Punicalagin Promotes Peripheral Nerve Repair by Enhancing Mitophagy via the <scp>TLR4</scp> / <scp>MAPK</scp> Signaling Pathway and Facilitating Angiogenesis

Peripheral nerve injury (PNI) often leads to functional impairment, and current therapeutic options are limited. Punicalagin (PUN), a polyphenolic compound derived from Punica granatum, exhibits antioxidant and anti-inflammatory properties. This study investigated the therapeutic potential of PUN for PNI and its underlying mechanisms, focusing on mitochondrial autophagy (mitophagy), TLR4/MAPK signaling, and angiogenesis. In vitro, Schwann cells were treated with PUN under oxidative stress induced by tert-butyl hydroperoxide to evaluate cell viability, mitochondrial function, mitophagy, reactive oxygen species (ROS) levels, and apoptosis. PUN at non-toxic concentrations (≤ 20 μM) promoted mitophagy, attenuated ROS accumulation, and inhibited apoptosis. These effects were partially reversed by the mitophagy inhibitor Bafilomycin A1. Network pharmacology and molecular docking identified TLR4 as a primary target, and Western blot analyses demonstrated that PUN modulated downstream MAPK signaling. In vivo, intraperitoneal PUN administration in rats after sciatic nerve crush injury improved gastrocnemius muscle preservation, promoted axonal regeneration and remyelination, enhanced neovascularization, and significantly improved functional recovery, as measured by the sciatic functional index. Collectively, these findings indicate that PUN facilitates peripheral nerve repair through coordinated regulation of mitophagy, TLR4/MAPK signaling, and angiogenesis, highlighting its potential as a non-surgical therapeutic agent to promote nerve regeneration and functional recovery after PNI.