circSETD3 confers radiotherapy resistance in nasopharyngeal carcinoma by attenuating ER stress-induced autophagy and apoptosis via PDIA6 upregulation.

Nasopharyngeal carcinoma (NPC) is a malignant tumor of the head and neck with a high prevalence in Southeast Asia. Although radiotherapy remains the primary treatment modality, resistance to radiation in a subset of patients with advanced-stage disease significantly limits therapeutic outcomes, and the underlying molecular mechanisms remain poorly understood. In this study, we identified the circular RNA circSETD3 as a critical regulator of radioresistance in NPC. Functional assays in both in vitro and in vivo models demonstrated that circSETD3 enhances radioresistance by suppressing autophagy and apoptosis. Mechanistically, circSETD3 binds to the 3' untranslated region (3'UTR) of PDIA6 mRNA, stabilizing the transcript and increasing PDIA6 protein expression and its localization to the endoplasmic reticulum (ER). Elevated PDIA6 promotes the refolding of radiation-induced misfolded proteins, maintains ER proteostasis, and suppresses the unfolded protein response (UPR). This alleviation of ER stress reduces radiation-induced autophagy and apoptosis, ultimately enhancing NPC cell survival under radiotherapeutic stress. Together, these findings reveal a pivotal role for circSETD3 in promoting NPC radioresistance via PDIA6-mediated modulation of endoplasmic reticulum stress, and they provide a novel mechanistic framework and promising therapeutic target for improving radiotherapy efficacy in NPC.