Amphiregulin and Epiregulin Confer Radioresistance in Esophageal Squamous Cell Carcinoma Through Oxidative Phosphorylation

  • Adv Sci (Weinh). 2025 Nov 9:e07524. doi: 10.1002/advs.202507524.
Zhang Lin  1 ,  Meilian Yao  1 ,  Xin Xu  2 ,  Dong Zhang  1 ,  Lei Xu  2 ,  Ling Rong  2 ,  Xiaohang Wang  2 ,  Yi Duan  1 ,  Chengkun Chen  1 ,  Jun Gu  1 ,  Yao Zhang  3 ,  Qiang Liu  4 ,  Qing Ye  5 ,  Gaoping Cui  1 ,  Yujun Hao  1 ,  Xiumei Ma  2
Affiliations
  • 1. State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200032, China.
  • 2. Department of Radiation Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
  • 3. Department of Gastroenterology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
  • 4. Department of Pathology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
  • 5. Department of Thoracic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
PMID: 41208199 DOI: 10.1002/advs.202507524
Abstract

Neoadjuvant chemoradiotherapy (nCRT) improves outcomes for locally advanced esophageal squamous cell carcinoma (ESCC) but exhibits variable efficacy due to heterogeneous radiosensitivity. In this study, metabolic profiling of 59 ESCC patients revealed significant alterations in tricarboxylic acid cycle (TCA) cycle intermediates in pathological complete responders (pCR) vs. non-responders (non-pCR) ESCC patients after nCRT. Functional experiments demonstrated that radioresistant ESCC cells (KYSE410R) exhibited elevated OXPHOS activity, which is reversed by targeting TCA cycle Enzymes (CPI-613 (Devimistat), fumarate hydratase-IN-1 (FH-IN-1), etc.) or Oxidative Phosphorylation (OXPHOS) inhibitors (IACS-010759, Rotenone, etc.). Irradiation-induced CCAAT Enhancer Binding Protein Beta (CEBPB) upregulated AREG/EREG expression, activating the ERBB/mTOR pathway to promote OXPHOS flux. Knockdown of CEBPB/AREG/EREG disrupted OXPHOS and sensitized ESCC cells to radiation. Clinically, high Amphiregulin/Epiregulin (AREG/EREG) levels correlated with nCRT resistance and poor prognosis. Collectively, the CEBPB/AREG/EREG axis drives radioresistance by reprogramming OXPHOS, suggesting inhibition of this pathway or OXPHOS itself as a promising strategy to enhance ESCC therapeutic responses.

Keywords
AREG; CEBPB; EREG; OXPHOS; esophageal squamous cell carcinoma; neoadjuvant chemoradiotherapy.
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