Hsdl2, or hydroxysteroid dehydrogenase-like 2, is a protein-coding gene with its encoded protein being involved in multiple biological functions. It is a mitochondrial protein that links nutritional cues to bile acid and cholesterol homeostasis. It is also associated with lipid metabolism and may be involved in several signaling pathways related to cell proliferation, apoptosis, and ferroptosis [1-3].

In gene-knockout (KO) and related functional studies, depletion of HSDL2 in hepatocytes decreases cholesterol conversion to bile acids, impairs FXR activity, and reduces mitochondrial respiration, fatty acid oxidation, and TCA cycle activity [1]. In bladder cancer cells, lentiviral-mediated HSDL2 knockdown inhibits cell proliferation and colony formation while promoting apoptosis [2]. In cholangiocarcinoma, HSDL2 knockdown promotes cancer progression by inhibiting ferroptosis through the P53/SLC7A11 axis [3]. In rectal cancer, high expression of HSDL2 promotes cell proliferation and cell-cycle progression [4]. In pancreatic cancer, silencing HSDL2 reduces cell proliferation and inhibits lipid metabolism [5].

In conclusion, HSDL2 plays a crucial role in maintaining bile acid and cholesterol homeostasis, and is also involved in the progression of multiple cancers. Gene-knockout mouse models have been instrumental in revealing these functions, highlighting HSDL2 as a potential therapeutic target in metabolic disorders and cancer treatment.