Cadmium-induced ATP6V0A1 destabilization impairs lysosomal function to disrupt hepatic lipid homeostasis

Chronic cadmium (Cd²⁺) exposure is epidemiologically linked to metabolic disorders like hypertriglyceridemia, but the precise mechanisms disrupting hepatic lipid metabolism are unclear. Lysosomal function, critical for lipid degradation via autophagy, represents a potential yet unexplored target in Cd²⁺-induced steatosis. We utilized multi-strain mouse models and human hepatocytes to investigate the effects Cd²⁺ exposure. Serum metabolomics and biochemical assays were employed to assess lipid profiles. The role of ATP6V0A1, a key subunit of the V-ATPase proton pump, was systematically examined using genetic approaches (knockdown and overexpression) in conjunction with lysosomal pH probes, autophagic flux assays, and protein stability measurements. Cd²⁺ exposure consistently induced hypertriglyceridemia in mice, accompanied by a significantly altered serum triglyceride metabolomic profile. In the liver, Cd²⁺ downregulated ATP6V0A1 protein, which impaired lysosomal acidification and thereby blocked autophagic flux. Mechanistically, Cd²⁺ did not affect ATP6V0A1 mRNA levels but promoted its protein degradation, which could be attenuated by inhibitors of both the proteasome and the autophagy-lysosomal pathway. Functionally, either pharmacological inhibition of lysosomal acidity or genetic knockdown of ATP6V0A1 recapitulated Cd²⁺-induced intracellular and secreted triglyceride accumulation. Crucially, overexpression of ATP6V0A1 rescued Cd²⁺-induced lysosomal dysfunction, restored autophagic flux, and normalized triglyceride levels. Our study uncovers a novel molecular pathway wherein Cd²⁺ post-transcriptionally destabilizes ATP6V0A1, which paradoxically leads to lysosomal dysfunction and autophagic block, ultimately driving hepatic triglyceride accumulation, thereby nominating ATP6V0A1 as a central regulator and potential therapeutic target for chemical-associated fatty liver disease.