TRPM7 kinase: a target for multimodal drug development in neurological disorders.

Neurological disorders impose a rising global burden and often remain challenging to treat with conventional interventions, as their pathologies arise from interconnected cascades involving ionic imbalance, oxidative stress, mitochondrial dysfunction, and neuroinflammation. Transient receptor potential melastatin 7 (TRPM7) is a bifunctional "chanzyme" combining a divalent-permeable cation channel with a C-terminal α-kinase domain. This review synthesizes current knowledge of TRPM7 kinase, including its structural organization and regulation, and surveys its physiological roles in the nervous system. Converging genetic and pharmacological evidence links TRPM7 kinase activity to diverse brain pathologies, including ischemic and hypoxic-ischemic injury, epilepsy, Alzheimer's disease, and glioblastoma. Notably, TRPM7 kinase inactivation or inhibition exerts multimodal neuroprotection by attenuating apoptosis, oxidative stress, inflammation, and cytoskeletal remodeling. We also summarize emerging small-molecule modulators that probe kinase function, while acknowledging key limitations in selectivity, potential off-target effects, and uncertain brain penetration. Beyond these pharmacological challenges, critical gaps remain in defining kinase-channel coupling, cell type-specific substrate networks, and therapeutic windows in translational models. Overall, by integrating oxidative, inflammatory, and metabolic signaling with cytoskeletal control, TRPM7 kinase represents an underexplored but promising therapeutic node for modulating the complex injury pathways that underlie many neurological disorders. TRPM7 structure and its kinase-regulated signaling pathways in neurological disease. Schematic overview of TRPM7 structure and its involvement in cytoskeletal remodeling and glioblastoma progression, glial stem cells maintenance, nuclear translocation under OGD/R, Aβ degradation in Alzheimer's disease, seizure susceptibility and ischemic-related apoptosis and neuroinflammation. Abbreviations: Aβ amyloid-beta, OGD/R oxygen-glucose deprivation/reoxygenation. Created in https://BioRender.com .