ITGA5 promotes homologous recombination mediated radioresistance in esophageal squamous cell carcinoma by upregulating RAD51AP1 expression

Radiotherapy resistance represents a critical barrier to successful treatment of esophageal squamous cell carcinoma (ESCC), driving tumor recurrence and poor patient survival. We establish constitutive overexpression of integrin α5 (ITGA5) as a central molecular determinant of ESCC radioresistance. Clinically, elevated ITGA5 expression correlates with radiation therapy failure and reduced overall survival. Mechanistically, ITGA5 sustains persistent FAK/AKT/GSK-3β/β-Catenin signaling activation, which drives MYC-dependent transactivation of RAD51AP1. This signaling axis enhances homologous recombination repair efficiency by facilitating RAD51 chromatin loading, enabling effective DNA damage resolution and radioresistance maintenance. Genetic validation confirms the indispensable roles of RAD51AP1 and MYC in this process. Critically, pharmacological inhibition of ITGA5 with ATN-161 restores radiation sensitivity in preclinical models, suppressing tumor growth and enhancing DNA damage accumulation. Our work defines the ITGA5/FAK/β-catenin/MYC/RAD51AP1 pathway as a key mechanistic driver of radioresistance and validates ITGA5 as a clinically actionable target for ESCC therapy.