Circular RNA circADARB1 enhances radiotherapy resistance in nasopharyngeal carcinoma via suppressing ferroptosis

Abstract

Abstract Background Nasopharyngeal carcinoma (NPC) is a prevalent head and neck malignancy in Southeast Asia. Radiotherapy is the primary clinical treatment for NPC, but radiotherapy resistance stands as the fundamental reason for treatment failure and patient mortality. Nevertheless, the mechanism underlying radiotherapy resistance in NPC remains elusive. Methods The expression of circADARB1 in NPC tissues was examined by quantitative real-time polymerase chain reaction and in situ hybridization. Colonies assay, MTT, ROS and lipid peroxidation level measurement, and nude mouse tumor model were employed to explore the role of circADARB1 enhances radiotherapy resistance via suppressing ferroptosis in vitro or in vivo. The target proteins regulated by circADARB1 were screened using mass spectrometry. The interactions between HSP90B1 and SLC7A11 or GPX4 were verified through co-immunoprecipitation and immunofluorescence assay. Results We identified a novel circular RNA, circADARB1, which is significantly upregulated in NPC tissues, is closely associated with unfavorable prognosis and radiotherapy resistance in NPC patients. Intriguingly, in vitro and in vivo experiments demonstrated that circADARB1 promotes radiotherapy resistance in NPC by inhibiting ferroptosis. Mechanistically, circADARB1 upregulates the expression of heat shock protein HSP90B1 through competitive adsorption of miR-615-5p. Elevated intracellular levels of HSP90B1 serve to repair misfolded proteins such as SLC7A11 and GPX4 which are typically affected by radiotherapy, thereby maintaining the stability and biological function of these proteins. In turn, SLC7A11 facilitates the transport of cystine into cells and the synthesis glutathione, while GPX4 utilizes glutathione to catalyze the reduction of intracellular lipid peroxidation induced by radiotherapy, which suppresses ferroptosis in cells and ultimately leads to radiotherapy resistance in NPC cells. Building on these findings, we have developed innovative polymer-coated quantum dot biomimetic nanoparticles that carry siRNA sequences targeting circADARB1 and ferrous ion (Fe2+). The results demonstrated that targeted inhibition of circADARB1, along with an increase in intracellular Fe2+, synergistically enhances ferroptosis of NPC cells following radiotherapy. Conclusions This work demonstrates that circADARB1 as a promising novel target for augmenting sensitivity of NPC to radiotherapy.