PIKfyve preserves endolysosomal function in photoreceptors and RPE cells to maintain retinal integrity.

Photoreceptors rely on efficient clearance of outer segment material and mislocalized proteins to maintain cellular health and visual function. While retinal pigment epithelial (RPE) cells remove shed outer segment tips through daily phagocytosis, the mechanisms by which photoreceptors eliminate misfolded or mistargeted proteins are not well understood. Here, we identify PIKfyve, a lipid kinase that synthesizes phosphatidylinositol 3,5-bisphosphate [PI(3,5)P₂], as a key regulator of degradative and metabolic pathways in the retina. PIKfyve is highly expressed in rod photoreceptors, and its selective deletion causes progressive retinal degeneration marked by vacuolation, increased lysosomal markers, loss of outer nuclear layer thickness, and decline of rod and cone function. Partial or complete reduction of PIKfyve further accelerates degeneration in P23H rhodopsin mutant mice. In the RPE, PIKfyve deficiency disrupts phagocytosis and autophagy, leading to the accumulation of rhodopsin, lysosomal proteins, and lipid droplets, accompanied by metabolic imbalance. These results demonstrate that PIKfyve is essential for maintaining photoreceptor and RPE integrity by supporting lysosomal function, protein turnover, and metabolic stability, and suggest that enhancing PIKfyve activity may offer therapeutic potential for retinal degenerative diseases. This study is timely, as pharmacological inhibition of PIKfyve with apilimod-currently under clinical investigation for autoimmune, neurodegenerative, and infectious diseases-raises significant safety concerns, including lysosomal swelling, vacuolization, and impaired protein degradation, which could ultimately compromise retinal homeostasis and vision.