HSD17B4, encoding 17β-hydroxysteroid dehydrogenase type 4, is a peroxisomal bifunctional enzyme pivotal for peroxisomal β-oxidation of very long-chain fatty acids (VLCFA) and acetyl-CoA synthesis [1,2,4]. It also plays a role in estradiol metabolism, with the highest levels of its mRNA transcription and specific activity found in the liver, kidney, ovary, and testes [4]. Mutations in HSD17B4 are associated with a fatal form of Zellweger syndrome [4].

In Hsd17B4 -knockout mice, acetate administration restores motor function, enhances primary cilia formation, and preserves the Purkinje layer, suggesting HSD17B4 deficiency impairs primary ciliogenesis and cilia-mediated signaling, and this can be rescued by acetyl-CoA [1]. In BT-474 breast cancer cells, HSD17B4 knockout suppresses cellular proliferation, enhances sensitivity to lapatinib, and leads to metabolic changes including VLCFA accumulation and PUFA decrease [2]. In prostate cancer cells, knockdown of HSD17B4 significantly suppresses proliferation, migration, and invasion, while overexpressing it has opposite effects [3].

In conclusion, HSD17B4 is crucial for peroxisomal metabolism, primary cilia regulation, and is involved in the progression of certain cancers. Gene-knockout mouse models have been instrumental in revealing its role in ciliopathy-like symptoms, breast cancer metabolism, and prostate cancer progression, providing insights into potential therapeutic targets for related diseases.