PACAP Alleviates Paclitaxel‐Induced Peripheral Neuropathy by Targeting Oxidative Stress and Mitochondrial Damage via the PGC‐1α Pathway

Background Paclitaxel‐induced peripheral neuropathy (PIPN) is a severe and dose‐limiting side effect. This study investigated the therapeutic potential of Pituitary Adenylate Cyclase‐Activating Polypeptide (PACAP) and its underlying mechanism. Methods A murine PIPN model was established. Behavioral tests assessed neuropathic pain. Molecular and cellular analyzes, including western blot, ELISA, and transmission electron microscopy, evaluated oxidative stress, mitochondrial function, and key protein expression in dorsal root ganglia (DRG) and SH‐SY5Y cells. The PGC‐1α inhibitor SR‐18292 was used for mechanistic validation. Results High‐dose PACAP (100 μg/kg) significantly alleviated PTX‐induced mechanical allodynia and thermal/cold hyperalgesia. It reduced oxidative stress (lowered ROS/MDA, increased SOD) and restored mitochondrial function (improved membrane potential, ATP, and ultrastructure) in DRG neurons. PACAP upregulated PGC‐1α and HO‐1 expression, and its protective effects were abolished by PGC‐1α inhibition. Crucially, PACAP did not interfere with PTX's antitumor efficacy. Conclusion PACAP alleviates PIPN by activating the PGC‐1α pathway to improve mitochondrial function and counteract oxidative stress, presenting a promising adjunct therapy that does not compromise chemotherapy.