ATP6V0D1 promotes alkaliptosis by blocking STAT3-mediated lysosomal pH homeostasis

Alkaliptosis, a type of regulated cell death driven by intracellular alkalization, was first described in pancreatic ductal adenocarcinoma (PDAC) cells after treatment with the opioid analgesic drug JTC801. Here, we used mass-spectrometry-based drug target identification, cellular thermal shift assay, and point mutation technologies to reveal ATP6V0D1 as a direct JTC801 target that drives alkaliptosis in human PDAC cells. Functionally, the protein stability of ATP6V0D1, when mediated by JTC801, increases the interaction between ATP6V0D1 and STAT3, resulting in increased expression and activity of STAT3 for sustaining lysosome homeostasis. Consequently, the pharmacological or genetic inhibition of STAT3 restores the sensitivity of ATP6V0D1-deficient cells to alkaliptosis in vitro or in suitable mouse models. Clinically, a high expression of ATP6V0D1 correlates with prolonged survival of patients with PDAC. Together, these results illustrate a link between ATP6V0D1 and PDAC and advance our understanding of alkaliptosis in targeted therapy.