Hypoxia-inducible lipid droplet-associated protein (HILPDA)

Hypoxia-inducible lipid droplet-associated protein (HILPDA), originally identified as Hypoxia-inducible gene 2 (HIG2), is a 7-kDa protein that acts as a potent inhibitor of intracellular lipolysis. It predominantly functions by binding to adipose triglyceride lipase (ATGL), thereby blocking the hydrolysis of triglycerides and promoting the expansion of lipid droplets. This metabolic adaptation is frequently exploited by tumor cells, particularly in clear cell renal cell carcinoma (ccRCC) and glioblastoma, to survive the metabolic stresses of the tumor microenvironment. Beyond lipid storage, HILPDA has been implicated in augmenting oncogenic Wnt signaling and promoting tumor cell proliferation in an autocrine fashion. Clinically, HILPDA is a promising therapeutic target because its expression is largely restricted to hypoxic or diseased tissues, such as fatty livers and atherosclerotic plaques, while being minimally expressed in most healthy tissues. Preclinical studies have demonstrated that targeting HILPDA using antibodies or RNA interference can significantly reduce tumor growth and sensitize cells to ferroptosis. It also serves as a sensitive biomarker, as its secreted form is detectable in the plasma of patients with early-stage renal cell carcinoma. Current therapeutic development focuses on disrupting its interaction with ATGL or reducing its expression to combat both cancer progression and chronic metabolic diseases.

Other names

Hypoxia-inducible gene 2 proteinHIG2C7orf28Hypoxia-inducible protein 2

Inhibits intracellular lipolysis by physically binding to and suppressing the activity of adipose triglyceride lipase (ATGL), leading to increased lipid droplet accumulation and providing a survival advantage in hypoxic environments.