ATP6V0D1 is a subunit of the V0 complex of vacuolar H+-ATPase (V-ATPase), a multisubunit enzyme that hydrolyzes ATP to translocate protons across membranes 123. This enzyme is responsible for acidifying intracellular compartments and, when targeted to the plasma membrane, acidifying the extracellular environment 2. ATP6V0D1 plays a critical role in intracellular iron homeostasis under aerobic conditions by regulating Fe2+ prolyl hydroxylase activity and HIF1A degradation 1. Beyond canonical acidification functions, ATP6V0D1 regulates alkaliptosis, a regulated cell death pathway triggered by intracellular alkalization; pharmacological inhibition of ATP6V0D1 via JTC801 promotes STAT3-mediated loss of lysosomal pH homeostasis in pancreatic ductal adenocarcinoma cells 4. ATP6V0D1 modulates multidrug resistance by suppressing ABCB1 expression, offering potential therapeutic strategies for paclitaxel-resistant ovarian cancer 5. In neuroinflammation, microglial ATP6V0D1 regulates V-ATPase assembly downstream of Tmem9, controlling complement activation and synaptic loss in Alzheimer's disease 6. ATP6V0D1 also interacts directly with phosphorylated tau in Alzheimer's disease brains and is associated with neurofibrillary tangle pathology 7. Additionally, ATP6V0D1 expression in circulating monocytes serves as a potential sepsis biomarker associated with 28-day mortality 8. ATP6V0D1 facilitates LC3-associated microautophagy through V-ATPase interactions, maintaining lysosomal homeostasis under cellular stress 9.