SETD7-mediated H3K4me1 activates ALDH1A3 to drive ferroptosis resistance in esophageal squamous cell carcinoma

SET domain-containing 7 (SETD7, also known as KMT7 or SET7/9), a histone lysine methyltransferase (HKMT) responsible for catalyzing histone H3 lysine 4 monomethylation (H3K4me1), has emerged as a key regulator in multiple cancers. However, the biological functions and epigenetic regulatory mechanisms of SETD7 in esophageal squamous cell carcinoma (ESCC) remain unclear. Our study found that SETD7 expression is significantly upregulated in ESCC tissues and positively correlates with clinical staging. Functional analyses revealed that SETD7 promotes ESCC cell proliferation and migration in vitro, while accelerating tumor growth in vivo. Additionally, SETD7 knockdown increased ESCC cell sensitivity to ferroptosis induction, indicating its dual functionality in tumorigenesis and ferroptosis resistance. Cleavage Under Targets and Tagmentation (CUT&Tag) sequencing analysis systematically mapped H3K4me1 modifications in ESCC cells, identifying ALDH1A3 (aldehyde dehydrogenase 1 family member A3) as a key downstream target. Mechanistically, SETD7-mediated H3K4me1 deposition at the ALDH1A3 promoter drives transcriptional activation, increasing the level of reduced coenzyme Q10 (CoQ10H₂) and inhibiting lipid peroxidation. 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. Schematic diagram illustrating the mechanism by which SETD7 accelerates ESCC progression through enhancing ferroptosis resistance. Created with BioRender.