RBFOX2 suppresses NETosis and glioma growth via 5hmC-dependent PDGFB decay

  • Cell Rep. 2026 Jun 23;45(6):117546. doi: 10.1016/j.celrep.2026.117546.
Xi Chen  1 ,  Weiwei Dai  1 ,  Hanlin Wang  2 ,  Jianing Fang  1 ,  Bowen Yin  1 ,  Changwei Liu  1 ,  Yuling Chen  2 ,  Ruixin Wu  3 ,  Yiheng Cai  4 ,  Shasha Bian  2 ,  Rihan Hai  1 ,  Jin Li  2 ,  Yiqian Zhu  5 ,  Minfeng Shu  6
Affiliations
  • 1. Department of Pharmacology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Microbiology, Key Laboratory of Medical Molecular Virology (Ministry of Education/ National Health Commission/ Chinese Academy of Medical Sciences), Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; Nanhu Laboratory, Jiaxing, Zhejiang Province 314002, China.
  • 2. Department of Pharmacology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Microbiology, Key Laboratory of Medical Molecular Virology (Ministry of Education/ National Health Commission/ Chinese Academy of Medical Sciences), Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
  • 3. Department of Pharmacology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China.
  • 4. Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
  • 5. Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China.
  • 6. Department of Pharmacology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Microbiology, Key Laboratory of Medical Molecular Virology (Ministry of Education/ National Health Commission/ Chinese Academy of Medical Sciences), Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; Nanhu Laboratory, Jiaxing, Zhejiang Province 314002, China. Electronic address: [email protected].
PMID: 42284147 DOI: 10.1016/j.celrep.2026.117546
Abstract

Neutrophil extracellular traps (NETs) are increasingly recognized as key regulators of tumor progression, yet the molecular circuitry that governs their induction in Cancer remains elusive. Here, we identify the RNA-binding protein RBFOX2 as a tumor suppressor that curtails glioma growth by coordinately restraining tumor cell proliferation and NETosis. RBFOX2 expression is markedly reduced in glioma and positively correlates with patient survival. Mechanistically, RBFOX2 binds to 5-hydroxymethylcytidine (5hmC)-modified sites within PDGFB mRNA and promotes its decay, thereby dampening AKT-SP1 signaling and repressing CSF3 transcription. This repression limits neutrophil-mediated NET formation in the tumor microenvironment, as confirmed in PAD4-/- mice and upon CSF3 neutralization. Collectively, our study uncovers a 5hmC-dependent post-transcriptional mechanism linking RBFOX2 to NETosis control and glioma suppression, revealing RBFOX2 as a potential biomarker and therapeutic lever and establishing a broader paradigm in which RNA-binding proteins couple post-transcriptional RNA modification and immune regulation in tumor evolution.

Keywords
CP: cancer; NETosis; RBFOX2; glioma; tumor microenvironment.
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