ATP6V0D2 encodes a macrophage-specific subunit of the vacuolar H+-ATPase (V-ATPase) complex that plays critical roles in autophagy regulation and cellular homeostasis. The protein facilitates autophagosome-lysosome fusion by interacting with SNARE proteins STX17 and VAMP8, as well as RAB7 and VPS41, promoting SNARE complex assembly and enhancing lysosomal acidification and activity 12. ATP6V0D2 deficiency in macrophages leads to impaired autophagy, increased mitochondrial damage, enhanced inflammasome activation, and reduced bacterial clearance 1. In metabolic dysfunction-associated steatohepatitis (MASH), ATP6V0D2 regulates XBP1-mediated cholesterol metabolism and maintains hepatic lipid homeostasis, with deficiency exacerbating disease progression 3. The protein also contributes to antiviral immunity by promoting YAP lysosomal degradation, which enhances interferon-β production 4. Additionally, ATP6V0D2 plays roles in cancer biology, where it promotes autophagic degradation of EPAS1/HIF2α in renal cell carcinoma and reverses sunitinib resistance 2. Beyond macrophages, ATP6V0D2 is expressed in pulmonary ciliated cells and club cells, potentially contributing to high-altitude adaptation 5, and influences osteoblast-osteoclast communication in bone homeostasis 6.