Targeting oxaliplatin-induced peripheral neuropathy: neurobiological mechanisms, therapeutic evidence, and translational perspectives.

Oxaliplatin-induced peripheral neuropathy (OIPN) is a frequent dose-limiting toxicity of oxaliplatin-based chemotherapy and remains a major challenge in oncology practice. Clinically, OIPN presents as acute cold-induced dysesthesia, paresthesia, and numbness, as well as chronic cumulative sensory neuropathy that can impair neurological function, reduce quality of life, and lead to chemotherapy dose reduction or discontinuation. Increasing evidence indicates that OIPN is driven by an interconnected pathogenic network involving selective platinum accumulation in dorsal root ganglion neurons, oxidative stress, mitochondrial dysfunction, ion channel dysregulation, calcium overload, neuroinflammation, glial activation, and maladaptive nociceptive signaling. These overlapping mechanisms help explain why single-target interventions have often shown limited or inconsistent clinical efficacy. This review provides a mechanism- and stage-oriented synthesis of conventional pharmacological interventions, ion- and metal-ion-related approaches, natural compounds, herbal formulas, and acupuncture-based therapies. Its novel contribution lies in evaluating these diverse interventions within a unified neurobiological and evidence-tiered framework that links mechanistic targets and disease stages while explicitly distinguishing promising preclinical findings from established clinical efficacy. The available evidence remains uneven: conventional pharmacological agents have generally undergone more clinical evaluation but show limited or inconsistent benefit, whereas most natural compounds and traditional medicine-related interventions remain supported predominantly by preclinical studies or preliminary clinical evidence. Stage-specific and multimodal management may represent a promising framework for future investigation; however, the superiority of specific combinations has not been established and should be tested through biomarker-guided prospective clinical studies.