Calcium-iron crosstalk in epileptogenesis: Unraveling mechanisms and therapeutic opportunities

Epilepsy, a chronic neurological disorder affecting millions globally, remains poorly understood in its etiology and therapeutic management. Emerging evidence highlights the intricate interplay between calcium (Ca2+) and iron (Fe2+/Fe3+) ions in modulating neuronal excitability, oxidative stress, and synaptic plasticity-key processes implicated in epileptogenesis. This review synthesizes current knowledge on the dual roles of Ca2+ and Fe2+/Fe3+ in epilepsy, emphasizing their bidirectional regulatory mechanisms and pathological synergism. Calcium dysregulation, mediated through voltage-gated channels (e.g., Cav1.2, Cav3.2), store-operated calcium entry (SOCE), and mitochondrial calcium uniporters (MCU), exacerbates neuronal hyperexcitability and seizure propagation. Concurrently, iron overload drives ferroptosis via lipid peroxidation and glutathione depletion, while iron deficiency impairs neurodevelopmental processes. Crucially, Ca2+-Fe2+ crosstalk intersects at multiple nodes: TRP channels (e.g., TRPC6, TRPML1) facilitate dual ion transport; mitochondrial dysfunction links Ca2+ overload with Fe2+-dependent ROS generation; and inflammatory cascades disrupt both ion homeostasis. Clinically, antiepileptic drugs targeting Ca2+ channels (e.g., ethosuximide, zonisamide) and emerging ferroptosis inhibitors (e.g., deferoxamine, RTA 408) underscore the therapeutic potential of modulating these pathways. However, drug resistance and incomplete seizure control necessitate novel strategies leveraging ion interaction networks. We propose that combinatorial approaches targeting Ca2+-Fe2+ signaling hubs-such as MCU-TRPML1 axes or redox-sensitive RyR channels-may offer synergistic benefits. Future research must prioritize cross-model validation, advanced neuroimaging biomarkers, and multidisciplinary frameworks to translate mechanistic insights into precision therapies. This comprehensive analysis positions Ca2+-Fe2+ crosstalk as a pivotal frontier in epilepsy research, bridging molecular pathophysiology with innovative treatment paradigms.