Targeting the SNAI1-LAMP3 axis to restore lysosomal function and alleviate autophagic flux impairment to delay retinal degeneration.

Abstract

Retinal degenerative diseases are a leading cause of irreversible blindness. Their pathogenesis is intricately linked to oxidative stress-induced dysfunction of retinal pigment epithelial (RPE) cells and subsequent retinal degeneration. Macroautophagy/autophagy, a critical cellular degradation pathway, plays a vital role in maintaining RPE homeostasis, yet its dysregulation in retinal degenerative diseases remains poorly understood. In this study, we observed that sodium iodate (NaIO3), an oxidative stress inducer, triggered lysosomal dysfunction via lysosomal membrane permeabilization (LMP), thereby impairing autophagic flux in RPE cells and exacerbating retinal degeneration. RNA sequencing identified Lamp3 (lysosomal-associated membrane protein 3) as a downregulated gene following NaIO3 treatment. Functionally, LAMP3 overexpression alleviated NaIO3-induced LMP, improved lysosomal function, and alleviated autophagic impairment. Furthermore, upregulation of LAMP3 reduced oxidative stress and apoptosis in RPE cells, while alleviating retinal degeneration in a NaIO3-induced mouse model. Mechanistically, our data suggested that NaIO3 upregulated the transcription factor SNAI1, which acts as a transcriptional repressor of LAMP3. SNAI1 knockdown increased LAMP3 expression, thereby facilitating the recovery of lysosomal function and the alleviation of autophagic impairment. Collectively, our findings indicate that the SNAI1-LAMP3 axis contributes to the regulation of the autophagy-lysosomal pathway in retinal degeneration, highlighting a potential therapeutic target for delaying disease progression.