2. Academic Validation
  3. Targeting the HNRNPA2B1/HDGF/PTN Axis to Overcome Radioresistance in Non-Small Cell Lung Cancer

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

  • Antioxid Redox Signal. 2025 Aug;43(4-6):189-214. doi: 10.1089/ars.2024.0808.
Fushi Han 1 2,  Shuzhen Chen 3,  Kangwei Zhang 1 2,  Kunming Zhang 4,  Meng Wang 5,  Peijun Wang 1 2
Affiliations

Affiliations

  • 1 Department of Medical Imaging, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China.
  • 2 Institute of Medical Imaging Artificial Intelligence, Tongji University School of Medicine, Shanghai, China.
  • 3 Department of Nuclear Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.
  • 4 Department of Internal Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.
  • 5 Department of Radiotherapy, Tongji Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.
PMID: 40643435 DOI: 10.1089/ars.2024.0808
Abstract

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 PCR. Innovation: This study provides new insights into how the HNRNPA2B1/HDGF/PTN pathway promotes radioresistance by influencing autophagy-dependent Ferroptosis. This mechanism represents a potential vulnerability that could be therapeutically targeted to improve radiotherapy efficacy in lung Cancer. Conclusion: Our findings demonstrate that the HNRNPA2B1/HDGF/PTN signaling pathway plays a crucial role in sustaining radioresistant phenotypes by modulating Autophagy and Ferroptosis. Targeting this pathway may enhance the therapeutic response in NSCLC, offering a novel strategy to combat treatment resistance. Antioxid. Redox Signal. 43, 189-214.

Keywords

HNRNPA2B1 signaling; autophagy; ferroptosis; lung cancer; radioresistance.

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