Chemotherapy-induced peripheral neuropathy: emerging roles of metabolic reprogramming, signal sensing, and epigenetic plasticity

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common and persistent adverse effects of cancer treatment, particularly associated with platinum-based compounds (e.g., oxaliplatin and cisplatin), taxanes (e.g., paclitaxel and docetaxel), vinca alkaloids, and proteasome inhibitors. Traditional studies have linked its development to microtubule damage, mitochondrial dysfunction, and ion channel abnormalities. However, with the advancement of metabolomics in recent years, the contribution of systemic metabolic remodeling and gut microbiota-derived metabolites to CIPN pathogenesis has become increasingly recognized. The role of metabolites and their corresponding receptors in regulating neuropathy have become increasingly recognized, including their impact on epigenetic modifications. To date, a comprehensive understanding of how various metabolites contribute to the onset and persistence of CIPN is still lacking. This review synthesizes current evidence on chemotherapy-induced metabolic reprogramming, focusing on bile acids, short-chain fatty acids, amino acids, and lipids, while highlighting the involvement of microbiota–host metabolic interactions in shaping these metabolic changes. We further explore how these metabolites, through their specific receptors (e.g., FXR/TGR5, FFAR2/3, mGluRs, LPAR), transduce metabolic signals into changes in neuroinflammation and neuronal excitability. Crucially, epigenetic modifications (DNA methylation, non-coding RNAs, and histone modifications) may contribute to the long-term persistence of these alterations by regulating transcriptional programs associated with neuronal plasticity and inflammation, providing a potential molecular basis for the concept of pain "memory" after chemotherapy cessation. Based on this analysis, we propose a "metabolites- metabolite-linked receptors- epigenetic regulation" framework, aiming to connect systemic metabolic disturbances with local neuropathic changes, and acute injury with chronic pain. This framework integrates chemotherapy-induced metabolic remodeling, metabolite sensing pathways, and epigenetic mechanisms, providing a conceptual basis for understanding CIPN development and maintenance. It may also offer novel therapeutic opportunities through metabolic intervention, receptor targeting, and epigenetic modulation. Chemotherapy induces changes in the "metabolism- metabolite-linked receptors- epigenetics" framework and potentially influences the development of CIPN. CIPN, Chemotherapy-Induced Peripheral Neuropathy; BA, Bile Acid; DCA, Deoxycholic Acid; ω-MCA, ω-Muricholic acid; Glu, Glutamate; BCAA, branched chain amino acid; Trp, Tryptophan; Kyn, Kynurenine; Cer, Cer, Ceramide; Sph, Sphingosine; S1P, Sphingosine-1-phosphate.