Cancer-associated fibroblast-derived fibulin-5 promotes radioresistance in non-small-cell lung cancer

  • Cell Rep. 2025 Aug 26;44(8):116018. doi: 10.1016/j.celrep.2025.116018.
Ran Zhang  1 ,  Weiwei Yan  1 ,  Jupeng Yuan  1 ,  Yuequn Ma  1 ,  Ziyuan Ren  2 ,  Xi Chen  2 ,  Juncai Lv  1 ,  Meng Wu  1 ,  Jinming Yu  3 ,  Dawei Chen  4
Affiliations
  • 1. Department of Radiation Oncology and Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China.
  • 2. Department of Radiation Oncology and Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China; Cheeloo College of Medicine, Shandong University Cancer Center, Jinan, Shandong, China.
  • 3. Department of Radiation Oncology and Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China; Cheeloo College of Medicine, Shandong University Cancer Center, Jinan, Shandong, China. Electronic address: [email protected].
  • 4. Department of Radiation Oncology and Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China; Cheeloo College of Medicine, Shandong University Cancer Center, Jinan, Shandong, China. Electronic address: [email protected].
PMID: 40711881 DOI: 10.1016/j.celrep.2025.116018
Abstract

Radioresistance impedes the effectiveness of Cancer radiotherapy, particularly due to the persistence of cancer-associated fibroblasts (CAFs) post-radiation. This study aims to identify CAF-expressed molecules predicting radiotherapy efficacy and to clarify the resistance mechanisms in non-small-cell lung Cancer (NSCLC). We identified higher Fibulin-5 (FBLN5) expression in the stromal regions of recurrent patients after radiotherapy utilizing spatial transcriptomics and FBLN5 knockdown in CAFs enhanced radiosensitivity. Mechanistically, Fibulin-5 binds to Integrin αVβ5 receptor, activates the Src-STAT3 pathway in CAFs and Cancer cells, downregulates acyl-CoA synthetase long-chain family member 4 (ACSL4), and impairs irradiation-activated Ferroptosis. Radioresistant Cancer cells are more capable of converting normal fibroblasts to CAFs, upregulating FBLN5 via exosomal miRNA. Activated CAFs further promote tumor radioresistance, confirmed by single-cell RNA Sequencing. Clinical tissue analysis showed that elevated Fibulin-5 expression is correlated with fibroblast activation and radioresistance. Thus, high Fibulin-5 expression in CAFs serves as a predictive biomarker for radiotherapy efficacy and a potential therapeutic target to improve NSCLC radiosensitivity.

Keywords
CP: Cancer; Fibulin-5; cancer-associated fibroblasts; ferroptosis; non-small cell lung cancer; radioresistance.
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