Our results indicated that KLF5 downregulation increased lipid peroxidation, iron content, and ACSL4 and MDA expression and decreased SOD, GSH, and GPX4 levels, accompanied by morphological cellular changes that are characteristics of ferroptosis, indicating KLF5 knock down‐mediated promotion of ESCC ferroptosis. The gene discussed is ACSL4; the disease is esophageal squamous cell carcinoma.