Neuroinflammatory Mechanisms and Therapeutic Targets in Oxaliplatin-Induced Peripheral Neuropathy: a Comprehensive Review

Oxaliplatin-induced peripheral neuropathy (OIPN) is a severe, dose-limiting complication that significantly reduces quality of life in Cancer patients, with no effective preventive or therapeutic options currently available. There is increasing evidence that neuroinflammation plays a central role in OIPN initiation and progression. This review provides a critical and up-to-date analysis of recent studies on the molecular mechanisms of oxaliplatin-induced neuroinflammation, with a particular focus on the integration of mitochondrial dysfunction, immune-mediated inflammation, glial activation, MicroRNA dysregulation, and gut-nerve axis disruption. Recent findings demonstrate that oxaliplatin disrupts mitochondrial dynamics, increases oxidative stress, and impairs blood-nerve barrier integrity, triggering neuroinflammatory responses. Neuroinflammation in OIPN is mediated through the activation of several key signaling pathways, including MAPK, NF-κB, Wnt/β-catenin, TLR4, and mTOR, which lead to increased production of pro-inflammatory cytokines and activation of glial cells. Furthermore, emerging evidence has identified dysregulation of the gut-nerve axis and alterations in gut microbiota composition as contributing factors that exacerbate oxaliplatin-induced neuroinflammation and neuropathic pain. Various pharmacological and plant-derived compounds, such as naringin, baicalein, and puerarin, as well as selective inhibitors of inflammatory pathways, have shown promising neuroprotective effects in animal models by attenuating inflammatory responses and alleviating neuropathic symptoms. By synthesizing these converging lines of evidence, this review further outlines potential future directions, including the development of combination therapies targeting multiple inflammatory pathways, microbiome-based interventions, and the translation of preclinical findings into well-designed clinical trials.

MAPK; Neuroinflammation; Neuropathy; Oxaliplatin; TLR4.