The multifaceted role of ASICs channels into the nervous system and their potential use as a therapeutic target for neuro-disorders.

Acid-sensing ion channels (ASICs) are increasingly recognized as promising therapeutic targets within both the central and peripheral nervous systems, with significant relevance to neurodegenerative and neuroinflammatory pathologies. Among these, ASIC1a has been most closely implicated in the progression of neurodegeneration, primarily through its roles in mediating excitotoxicity, intracellular Ca²⁺ overload, and pro-inflammatory signalling cascades. Pathological acidification, a common feature of many neurological disorders, activates ASICs, contributing to neuronal injury and the activation of glial cells, which together sustain a deleterious cycle of inflammation and neurodegeneration. Importantly, ASICs are not confined to neurons but are also expressed in glial populations, including astrocytes and microglia, where their activation by extracellular acidosis can initiate and amplify immune responses. This glial involvement positions ASICs as modulators of neuroimmune dynamics, suggesting that their inhibition could mitigate both neuronal and glial-mediated pathology. A growing body of preclinical evidence supports the therapeutic potential of ASICs inhibition, with several pharmacological antagonists demonstrating the capacity to preserve synaptic integrity, attenuate glial activation, and reduce neuronal loss. Targeting ASICs thus offers a dual-pronged strategy that addresses both neuronal damage and glial-driven inflammation. This review aims to examine the roles of ASICs in both neuronal and glial cells across the CNS and PNS, and to evaluate whether modulation of ASICs activity may represent a strategy to move beyond symptomatic relief toward disease-modifying therapies that target the underlying mechanisms of neurodegenerative disorders.