Atp6v0d1, encoding the ATPase H+ transporting V0 subunit D1, is a key subunit of vacuolar-type ATPase (V-ATPase) in lysosome [2]. V-ATPase is responsible for maintaining lysosomal acidification, which is crucial for many cellular processes such as protein degradation, nutrient recycling, and cell-death regulation [2,5]. It is also involved in pathways like the ATP6V0D1-STAT3 pathway related to alkaliptosis [1,3].

In pancreatic ductal adenocarcinoma (PDAC) cells, JTC801-mediated increase in ATP6V0D1 protein stability enhances its interaction with STAT3, sustaining lysosome homeostasis and promoting alkaliptosis. Pharmacological or genetic inhibition of STAT3 restores alkaliptosis sensitivity in ATP6V0D1-deficient cells in vitro and in mouse models. Clinically, high ATP6V0D1 expression correlates with prolonged PDAC patient survival [1]. In ovarian cancer, ATP6V0D1 can mediate the down-regulation of ABCB1, a multidrug-resistance protein, and inducing ATP6V0D1-dependent alkaliptosis may be a strategy against paclitaxel-resistant ovarian cancer cells [4].

In summary, Atp6v0d1 is vital for lysosomal function and homeostasis. Studies using in vitro and in vivo models, especially those with genetic manipulation of Atp6v0d1, have revealed its role in alkaliptosis-related cancer cell death mechanisms. These findings may offer potential therapeutic strategies for treating pancreatic and ovarian cancers [1,4].