Hilpda, also known as hypoxia-inducible gene 2 (HIG2), is a hypoxia-inducible lipid droplet-associated protein. It is a key regulator in lipid metabolism, mainly functioning to inhibit intracellular lipolysis, such as suppressing adipose triglyceride lipase-mediated lipolysis [2,3,4,5]. Hilpda is involved in pathways related to lipid storage and homeostasis, and is important for cells to adapt to fatty acid supply and oxidation capacity [5]. Genetic models like knockout (KO) mice are valuable for studying its functions.

In a hepatocyte-specific Hilpda knockout (HilpdaΔHep) mouse model induced with NASH-driven HCC, Hilpda deficiency led to reduced hepatic steatosis and tumorigenesis but increased oxidative stress in the liver. Lack of Hilpda triggered flux of polyunsaturated fatty acids to membrane phospholipids and of saturated fatty acids to ceramide synthesis, exacerbating lipid peroxidation and apoptosis in hypoxia [1]. This shows that Hilpda plays a role in protecting HCC cells and establishing a pro-tumorigenic immune microenvironment in NASH.

In conclusion, Hilpda is a pivotal regulator in lipid metabolism, especially in restraining intracellular fatty acid flux. The Hilpda KO mouse models have revealed its significance in NASH-driven HCC, suggesting it as a potential therapeutic target for this disease [1].