2. Academic Validation
  3. STAT1 increases the sensitivity of lung adenocarcinoma to carbon ion irradiation via HO-1-mediated ferroptosis

STAT1 increases the sensitivity of lung adenocarcinoma to carbon ion irradiation via HO-1-mediated ferroptosis

  • Mol Cell Biochem. 2025 Mar 14. doi: 10.1007/s11010-025-05240-z.
Yanliang Chen # 1 2,  Dandan Wang # 1 2,  Hongtao Luo 2 3,  Mingyu Tan 1 2,  Qian Wang 1 2,  Xun Wu 1 2,  Tianqi Du 1 2,  Qiuning Zhang 4 5,  Wenzhen Yuan 6 7
Affiliations

Affiliations

  • 1 The First School of Clinical Medicine, Lanzhou University, Chengguan District, No. 1, Donggang West Road, Lanzhou, 730030, Gansu, China.
  • 2 Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730030, Gansu, China.
  • 3 Graduate School, University of Chinese Academy of Sciences, Beijing, 101408, China.
  • 4 Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730030, Gansu, China. zhangqn@impcas.ac.cn.
  • 5 Graduate School, University of Chinese Academy of Sciences, Beijing, 101408, China. zhangqn@impcas.ac.cn.
  • 6 The First School of Clinical Medicine, Lanzhou University, Chengguan District, No. 1, Donggang West Road, Lanzhou, 730030, Gansu, China. yuanwzh@lzu.edu.cn.
  • 7 The First Hospital of Lanzhou University, Lanzhou, 730030, Gansu, China. yuanwzh@lzu.edu.cn.
  • # Contributed equally.
PMID: 40087208 DOI: 10.1007/s11010-025-05240-z
Abstract

Radiotherapy is a vital treatment agent for lung adenocarcinoma (LUAD) patients, while radioresistance remains a major factor in treatment failure. Here, we aimed to elucidate how signal transducer and activator of transcription 1 (STAT1) affected sensitivity to carbon ion irradiation for LUAD cells in vivo and in vitro. The results of colony formation, CCK-8, EdU, and calcein-AM/PI double-staining assays demonstrated that the overexpression of STAT1 markedly enhanced the inhibitory effect of carbon ion irradiation on the viability of LUAD cells (A549 and PC9 cells). Lactate Dehydrogenase (LDH) leakage assays identified Ferroptosis as the predominant form of cell death induced by STAT1 overexpression in LUAD cells. Meanwhile, the ferroptosis-related PCR array confirmed heme oxygenase 1 (HO-1) as a potential effector molecule of STAT1-induced Ferroptosis. Mechanistically, STAT1 overexpression resulted in phosphorylation at the serine 727 residue, triggering the upregulation of HO-1 expression and subsequent labile iron pool (LIP) accumulation. This process amplified the Fenton reaction, leading to increased Reactive Oxygen Species (ROS), lipid peroxides (LPO), and glutathione (GSH) depletion. HO-1 knockdown eliminated the Ferroptosis induced by the overexpression of STAT1. Furthermore, in vivo experiments showed that STAT1 overexpression enhanced the effect of carbon ion irradiation in inhibiting the growth of subcutaneous tumors in nude mice. These findings provide the foundation for the development of the STAT1-HO-1 axis as a radiosensitization target for LUAD patients.

Keywords

Carbon ion irradiation; Ferroptosis; HO-1; STAT1.

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