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

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.