Propofol Exerts Cerebroprotective Effects Against Cerebral Infarction by Up-Regulating TRIM67 to Mediate VDAC1 Ubiquitination and Degradation.

Propofol, an intravenous anesthetic, exhibits cerebroprotective effects against cerebral infarction (CI); however, its underlying mechanisms, particularly those involving ferroptosis, remain incompletely understood. This study employed oxygen-glucose deprivation/reperfusion (OGD/R)-treated SK-N-SH cells and middle cerebral artery occlusion (MCAO) rat models to investigate propofol's actions in vitro and in vivo. Propofol alleviated OGD/R-induced neuronal injury by enhancing cell viability, suppressing apoptosis, and reducing the release of inflammatory cytokines interleukin-6 (IL-6) and IL-1β. Importantly, propofol significantly suppressed ferroptosis, as evidenced by decreased levels of reactive oxygen species (ROS), Fe2+, and malondialdehyde (MDA), as well as restored mitochondrial membrane potential. Mechanistically, propofol up-regulated the expression of tripartite motif-containing 67 (TRIM67), which bound to voltage-dependent anion channel 1 (VDAC1), promoting its K63-linked polyubiquitination and proteasomal degradation. Conversely, VDAC1 overexpression or TRIM67 knockdown reversed the protective effects of propofol. Consistent with the in vitro results, propofol reduced cerebral infarct volume, improved neurological function, and suppressed neuroinflammation, effects that were concomitant with increased TRIM67 and decreased VDAC1 protein expression in brain tissues. In conclusion, this study reveals the TRIM67/VDAC1 pathway as a novel mechanism underlying propofol's cerebroprotective effects, thereby identifying a potential therapeutic target for CI.