Chemotherapy-induced painful peripheral neuropathy (CIPN) is the most common toxicity associated with widely used chemotherapeutics. CIPN is the major cause of dose reduction or discontinuation of otherwise life-saving treatment. Unfortunately, CIPN can persist in cancer- survivors which adversely affects their quality of life. Moreover, available treatments are vastly inadequate which necessitates the development of novel mechanism-based therapies that can either prevent or treat CIPN. Recently, HIF1A, PDHK1, and LDHA have been demonstrated to be the key molecular mediators that initiate and maintain bortezomib-induced neuropathic pain. However, those studies were carried out in tumor-free mice. Moreover, our preliminary results also implicate those molecular targets in paclitaxel and oxaliplatin-induced neuropathic pain. Hence, the objective of this proposal is to validate that HIF1A, PDHK1 and LDHA are shared mediators that lead to the development and maintenance of bortezomib, paclitaxel and oxaliplatin- induced neuropathic pain in tumor-bearing mice. Using biochemical, metabolic, behavioral and innovative imaging method of intact DRGs this application aims to systematically validate these targets for the prevention and treatment of CIPN. Successful completion of this project promises to lower the risk of adopting these targets in translational projects to develop novel non-addictive therapeutics for chemotherapy-induced neuropathic pain.