HMGCS1 (3-hydroxy-3-methylglutaryl-CoA synthase 1) catalyzes the rate-limiting step in the mevalonate pathway by condensing acetyl-CoA with acetoacetyl-CoA to form HMG-CoA, which is subsequently converted to mevalonate for cholesterol biosynthesis 1. The enzyme's activity is tightly regulated through multiple mechanisms including post-translational modifications and protein degradation. KAT5-mediated acetylation on K273 enhances HMGCS1 protein stability in glioblastoma stem cells 2, while the mTORC1-CTLH E3 ligase system regulates HMGCS1 degradation through the Pro/N-degron pathway during nutrient stress 3. HMGCS1 plays crucial roles in cancer progression through metabolic reprogramming. In hepatocellular carcinoma, the CSN6-SPOP-HMGCS1 axis promotes tumorigenesis via YAP1 activation 4, while in pancreatic neuroendocrine neoplasms, HMGCS1 mediates lipid metabolism reprogramming through the PI3K/AKT/mTOR pathway 5. The enzyme is also regulated by ERRα in endometrial cancer, where high glucose levels promote both glycolysis and cholesterol synthesis 6. ARID1A-inactivated cancers show particular dependence on residual mevalonate pathway activity, making HMGCS1 a potential therapeutic target 7. These findings highlight HMGCS1's central role in linking cholesterol metabolism to cancer cell survival and proliferation.