HMGCS1 catalyzes the condensation of acetyl-CoA with acetoacetyl-CoA to form HMG-CoA, the first committed step in the mevalonate pathway leading to cholesterol and isoprenoid synthesis. The enzyme functions as a homodimer and is primarily regulated at the transcriptional level through sterol-responsive elements. During nutrient stress, mTORC1 inhibition promotes CTLH E3 ligase-mediated proteasomal degradation of HMGCS1 via the Pro/N-degron motif, modulating mevalonate pathway flux 1. In cancer contexts, HMGCS1 plays a central role in supporting malignant progression. In clear cell ovarian carcinoma with ARID1A inactivation, mevalonate pathway inhibition by simvastatin suppresses tumor growth and synergizes with anti-PD-L1 immunotherapy by promoting inflammasome-regulated pyroptosis 2. In hepatocellular carcinoma, CSN6-mediated stabilization of HMGCS1 activates YAP1 to promote tumorigenesis, and HMGCS1 depletion enhances efficacy of YAP inhibitors in patient-derived models 3. In glioblastoma, lymphatic endothelial cell-derived CCL21 induces KAT5-mediated acetylation of HMGCS1 at K273, enhancing protein stability and cholesterol synthesis in glioblastoma stem cells 4. In pancreatic neuroendocrine neoplasms, HMGCS1 works downstream of ACSS2 to activate the PI3K/AKT/mTOR pathway and promote lipid metabolism reprogramming 5. These findings establish HMGCS1 as a druggable metabolic vulnerability in multiple cancer types.