Targeting CRMP2 for Chronic Pain: From Molecular Mechanisms to Therapeutic Strategies

Collapsin Response Mediator Protein 2 (CRMP2) has emerged as a central node in the pathogenesis of chronic pain, functioning as a multimodal ‘molecular switch’ that regulates microtubule dynamics, ion channel trafficking, and synaptic plasticity. The dysregulation of CRMP2, particularly through aberrant post-translational modifications (PTMs) such as phosphorylation and SUMOylation, is a critical driver of both peripheral and central sensitization. This review systematically examines the structure, regulation, and multifaceted roles of CRMP2 in pain signaling pathways. We then critically evaluate a spectrum of CRMP2-targeted therapeutic strategies, including small-molecule inhibitors, peptide-based agents, and gene silencing, highlighting their promising preclinical efficacy and safety profiles. Despite challenges in targeting specificity and central nervous system delivery, we posit that innovations in delivery systems, precision medicine, and AI-assisted drug design will catalyze the clinical translation of CRMP2-based, non-opioid analgesics, offering a paradigm shift in chronic pain management.