This study reveals a novel epigenetic-metabolic axis (SETD7-H3K4me1-ALDH1A3/NADH/CoQ10H2) that regulates ESCC progression and ferroptosis sensitivity, which highlights the clinical translational value of SETD7 in ESCC prognosis assessment and therapeutic development. The gene discussed is ALDH1A3; the disease is esophageal squamous cell carcinoma.