The peripheral nervous system can encounter alterations due to exposure to some of the most commonly used anticancer drugs (platinum drugs, taxanes, vinca alkaloids, proteasome inhibitors, thalidomide), the so-called chemotherapy-induced peripheral neurotoxicity (CIPN). CIPN can be long-lasting or even permanent, and it is detrimental for the quality of life of cancer survivors, being associated with persistent disturbances such as sensory loss and neuropathic pain at limb extremities due to a mostly sensory axonal polyneuropathy/neuronopathy. In the state of the art, there is no efficacious preventive/curative treatment for this condition. Among the reasons for this unmet clinical and scientific need, there is an uncomplete knowledge of the pathogenetic mechanisms. Ion channels and transporters are pivotal elements in both the central and peripheral nervous system, and there is a growing body of literature suggesting that they might play a role in CIPN development. In this review, we first describe the biophysical properties of these targets and then report existing data for the involvement of ion channels and transporters in CIPN, thus paving the way for new approaches/druggable targets to cure and/or prevent CIPN.

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common and significant side effect of cancer treatment, triggered by exposure to widely used chemotherapeutic agents such as vinca alkaloids, taxanes, platinum-based compounds, proteasome inhibitors, thalidomide, epothilones, and antibody-drug conjugates. CIPN can be long-lasting or even permanent, leading to a decline in patients' quality of life and negatively impacting the well-being of cancer survivors. It is typically characterized by polyneuropathy or neuronopathy, neuropathic pain, and axonal damage, primarily affecting the peripheral sensory nervous system. Emerging evidence suggests that anticancer agents may directly alter neuronal voltage-gated sodium channels (NaV), which could play a crucial role in the development of CIPN. This review explores the mechanisms underlying CIPN, with particular focus on the potential involvement of NaV alterations. Additionally, it examines pharmacological modulators of NaV, offering key insights into the prevention of axonal damage and the management of neuropathic pain associated with CIPN. Despite the availability of various strategies to manage CIPN, there are currently few evidence-based options for its prevention or effective treatment once it develops. As a result, CIPN remains an unmet clinical challenge, highlighting the need for further research into its underlying pathophysiological mechanisms to develop innovative therapies.

Background/Objectives: Oxaliplatin (OHP) is a key component of colorectal cancer chemotherapy, but OHP-induced peripheral neurotoxicity (OIPN) is a major dose-limiting adverse effect. OHP-related sodium-channel dysfunction could increase intracellular Na⁺ and sustain depolarization, conditions that may theoretically favor reverse-mode NCX activity, in which the exchanger promotes Ca²⁺ entry rather than Ca²⁺ extrusion. This study evaluated whether NCX2 targeting could reduce OHP-induced sensory neuron injury. Methods: Primary mouse dorsal root ganglion neurons were exposed to OHP, with or without SEA0400 (NCX modulator) pretreatment or siRNA-mediated NCX2 knockdown. Neuronal viability, neurite elongation, live-cell morphology, NCX2 fluorescence, and lipid droplet accumulation were quantified. Results: OHP reduced neuronal survival and neurite elongation and induced stress-related morphological changes and lipid droplet accumulation. NCX2-associated fluorescence varied by neuronal subtype, dose, and time. SEA0400 and partial NCX2 knockdown attenuated selected injury endpoints, mainly under low-dose conditions. Conclusions: These findings suggest that NCX2 may be involved in selected OHP-induced sensory neuron injury endpoints and support further investigation of NCX2 as a potential preventive target. However, reverse-mode NCX activity, Na⁺/Ca²⁺ fluxes, NCX2 directionality, and translational relevance require direct validation.