Hmgcl, also known as 3-hydroxy-3-methylglutaryl-CoA lyase, is a key enzyme. It catalyzes the cleavage of HMG-CoA into acetyl-CoA and acetoacetic acid, serving as a rate-limiting enzyme in ketone body metabolism and being involved in leucine degradation [1,2,3]. It is associated with multiple biological pathways related to energy metabolism and epigenetic regulation. Genetic models are valuable for studying its functions.

In hepatocellular carcinoma (HCC), Hmgcl depletion promoted proliferation and metastasis, while overexpression reversed this trend. Hmgcl-induced β-hydroxybutyrate production increased histone H3K9 acetylation, promoting DPP4 transcription, leading to HCC cells' vulnerability to ferroptosis [1]. In glioblastoma, knockdown of Hmgcl suppressed proliferation and invasion, as Hmgcl-mediated changes in acetyl-CoA levels altered H3K27ac modification, activating the FOXM1/β-catenin pathway [2]. In osteosarcoma, Hmgcl is downregulated, and its overexpression inhibits cell proliferation, migration, and invasion, as well as tumor growth in vivo, by inhibiting the PI3K/AKT/mTOR signaling pathway via β-HB [3]. In lung cancer, Hmgcl is downregulated, and TNFα-mediated phosphorylation by IKKβ promotes its degradation via NEDD4, with overexpression of Hmgcl inhibiting tumorigenicity [4]. In pancreatic cancer, depletion of Hmgcl impedes migration, invasiveness, and tumor growth, while β-OHB (produced by Hmgcl) stimulates metastatic dissemination [5]. In nasopharyngeal carcinoma, inactivation of Hmgcl promotes proliferation and metastasis by suppressing oxidative stress [6]. In benign prostatic hyperplasia, miR-1202 targets Hmgcl to regulate cell proliferation, apoptosis, and epithelial-to-mesenchymal transition [7].

In conclusion, Hmgcl plays crucial roles in energy metabolism-related biological processes. Through gene knockout or conditional knockout mouse models and other functional studies, its functions in various cancers and benign prostatic hyperplasia have been revealed. Understanding Hmgcl's functions provides potential therapeutic targets for these diseases.