Acrolein-induced PKM2 modification drives NETosis and glioma progression
Hsiang-Tsui Wang1, Zhen-Jie Tong2, Ya-Rou Lin2
1Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan; Institute of Food Safety and Health Risk Assessment, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan; Doctor Degree Program in Toxicology, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
Free Radical Biology & Medicine
|October 6, 2025
Summary
Acrolein, a molecule linked to brain tumors, drives neutrophil extracellular trap (NET) formation in glioblastoma. Inhibiting this process, known as NETosis, may offer a new therapeutic strategy for aggressive brain cancers.
Area of Science:
- Neuro-oncology
- Immunology
- Metabolic pathways
Background:
- Glioblastoma (GBM) is an aggressive brain tumor associated with hypoxia and treatment resistance.
- Hypoxia promotes lipid peroxidation, generating acrolein, which causes cellular damage and oxidative stress.
- Neutrophil extracellular traps (NETs) released via NETosis are implicated in tumor progression and poor prognosis.
Purpose of the Study:
- To investigate the role of acrolein in regulating NETosis in glioma.
- To elucidate the molecular mechanisms linking acrolein, PKM2, and NETosis in glioblastoma.
- To evaluate therapeutic strategies targeting the acrolein-PKM2-NET axis.
Main Methods:
- Transcriptomic profiling of peripheral neutrophils from glioma patients.
- In vitro co-culture systems of glioma cells and neutrophils.
- Analysis of acrolein and NET levels in patient plasma and tumor tissues.
- Pharmacological inhibition of PKM2 and acrolein scavenging.
- Assessment of tumor growth in subcutaneous and orthotopic glioma models.
Main Results:
- Glioma patients exhibit upregulated NET-associated pathways and elevated NET levels correlating with acrolein accumulation.
- Hypoxia-induced acrolein promotes NETosis, enhancing glioma cell proliferation and migration.
- Acrolein modifies PKM2, inducing its nuclear translocation and co-activation of HIF-1α, leading to increased IL-6 and IL-8 expression.
- PKM2 activation (TEPP-46) and acrolein scavenging (hydralazine) inhibited NETosis in vitro and suppressed tumor growth in vivo.
Conclusions:
- Acrolein is a key regulator of NETosis in glioblastoma, forming an acrolein-PKM2-NET axis.
- Targeting NETosis, potentially through acrolein scavenging or PKM2 modulation, represents a promising therapeutic avenue for glioblastoma.
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