Lidocaine suppresses glioma growth through DPP9-mediated ferroptosis

Glioma is one of the most aggressive malignant tumors of the central nervous system, with limited benefit from current therapeutic strategies. Identifying novel, safe, and effective therapeutic agents remains an urgent unmet need. Lidocaine, a widely used clinical local anaesthetic, has recently attracted attention for its potential anti-tumor effects. This study aimed to evaluate the inhibitory effects of lidocaine on glioma, identify potential molecular targets, and explore whether its anti-tumor activity is mediated through ferroptosis.

Human glioma cell lines U251 and LN229 were used to assess the effects of lidocaine on cell proliferation, migration, and invasion. Antitumor efficacy in vivo was evaluated using subcutaneous and orthotopic xenograft models in nude mice, combined with PET/CT and bioluminescence imaging. Network pharmacology integrated with glioma transcriptomic datasets was applied to screen potential targets. SMR analysis based on human serum and brain tissue datasets identified DPP9 as a glioma-associated risk gene. Single-cell RNA sequencing was used to characterise DPP9 expression, and DPP9 knockout models were established to investigate its role in ferroptosis. Intracellular ROS, MDA levels, and ferroptosis-related gene expression were subsequently analysed.

Lidocaine significantly inhibited glioma cell proliferation, migration, and invasion in vitro, and markedly reduced tumor growth in vivo. Integrated analyses identified DPP9 as a high-risk gene promoting glioma progression, predominantly expressed in malignant astrocytes. Both lidocaine treatment and DPP9 interference increased ROS and MDA levels, downregulated GPX4 and SLC7A11, and upregulated ACSL4.

Lidocaine suppresses glioma growth by targeting DPP9 and inducing ferroptosis, providing a mechanistic basis for its potential repurposing as an adjunctive therapeutic strategy for glioma.