Targeting lipid metabolism-associated lncHMGCS1 suppressed cell proliferation and restored intracellular lipid homeostasis by regulating ACSL3 in gastric cancer.

Previous work has indicated that lipid metabolic reprogramming plays a critical role in gastric cancer (GC) development, yet the underlying molecular mechanisms remain largely undefined. In the present study, we identified a novel lipid metabolism-associated long non-coding RNA, 3-Hydroxy-3-Methylglutaryl-CoA Synthase 1 (lncHMGCS1), which is aberrantly upregulated in GC tissues and cell lines. Functional assays demonstrated that lncHMGCS1 overexpression could promote intracellular lipid droplet accumulation, elevate the triglyceride, total cholesterol, and low-density lipoprotein cholesterol levels, and enhance GC cell proliferation. Mechanistically, lncHMGCS1 can suppress expression of miR-18b-5p, a microRNA that directly targets both lncHMGCS1 and acyl-CoA synthetase long-chain family member 3 (ACSL3). ACSL3 knockdown reversed the oncogenic effects of lncHMGCS1 on GC cells in a miR-18b-5p-dependent manner, highlighting the critical role of the lncHMGCS1-ACSL3 axis in lipid metabolic reprogramming. Collectively, our findings establish lncHMGCS1 as a driver of lipid metabolism and tumorigenesis in GC, laying the groundwork for the development of novel diagnostic and therapeutic targets for managing this disease.