2. Academic Validation
  3. Cancer-associated fibroblast-derived fibulin-5 promotes radioresistance in non-small-cell lung cancer

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

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: sdyujinming@126.com.
  • 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: dave0505@yeah.net.
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.

Figures
Products