Gomisin A exerts neuroprotective effects on spinal cord injury through the EGFR/JAK2/STAT3 signaling pathway to inhibit ferroptosis.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE: Schisandra chinensis (Turcz.) Baill. is traditionally used to tonify the Kidney and nourish the Marrow, with the spinal cord considered a manifestation of Marrow. Gomisin A (GA), a major lignan from S. chinensis, possesses antioxidant, anti-inflammatory, and anti-apoptotic properties, but its neuroprotective mechanisms in spinal cord injury (SCI) remain to be investigated. AIM OF THE STUDY: This research is designed to investigate the neuroprotective effects of GA in SCI and determine whether it inhibits neuronal ferroptosis by suppressing the EGFR/JAK2/STAT3 pathway. MATERIALS AND METHODS: We generated an in vitro oxidative damage model using HO-induced PC12 cells and an in vivo SCI model in mice via the modified Allen method. Assessments included motor function, histology, and markers of apoptosis, oxidative stress (SOD, MDA, GSH), and ferroptosis (GPX4, xCT, ACSL4, Fe). The ferroptosis inhibitor Ferrostatin-1 (Fer-1) and activator RSL3 were utilized to validate the mechanism. The activation status of the EGFR/JAK2/STAT3 axis was analyzed via Western blotting. RESULTS: GA alleviated oxidative damage and apoptosis. Crucially, it inhibited ferroptosis, by upregulating GPX4 and xCT while downregulating ACSL4 and Feaccumulation. It mirrored the effects of Fer-1, whereas the application of RSL3 notably abrogated GA's neuroprotective benefits and its modulation of the EGFR/JAK2/STAT3 pathway. In vivo, GA promoted motor recovery, reduced lipid peroxidation, and enhanced antioxidant enzyme activity. These neuroprotective effects were mediated by suppressing EGFR, JAK2, and STAT3 phosphorylation. CONCLUSIONS: GA exerts significant neuroprotection effects in SCI by alleviating oxidative stress and blocking neuronal ferroptosis by suppressing the EGFR/JAK2/STAT3 axis, alongside reducing classical apoptosis. These data support GA as a promising drug for SCI therapeutics.