HILPDA (hypoxia inducible lipid droplet associated) is a hypoxia-responsive protein that regulates intracellular lipid metabolism by inhibiting adipose triglyceride lipase (ATGL)-mediated lipolysis 1. Under hypoxic conditions, HILPDA accumulates on lipid droplets and prevents triglyceride breakdown, leading to increased lipid storage 2. This mechanism involves direct inhibition of ATGL protein levels, thereby reducing fatty acid mobilization from triglyceride stores 2. HILPDA expression is regulated by the HIF-1α pathway, which is activated under hypoxic conditions and during metabolic stress 3. The protein plays critical roles in cancer biology, where it promotes tumor cell survival under hypoxic conditions by preventing lipotoxic cell death 4. In NASH-driven hepatocellular carcinoma, HILPDA protects cancer cells by restraining fatty acid flux and reducing lipid peroxidation-induced apoptosis 4. HILPDA also contributes to clear-cell carcinoma characteristics by enriching polyunsaturated lipids and creating vulnerability to ferroptosis 5. Beyond cancer, HILPDA regulates inflammatory responses in macrophages by modulating lipid precursor availability for prostaglandin synthesis 2. Clinically, HILPDA expression is associated with poor prognosis in various cancers and serves as a potential therapeutic target for metabolic diseases 4.