HMGA1 drives chemoresistance in esophageal squamous cell carcinoma by suppressing ferroptosis

• DOI: 10.1038/s41419-024-06467-2
• Publication Date: 2024-02-21T08:03:09Z
• Authors: Jing-Yu Yang; Xin-Yuan Lei; Kai-Yue He; Jin-Rong Guo; Meng-Jie Liu; Jun-Qi Li; Qiu-Tong Li; Zhi-Hao Jiang; Lei Zhang; Dan-Hui Wu; Yu-Jia Li; Qian-Hui Sun; Yong-Ping Jian; Zhi-Xiang Xu
• Keywords: Chromatin immunoprecipitation

Abstract Chemotherapy is a primary treatment for esophageal squamous cell carcinoma (ESCC). Resistance to chemotherapeutic drugs an important hurdle effective treatment. Understanding the mechanisms underlying chemotherapy resistance in ESCC unmet medical need improve survival of ESCC. Herein, we demonstrate that ferroptosis triggered by inhibiting high mobility group AT-hook 1 (HMGA1) may provide novel opportunity gain therapeutic strategy against chemoresistance HMGA1 upregulated and works as key driver cisplatin (DDP) repressing ferroptosis. Inhibition enhances sensitivity With transcriptome analysis following-up assays, demonstrated upregulates expression solute carrier family 7 member 11 (SLC7A11), transporter maintaining intracellular glutathione homeostasis accumulation malondialdehyde (MDA), thereby suppressing acts chromatin remodeling factor promoting binding activating transcription 4 (ATF4) promoter SLC7A11, hence enhancing SLC7A11 redox balance. We characterized enhanced chemosensitivity primarily attributed increased susceptibility resulting from depletion HMGA1. Moreover, utilized syngeneic allograft tumor models genetically engineered mice induce validated promotes restores DDP, efficacy. Our finding uncovers critical role repression thus establishment DDP ESCC, highlighting HMGA1-based rewiring strategies potential approaches overcome resistance.