Interference with HMGCS1 or treatment with the HMGCS1 inhibitor of hymeglusin significantly promoted intracellular Fe2+, ROS and lipid peroxidation levels in SKMES cells, and induced ferroptosis in LUSC cells; Western blot assay showed that inhibition of HMGCS1 significantly promoted the expression of ACSL4.<h4>Conclusions</h4>Inhibition of HMGCS1, a target of LUSC, promotes ferroptosis in lung cancer cells and provides a research basis for screening new therapeutic targets for LUSC. This evidence concerns the gene HMGCS1 and lung carcinoma.