Hesperidin Promotes Peripheral Nerve Repair by Inducing Autophagy and Inhibiting Apoptosis via the STAT3 /Bcl‐2 Pathway

This study explores the therapeutic potential and mechanisms of Hesperidin, a natural flavonoid, in promoting peripheral nerve injury (PNI) repair. We focused on its regulation of autophagy and apoptosis, and examined whether these effects are mediated through the STAT3/Bcl-2 signaling pathway. In vitro, a TBHP-induced RSC96 Schwann cell injury model was used to assess cell viability, cytotoxicity, and mitochondrial membrane potential, alongside autophagy and apoptosis analysis by electron microscopy, immunofluorescence, and Western blot. STAT3 and autophagy inhibitors were used to clarify pathway involvement. In vivo, a rat sciatic nerve crush model evaluated functional recovery, muscle atrophy, and nerve tissue markers. Network pharmacology and molecular docking further identified potential Hesperidin targets. Hesperidin restored mitochondrial membrane potential, reduced ROS, increased Beclin-1 and LC3B expression, enhanced autophagic flux, and inhibited cleaved Caspase-3 and p62. Its protective effects were enhanced by STAT3 inhibition and abolished by autophagy inhibition, indicating an autophagy-dependent mechanism. In vivo, Hesperidin promoted axonal and myelin regeneration, improved functional recovery, and reduced muscle atrophy. Downregulation of p-STAT3 and Bcl-2 supported involvement of the STAT3/Bcl-2 pathway. Molecular docking demonstrated strong binding of Hesperidin to Bcl-2 and Caspase-3. In the context of peripheral nerve injury, Hesperidin contributes to neuronal repair by down-regulating the STAT3/Bcl-2 axis, which in turn activates autophagy and mitigates programmed cell death. The study underscores Hesperidin's potential as a pleiotropic agent that promotes peripheral nerve regeneration and provides molecular insight beneficial for translation to clinical settings.