Emerging targets and translational challenges in treating paclitaxel-induced peripheral neuropathy

Paclitaxel-induced peripheral neuropathy (PIPN) is a frequent, dose-limiting toxicity that affects up to 70% of patients undergoing paclitaxel-based chemotherapy. Its pathophysiology involves disrupted microtubule dynamics, mitochondrial dysfunction, altered calcium signalling, and neuroinflammation. Current treatment strategies for the management of PIPN are limited and underscore the urgent need to identify novel molecular targets to mitigate its adverse effects. Recent advances in molecular and neurological research highlight potential molecular targets including toll-like receptors (TLRs), transient receptor potential (TRP) channels, transcriptional regulators like peroxisome proliferator-activated receptor gamma co-activator 1 α (PGC-1α), and inflammatory cytokines. Epigenetic modulators and non-coding RNAs also hold significant potential as therapeutic agents in the management of PIPN. This review summarizes these emerging targets and explores therapeutic agents currently in preclinical and clinical development, aiming to guide future personalized strategies for PIPN management. (Figure created with BioRender.com and received the publishing license.).