Corynoxine inhibts ferroptosis by SIRT1/p53/SLC7A11 axis on traumatic brain injury.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE: Corynoxine, an alkaloid derived from Uncaria species traditionally used for treating neurological disorders, was investigated for its neuroprotective potential in traumatic brain injury (TBI). AIM OF THE STUDY: This study aimed to evaluate the neuroprotective effects of Corynoxine against TBI and to elucidate its underlying mechanism in inhibiting ferroptosis via the SIRT1/p53/SLC7A11 signaling axis. MATERIALS AND METHODS: A mouse model of TBI and Erastin-induced HT-22 neuronal cells were employed. In vivo assessments included evaluation of neuronal damage, cognitive function (Morris water maze), and protein expression. In vitro analyses examined mitochondrial morphology, oxidative stress markers (MDA, ROS, GSH, SOD), ferroptosis-related proteins (GPX4, SLC7A11, SIRT1, Ac-p53), and ferrous iron levels. The role of SIRT1 was further validated using siRNA-mediated knockdown. RESULTS: Corynoxine alleviated neuronal damage, improved cognitive deficits, and up-regulated neuroprotective proteins in TBI mice. In HT-22 cells, Corynoxine inhibited Erastin-induced ferroptosis, preserved mitochondrial morphology, reduced oxidative stress, decreased ferrous iron levels, and increased the expression of GPX4 and SLC7A11. Corynoxine up-regulated SIRT1 expression and decreased Ac-p53 levels, whereas knockdown of SIRT1 abolished these effects and its anti-ferroptotic action. CONCLUSION: Corynoxine exerts neuroprotective effects against TBI by suppressing neuronal ferroptosis through the activation of SIRT1, which promotes p53 deacetylation and enhances SLC7A11 expression. This study provides a novel mechanistic insight and a chemical foundation for further development.