Saffron as a natural modulator of reverse cholesterol transport genes in atherosclerotic rabbits, with molecular docking insights

Atherosclerosis is a major contributor to cardiovascular disease, and one of the mechanisms that contributes to atherosclerosis is the reverse cholesterol transport (RCT) pathway, which includes SR-BI, ABCA1, and PPARγ genes. Natural compounds that modulate RCT-related genes may present promising therapeutic alternatives. Saffron (Crocus sativus L.), rich in bioactive carotenoids, exhibits both lipid-lowering and antioxidant properties. This study investigated the effects of saffron extract on hepatic expression of SR-BI, ABCA1, and PPARγ genes in the atherosclerotic rabbit model and evaluated the molecular docking of its major phytocompounds. Fifty-five male New Zealand White rabbits (NZWR) were randomly assigned to three main groups: a normal diet (ND) group, a 1% high-cholesterol diet (HCD; 4 W, 8 W) group, and intervention groups. Rabbits in the HCD and intervention groups were induced for early atherosclerosis (4 weeks) and established atherosclerosis (8 weeks). Following these induction periods, each subgroup received 8 weeks of oral treatment with saffron ethanolic extract (50 or 100 mg/kg/day), statin (2.5 mg/kg/day), or placebo while maintained on a normal chow diet. The Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) analysis showed that saffron treatment significantly upregulated hepatic SR-BI expression in early atherosclerosis (S50: 3.65-fold, p < 0.05; S100: 4.59-fold, p < 0.05) and in established atherosclerosis (S100: 8.34-fold, p < 0.01). ABCA1 and PPARγ expression levels were also increased, though not statistically significant. Molecular docking demonstrated favorable binding affinities between saffron bioactives and RCT-related targets, with crocetin (a major carotenoid compound in saffron) binding to PPARγ (–7.75 kcal/mol) and SR-BI (–7.24 kcal/mol), and quercetin binding to ABCA1 (–8.35 kcal/mol). These findings suggest that saffron may positively modulate RCT-associated gene expression, supporting its potential as a natural adjunct in atherosclerosis research and management.