular docking, molecular dynamics simulation, and CETSA assays suggesting that delphinidin exerts its retinal protective effect by engaging the ATP-binding pocket of cGAS.
Diabetic retinopathy (DR) is characterized by progressive retinal microvascular injury, with oxidative stress and ferroptosis increasingly recognized as key pathogenic contributors. This study investigated whether ubiquitin C-terminal hydrolase L1 (UCHL1) regulates retinal endothelial ferroptosis through stabilization of nuclear factor erythroid 2-related factor 2 (NRF2). Analysis of the GSE102485 dataset identified UCHL1 as a downregulated deubiquitinating enzyme in DR. Streptozotocin-induced type 1 diabetic mice and high glucose (HG)-induced human retinal capillary endothelial cells (HRCECs) were used, together with UCHL1 inhibition/knockdown, AAV-mediated UCHL1 overexpression, and NRF2 knockdown. UCHL1 expression was reduced in diabetic retinas and HG-induced HRCECs, accompanied by ferroptosis activation, mitochondrial injury, and endothelial dysfunction. Pharmacological inhibition or siRNA-mediated depletion of UCHL1 intensified oxidative stress, Fe2⁺ accumulation, lipid peroxidation, mitochondrial fragmentation, and cristae disruption, while impairing endothelial barrier integrity, migration, and tube formation. In vivo, LDN57444 aggravated retinal vascular leakage and fundus vascular abnormalities, whereas AAV-UCHL1 preserved retinal architecture and reduced vascular permeability. Mechanistically, co-immunoprecipitation and ubiquitination assays demonstrated that UCHL1 interacted with NRF2 and stabilized NRF2 by removing K48-linked polyubiquitin chains. Nuclear-cytoplasmic fractionation further showed that UCHL1 overexpression restored NRF2 abundance and increased nuclear NRF2 accumulation under HG conditions. Ferrostatin-1 rescued UCHL1 depletion-induced ferroptotic injury, whereas NRF2 knockdown abolished the protection conferred by UCHL1 overexpression. These findings highlight the UCHL1/NRF2 axis may represent a therapeutic target in DR.
Sanhua Xu, Jun Huang, Yi-Cang Wang et al.· Biochemical Pharmacology· 0 citations
Findings suggest that EGCG alleviates RPE damage associated with NF-κB p65-mediated ferroptosis, providing new insights into AMD pathogenesis and a promising therapeutic strategy.
Xiao-Yang Chen, Miao Han, Yi-Wen An et al.· Experimental Eye Research· 0 citations
Investigating the potential role of the RNA-binding protein human antigen R (HuR) in mediating ferroptosis during DR progression, as well as the protective effects of Procyanidin C1 (PC1), demonstrated that PC1 significantly alleviated oxidative stress and ferroptosis in both diabetic mice and high-glucose-treated BV2s.
Qun Liu, Song-Min Wang, Tao Jiao et al.· Experimental Eye Research· 0 citations
EGb 761 exerts a protective effect on photoreceptor cell damage in retinal degeneration and is associated with a modification of the AMPK/ERK signaling pathway that regulates oxidative stress and autophagy.
Qiu-ye Teng, M. Chudhary, Wenkang Dong et al.· Current Eye Research· 0 citations
Eugenol exerts neuroprotective effects in glaucoma excitotoxicity models by suppressing ferroptosis through Mfn2-mediated regulation of mitochondrial-LD homeostasis and the SLC7A11/GSH/GPX4 antioxidant pathway.
Qian Wang, Lemeng Feng, Cheng Zhang et al.· Molecular and Cellular Bioch...· 0 citations
Background: Traumatic optic neuropathy (TON) causes progressive retinal ganglion cell (RGC) loss and oxidative injury, leading to visual dysfunction. Ephrin B2 (EFNB2) is elevated in optic nerve injury; however, it is unclear how the fat mass and obesity-associated gene (FTO) regulates it upstream. This study examined whether RGCs are shielded from hydrogen peroxide (H2O2)-induced oxidative damage through FTO-mediated EFNB2 overexpression.Methods: Primary RGCs were isolated and exposed to H2O2 to establish an in vitro oxidative stress injury model. We first verified the concentration-dependent induction of FTO and EFNB2 by H2O2. Gain- and loss-of-function assays were performed using FTO overexpression and knockdown plasmids to assess its effects on RGC viability, apoptosis, reactive oxygen species (ROS) accumulation, caspase-3 activity, and the expression of EFNB2, erythropoietin-producing hepatoma receptor B4 (EPHB4) and apoptosis-related proteins. Rescue experiments with EFNB2 knockdown were further conducted to confirm whether EFNB2 acts as a downstream effector of FTO.Results: H2O2 treatment elevated FTO and EFNB2 expression in RGCs in a concentration-dependent manner (p < 0.01). FTO overexpression alleviated H2O2-induced reductions in cell viability, as well as increases in apoptosis, caspase-3 activation, and ROS levels (p < 0.001), while FTO knockdown exacerbated these injuries (p < 0.001). Moreover, FTO overexpression enhanced EFNB2 and EPHB4 expression, and suppressed Bax and cleaved caspase-3 levels (p < 0.001). Knockdown of EFNB2 reversed the protective effects of FTO overexpression on RGC survival, oxidative stress, and apoptosis (p < 0.001).Conclusions: FTO upregulates EFNB2 and EPHB4 expression, reduces ROS and apoptosis, and is associated with the protection of RGCs against H2O2-induced oxidative damage. The FTO/EFNB2 axis may represent a protective mechanism against oxidative damage in RGCs in vitro, warranting further investigation in traumatic optic neuropathy models.
Yi Yin, Zhao-Yang Meng, Yu Wang et al.· Discover medicine· 0 citations
