Molecular mechanism underlying radiation resistance in esophageal squamous cell carcinoma

Abstract

Esophageal squamous cell carcinoma (ESCC) is a major global health challenge, especially in Asia, due to its high incidence, mortality and poor prognosis. As there are no reliable early - diagnosis biomarkers, ESCC is often detected at an advanced stage, when radiotherapy becomes the main treatment. However, the emergence of radioresistance significantly compromises treatment efficacy, leading to tumor recurrence and metastasis. Although some research has been done on the mechanisms of ESCC radiation resistance, a comprehensive understanding remains elusive. To address this knowledge gap and identify more molecular targets for overcoming radiation resistance, we established a radioresistant ESCC cell model and conducted systematic 4D label-free proteomic profiling. Quantitative analysis revealed 364 differentially expressed proteins, predominantly enriched in nucleotide excision repair, glutathione metabolism, and insulin resistance pathways. Functional validation identified TXNDC12 as a critical regulator of radioresistance, and its overexpression is significantly associated with enhanced glutathione synthesis and intracellular ROS scavenging. This study provides the first proteomic evidence linking redox homeostasis modulation through TXNDC12-GSH axis activation to ESCC radioresistance, offering novel therapeutic targets for overcoming radiation resistance and improving clinical outcomes in advanced ESCC management.