Targeting the HNRNPA2B1/HDGF/PTN Axis to Overcome Radioresistance in Non-Small Cell Lung Cancer

作者：Fushi Han, Shuzhen Chen, Kangwei Zhang, Kunming Zhang, Meng Wang, Peijun Wang · 发表于：Antioxidants and Redox Signaling · 年份：2025 · DOI：10.1089/ars.2024.0808 · 被引用次数：2 · 研究领域：RNA modifications and cancer、Cancer-related molecular mechanisms research、Fibroblast Growth Factor Research

Aims: Radioresistance in non-small cell lung cancer (NSCLC) presents a major barrier to effective treatment. This study explores the molecular mechanisms underlying this resistance, focusing on the heterogeneous nuclear ribonucleoprotein A2B1/hepatoma-derived growth factor/pleiotrophin (HNRNPA2B1/HDGF/PTN) signaling pathway and its role in autophagy-dependent ferroptosis regulation. Our aim is to uncover how this pathway contributes to tumor cell survival under radiotherapy stress, thereby identifying potential therapeutic targets to overcome radioresistance. Results: We developed radiotherapy-resistant lung cancer cell lines and assessed their proliferation and migration capabilities through Cell Counting Kit-8 and Transwell assays, respectively. Single-cell RNA sequencing revealed significant differences in gene expression profiles between radioresistance and radiation-sensitive cells. Functional studies, including immunofluorescence, flow cytometry, and biochemical staining, confirmed that radioresistance was associated with enhanced autophagy and altered ferroptosis. Furthermore, HNRNPA2B1 knockdown reduced the expression of Ki67 and proliferating cell nuclear antigen, markers of proliferation, in a mouse tumor model. In addition, modulation of HNRNPA2B1 affected protein interactions and N6-methyladenosine RNA modifications, as demonstrated by reverse transcription–quantitative polymerase chain reaction, Western blot, and methylation RNA immunoprecipitation–quantitative P...