A mechanistic framework for oxaliplatin-induced peripheral neuropathy: from neuronal vulnerability to neurotoxic...

Oxaliplatin-induced peripheral neuropathy (OIPN) is a common and dose-limiting adverse effect of oxaliplatin-based chemotherapy that markedly impairs treatment adherence and long-term quality of life. Despite extensive investigation, effective preventive and therapeutic strategies remain limited, reflecting the complex and multifactorial nature of its pathogenesis. In this review, we revisit the mechanisms underlying OIPN and propose an integrated, stage-dependent mechanistic perspective. Current evidence indicates that OIPN arises from dynamic interactions among multiple pathological processes operating across temporal and anatomical scales. Early oxaliplatin-induced neurotoxicity is primarily expressed as functional and electrophysiological disturbances, which manifest clinically as acute sensory symptoms such as cold hypersensitivity. With sustained exposure, these alterations progressively engage downstream neuroinflammatory and metabolic cascades, ultimately contributing to structural pathology, including axonal degeneration, and to chronic, often persistent, peripheral neuropathy. Importantly, these mechanisms form self-amplifying loops that facilitate the transition from reversible acute symptoms to irreversible structural damage, providing a mechanistic explanation for the limited success of single-target neuroprotective strategies. Emerging complementary mechanisms are briefly discussed to outline future research directions. By reorganizing current evidence into a hierarchical, stage-linked framework that connects upstream neuronal vulnerability, early functional dysfunction, and downstream inflammatory-structural persistence, this review aims to clarify not only the pathophysiological complexity of OIPN but also its implications for stage-specific and combination-based intervention strategies.