Delphinidin targets voltage-dependent anion channel 1 to inhibit ferroptosis and protect against retinal photochemical damage

Background: The molecular basis of retinal photochemical damage remains incompletely understood, limiting the development of targeted therapeutic strategies. Delphinidin, an anthocyanidin with reported protective effects, represents a promising candidate, but its direct molecular target and mechanism of action are unclear.

Methods: The molecular target of delphinidin was identified using Activity-Based Protein Profiling (ABPP), DARTS-MS, SPR, and CETSA. Its functional effects were investigated in 661 W photoreceptor cells and in a light-induced retinal damage model in Sprague-Dawley rats. Protein carbonylation was assessed via an alkynylaniline probe, and Voltage-Dependent Anion Channel 1 (VDAC1) oligomerization was examined by chemical crosslinking. Mitochondrial function, cGAS-STING pathway activation, and Ferroptosis markers were evaluated to delineate the underlying mechanism.

Results: VDAC1 was identified as a direct target of delphinidin. Light exposure induced VDAC1 carbonylation and oligomerization, leading to mitochondrial dysfunction characterized by cytochrome c release and mitochondrial DNA (mtDNA) leakage into the cytosol. Cytosolic mtDNA activated cGAS-STING pathway, which in turn promoted loss of the Ferroptosis suppressor GPX4 and triggered Ferroptosis. Delphinidin interrupted this cascade by binding to VDAC1 and inhibiting its carbonylation and oligomerization, thus limiting mtDNA leakage, attenuating cGAS-STING activation, preserving GPX4 abundance, and inhibiting Ferroptosis. In vivo, delphinidin intervention conferred significant protective effects, as evidenced by preservation of retinal histoarchitecture and reduced oxidative damage and Ferroptosis, CONCLUSION: This study identifies a novel mechanistic axis in RPD linking VDAC1 dysregulation to mtDNA-driven innate immune activation and Ferroptosis. It further establishes delphinidin as a direct VDAC1 targeting compound and highlights its therapeutic potential for the prevention of RPD.