{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n HILPDA (also known as HIG2) is a hypoxia‐inducible, lipid droplet–associated protein that plays a multifaceted role in rewiring cellular lipid metabolism under stress conditions. In clear‐cell carcinomas, for example, HIF signaling—particularly via HIF‐2α—stimulates HILPDA expression to enrich polyunsaturated lipids, thereby promoting vulnerability to lipid peroxidation and ferroptosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In hepatic cells, HILPDA is a direct target of PPARα; its overexpression increases triglyceride storage by both enhancing diacylglycerol acyltransferase 1 (DGAT1) activity through physical interaction and impairing triglyceride secretion, thereby contributing to steatotic phenotypes"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "and."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " In parallel, HILPDA regulates lipid droplet dynamics by directly inhibiting adipose triglyceride lipase (ATGL)—similar to the established inhibitor G0S2—which decreases intracellular triglyceride hydrolysis and favors lipid storage during hypoxia, fatty acid loading, or nutrient deprivation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "and."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Beyond these metabolic functions, HILPDA appears to influence tumor biology in various contexts; its hypoxia‐driven induction contributes to lipid droplet accumulation that can support tumor growth and resistance to therapy, as observed in colorectal and pancreatic cancers"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "and."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Moreover, in certain immune cells and hematologic malignancies such as mantle cell lymphoma and activated macrophages, HILPDA is part of transcriptional programs that affect both lipid storage and inflammatory responses"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "and"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ", with additional supportive insights from adipocyte studies."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Collectively, these observations underscore HILPDA as a critical mediator linking hypoxic and nutrient stress signals to reprogramming of lipid metabolism—a convergence that not only facilitates cellular energy storage but may also be exploited therapeutically in cancer and metabolic disorders.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Yilong Zou, Michael J Palte, Amy A Deik, et al. 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