Hmgcl, also known as 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-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 also involved in leucine degradation [3,8]. It is associated with multiple metabolic pathways and has significant biological importance in energy metabolism and cell-related processes. Genetic models, such as KO/CKO mouse models, are valuable for studying its functions.

In various cancers, Hmgcl shows diverse roles. In hepatocellular carcinoma (HCC), Hmgcl depletion promotes HCC proliferation and metastasis, while overexpression reverses this trend. Hmgcl increases acetylation at histone H3K9, promoting DPP4 transcription, leading to HCC cells' vulnerability to ferroptosis [1]. In glioblastoma, Hmgcl promotes progression and glioma stem cell maintenance. Knockdown of Hmgcl suppresses proliferation and invasion, as it decreases acetyl-CoA, reducing NFAT1 nuclear accumulation and H3K27ac level, and down-regulating FOXM1 and β-catenin [2]. In osteosarcoma, Hmgcl is downregulated, and its overexpression inhibits cell proliferation, migration, invasion, and tumor growth in vivo by inhibiting the PI3K/AKT/mTOR signaling pathway via β-HB [3]. In lung cancer, Hmgcl is downregulated, and overexpression inhibits tumorigenicity. TNFα treatment decreases HMGCL protein level through IKKβ-mediated phosphorylation and NEDD4-mediated degradation [4]. In pancreatic cancer, Hmgcl promotes tumor progression, and its depletion impedes migration, invasiveness, and tumor growth [5]. In nasopharyngeal carcinoma, Hmgcl inactivation 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-related metabolic processes and is significantly involved in multiple cancer-related biological processes. Studies using KO/CKO mouse models and other loss-of-function experiments have revealed its functions in cancer development, providing potential molecular targets for cancer treatment.