HPCAL1 (hippocalcin-like 1) is a calcium-binding protein that functions as a multifaceted regulator of cellular metabolism and cell fate decisions. Mechanistically, HPCAL1 directly binds to and regulates key signaling proteins: it inhibits RUVBL1-mediated mTOR pathway activation to suppress lipid biosynthesis 1, enhances LDHA phosphorylation to promote glycolytic metabolism in lung cancer 2, and suppresses TGF-β signaling in hepatic stellate cells through Smad2 ubiquitination regulation 3. HPCAL1 also serves as a selective autophagy receptor in chaperone-mediated autophagy pathways, promoting degradation of ferroptosis-related proteins 45. Clinically, HPCAL1 shows complex disease associations. High HPCAL1 expression correlates with poor prognosis in cholangiocarcinoma and non-small cell lung carcinoma, and is an independent predictor of reduced overall and relapse-free survival 62. Conversely, HPCAL1 loss in hepatocellular carcinoma renders tumors mTORC1-addicted and sensitive to mTOR inhibitors 1. HPCAL1 was identified as a biomarker in idiopathic pulmonary fibrosis 7 and functions as a fibrogenesis suppressor in liver fibrosis 3. In neural tissue, HPCAL1 is a layer-specific marker of primate visual cortex 8. These divergent roles suggest HPCAL1 functions as a context-dependent metabolic and signaling node with distinct therapeutic implications across disease types.