Atp6v0d1 encodes the ATPase H+ transporting V0 subunit D1, a major subunit of vacuolar-type ATPase (V-ATPase) in lysosome. V-ATPase is crucial for maintaining lysosomal pH homeostasis, which is involved in multiple biological processes such as protein degradation, nutrient sensing, and cell-death regulation [2,5].

In pancreatic ductal adenocarcinoma (PDAC), JTC801-mediated increase in ATP6V0D1 protein stability enhances its interaction with STAT3, maintaining lysosome homeostasis and promoting alkaliptosis. Pharmacological or genetic inhibition of STAT3 restores alkaliptosis sensitivity in ATP6V0D1-deficient cells [1]. In ovarian cancer, ATP6V0D1 mediates the down-regulation of ABCB1, a multidrug-resistance protein, and inducing ATP6V0D1-dependent alkaliptosis can overcome paclitaxel resistance [3]. Also, in a murine model with adipose-specific deletion of Atp6v0d1 (Atp6v0d1AKO), mice developed lipodystrophy and cardiomyopathy, showing its role in adipogenesis and cardiac function [4].

In summary, Atp6v0d1 is essential for lysosomal function and homeostasis. Studies using gene-knockout models, like Atp6v0d1AKO mice, have revealed its significance in diseases such as PDAC, ovarian cancer, and lipodystrophy-related cardiomyopathy, providing potential therapeutic targets for these conditions.