Inhibition of JNK signaling attenuates photoreceptor ferroptosis caused by all-trans-retinal.

The disruption of the visual cycle leads to the accumulation of all-trans-retinal (atRAL) in the retina, a hallmark of autosomal recessive Stargardt disease (STGD1) and dry age-related macular degeneration (AMD), both of which cause retinal degeneration. Although our previous studies have shown that atRAL induces ferroptosis and activates c-Jun N-terminal kinase (JNK) signaling in the retina, the relationship between JNK signaling and ferroptosis in atRAL-mediated photoreceptor damage remains unclear. Here, we reported that JNK activation by atRAL drove photoreceptor ferroptosis through ferritinophagy. In photoreceptor cells loaded with atRAL, activated JNK phosphorylated c-Jun, which facilitated its nuclear translocation and promoted the expression of the nuclear receptor coactivator 4 (NCOA4). Elevated NCOA4 induced ferritin degradation via lysosomal processing, a process known as ferritinophagy, thereby releasing a large amount of labile iron. Iron overload led to the generation of reactive oxygen species (ROS) and lipid peroxidation, ultimately culminating in ferroptosis. Treatment with the JNK inhibitor JNK-IN-8, as well as the knockout of Jnk1 and Jnk2 genes, significantly rescued atRAL-loaded photoreceptor cells from ferritinophagy-induced ferroptosis. Abca4Rdh8 mice, which exhibit atRAL accumulation in the retina following light exposure, are commonly used to study the pathological processes of STGD1 and dry AMD. In these mice, light exposure activated the JNK/c-Jun/NCOA4 axis, resulting in ferritinophagy in the neural retina. Importantly, intraperitoneal administration of JNK-IN-8 significantly rescued retinal function and photoreceptors from ferritinophagy-induced ferroptosis and effectively mitigated retinal degeneration in light-exposed Abca4Rdh8 mice. This study underscores the critical role of the JNK/c-Jun/NCOA4 axis in mediating atRAL-induced ferritinophagy, which drives ferroptosis and retinal atrophy, suggesting that targeting this pathway may offer a potential therapeutic approach for STGD1 and dry AMD.