In silico and in vivo targeting of Wnt/β-catenin/GSK-3β and redox pathways: geraniol–CoQ10 as a novel cardioprotective duo against I/R injury

Abstract

Abstract Background Although statins confer cardioprotection via HMG-CoA reductase inhibition, they are also known to reduce CoQ10 biosynthesis. In light of previous reports suggesting that geraniol, a natural monoterpene with pleiotropic cardioprotective effects, may intersect with the mevalonate pathway, we hypothesized that combining geraniol with CoQ10 could yield enhanced cardioprotective benefits. Using in silico analyses and a rat model of myocardial ischemia/reperfusion (I/R) injury (30-min LAD occlusion followed by 120-min reperfusion with continuous ECG monitoring), we evaluated geraniol alone and with CoQ10. Male Wistar rats were allocated into five groups: sham, I/R, geraniol + I/R, CoQ10 + I/R, and geraniol + CoQ10 + I/R. Results Preconditioning with geraniol and/or CoQ10 significantly decreased infarct size relative to the area at risk, preserved myocardial histoarchitecture, and mitigated cardiac biomarkers (CK-MB, LDH, cTn-I) and ST-segment elevation. Molecularly, treatments suppressed GSK-3β, a pivotal mediator of I/R injury, via activation of the Wnt/β-catenin pathway, while reinforcing antioxidant defenses (SOD, GSH) and reducing lipid peroxidation. They also inhibited inflammatory mediators (pSer536-NF-κB, TNF-α), neutrophilic infiltration (ICAM-1, MPO), curtailed caspase-3, and elevated Bcl-2, reflecting strong anti-inflammatory and antiapoptotic actions. In silico docking also predicted the ability of geraniol and CoQ10 to interact with GSK-3β and NF-κB. Notably, the combination therapy conferred the greatest protection. Conclusion Overall, these findings identify geraniol and CoQ10, particularly in combination, as promising cardioprotective agents against I/R injury through modulation of Wnt/GSK-3β/β-catenin signaling and associated antioxidative, anti-inflammatory, and antiapoptotic pathways. Graphical abstract