2. Academic Validation
  3. SETD7-mediated H3K4me1 activates ALDH1A3 to drive ferroptosis resistance in esophageal squamous cell carcinoma

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

  • Cell Death Dis. 2025 Nov 7;16(1):810. doi: 10.1038/s41419-025-08133-7.
Yang Feng 1 2,  Xingyue Liu 3,  Yangxia Wang 1 2,  Mingyuan Zhang 1 2,  Yangyang Ji 1 2,  Longfeng Zhang 1 2,  Yilu Tong 1 2,  Fuyou Zhou 4,  Hongyang Liu 5,  Liang Ming 1 2,  Junhu Wan 6 7
Affiliations

Affiliations

  • 1 Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • 2 Key Clinical Laboratory of Henan province, Zhengzhou, China.
  • 3 Anhui Province Key Laboratory of Immunology in Chronic Diseases, Bengbu Medical University, Bengbu, China.
  • 4 Thoracic Department, Anyang Tumor Hospital, Henan Key Medical Laboratory of Precise Prevention and Treatment of Esophageal Cancer, Anyang, China.
  • 5 Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • 6 Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. [email protected].
  • 7 Key Clinical Laboratory of Henan province, Zhengzhou, China. [email protected].
PMID: 41203594 DOI: 10.1038/s41419-025-08133-7
Abstract

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.

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