V-ATPase-targeted siRNA library screening reveals ATP6V1A negatively regulates UVB-induced keratinocyte senescence.

Photoaging is a form of premature skin aging mainly induced by long-term exposure to ultraviolet exposure. Lysosomes are key organelles responsible for the degradation and recycling of intracellular components and are essential for maintaining metabolic and nutrient homeostasis. Although lysosomal dysfunction is closely associated with cellular aging, the role of V-ATPase in regulating lysosomal function during photoaging remains incompletely understood. By screening a V-ATPase-targeted siRNA library and validating the results using publicly available single-cell transcriptomic datasets, we identified ATP6V1A as a key regulator of UVB-induced cellular senescence. Furthermore, ATP6V1A knockdown exacerbated the UVB-induced cellular senescence and impaired lysosomal acidification and membrane integrity, whereas ATP6V1A overexpression effectively alleviated keratinocyte senescence, lysosomal dysfunction and autophagy inhibition. Moreover, treatment with the V-ATPase inhibitor BafA1 aggregated cellular senescence phenotype and autophagy inhibition and this phenomenon partially reversed by ATP6V1A overexpression. Collectively, ATP6V1A promotes autophagy by regulating lysosomal function, thereby relieving UVB-induced cellular senescence.