2. Academic Validation
  3. HSF4 alleviates ferroptosis in colorectal cancer through transcriptional regulation of MBOAT1/2

HSF4 alleviates ferroptosis in colorectal cancer through transcriptional regulation of MBOAT1/2

  • Funct Integr Genomics. 2026 Feb 2;26(1):35. doi: 10.1007/s10142-026-01822-2.
Kelin Yue # 1,  Haolin Wu # 2,  Kexin Li 3,  Shu Yang 4,  Xuan Bai 1,  Wenjing Zhang 5,  Yu Zhang 6
Affiliations

Affiliations

  • 1 Department of Gastroenterology, the First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, #157 Jinbi Rd, Kunming, Yunnan, 650032, China.
  • 2 The Laboratory of Basic Pharmaceutical Research, The General Hospital of the People's Liberation Army (PLAGH), Beijing, China.
  • 3 Faculty of Medicine, Kunming University of Science and Technology, Kunming, China.
  • 4 Depatment of Medical Oncology, the First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, China.
  • 5 Depatment of Medical Oncology, the First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, China. [email protected].
  • 6 Department of Gastroenterology, the First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, #157 Jinbi Rd, Kunming, Yunnan, 650032, China. [email protected].
  • # Contributed equally.
PMID: 41622376 DOI: 10.1007/s10142-026-01822-2
Abstract

Heat shock factor (HSF) family proteins modulate Ferroptosis in various tumors. We previously confirmed that HSF4 performs a carcinogenic role in colorectal Cancer (CRC), but its function in Ferroptosis remains unclear. Therefore, this study aims to reveal whether HSF4 regulates the Ferroptosis process in CRC and its potential molecular mechanisms. This study found that HSF4 overexpression markedly attenuated Erastin-induced cell death and mitochondrial damage in HT29 and HCT116 cells. HSF4 effectively reduced lipid peroxidation and Fe2+ levels in CRC cells and reversed Erastin-induced changes in Ferroptosis marker, including GPX4, SLC7A11, and ACSL4. ChIP-seq combined with GEO dataset analysis identified 249 potential HSF4 target genes, among which the promoter region of the lipid metabolism-related gene MBOAT1/2 binds to HSF4 and is transcriptionally activated. In vitro experiments, MBOAT1/2 knockdown reversed the inhibitory effect of HSF4 overexpression on CRC cell death, mitochondrial damage, lipid peroxidation, Fe2 + accumulation, and changes in Ferroptosis marker. In vivo experiments, MBOAT1/2 knockdown effectively reduced tumor volume and downregulated the number of Ki-67-positive cells, GPX4, and SLC7A11, while upregulating ACSL4. In conclusion, HSF4 alleviates Ferroptosis in CRC cells and facilitates tumor progression by upregulating MBOAT1/2 transcription, thereby limiting lipid peroxidation and Fe2+ accumulation.

Keywords

Colorectal cancer; Ferroptosis; HSF4; Lipid metabolism; MBOAT1; MBOAT2; Transcriptional regulation.

Figures
Products