| 3-Hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) is the cytosolic isoform of HMG-CoA synthase and acts as the first committed enzyme of the mevalonate branch of cholesterol biosynthesis, catalyzing the condensation of acetyl-CoA with acetoacetyl-CoA to generate HMG-CoA that feeds directly into HMG-CoA reductase and the downstream production of sterols and non‑sterol isoprenoids. The enzyme belongs to the thiolase superfamily and functions as a homodimeric cytosolic protein with a catalytic site that positions acetyl-CoA and acetoacetyl-CoA for Claisen condensation, providing a gatekeeping step that determines the flux of acetyl units from central carbon metabolism into the mevalonate pathway. HMGCS1 activity links acetyl-CoA availability to the synthesis of mevalonate-derived products such as cholesterol, dolichols, ubiquinone, and prenyl donors, and thereby influences membrane biogenesis, protein prenylation, and other lipid‑dependent processes that support cell growth and survival. Expression of HMGCS1 is detectable in many tissues and aligns with sites of active cholesterol synthesis, and transcriptional control integrates with sterol regulatory networks that coordinate HMGCS1 with HMG-CoA reductase and other mevalonate enzymes to maintain intracellular sterol homeostasis. Elevated HMGCS1 expression is a recurrent feature of tumor cells with heightened mevalonate pathway activity, where increased HMGCS1 levels correlate with aggressive phenotypes and provide a metabolic signature of cancer stem cell–enriched subpopulations in luminal and basal breast cancer models, associating this enzyme with self‑renewal capacity and resistance‑related traits. Functional targeting of HMGCS1 in these breast cancer models diminishes cancer stem cell markers, sphere‑forming capacity, and tumorigenic features more strongly than standard statin treatment and acts at the level of HMG-CoA generation upstream of HMG-CoA reductase. In gastric cancer, HMGCS1 expression aligns with tumor progression, and pathway analyses place this enzyme as a regulatory node whose activity supports proliferation, migration, and other malignant properties through sustained provision of mevalonate intermediates required for oncogenic signaling and membrane dynamics. |
