Berberine-associated lipid-inflammatory regulation in atherosclerosis: an integrative transcriptomic, single-cell, and in vivo study.

Atherosclerotic plaques combine disturbed lipid metabolism with myeloid inflammation, yet the human plaque context of berberine (BBR)-related targets remains poorly defined. Paired GSE43292 samples were used to characterize plaque-associated changes, GSE100927 to test reproducibility, and GSE159677 to resolve their cellular distribution. Network pharmacology prioritized BBR-atherosclerosis candidates, with molecular docking and 100-ns molecular dynamics used for structural evaluation. High-fat diet-fed ApoE-/- mice received BBR or nanoliposomal BBR (BNL), with atorvastatin as a comparator. In GSE43292, inflammatory response, TNFA signaling via NF-κB, cholesterol homeostasis, and fatty acid metabolism were enriched in plaques. GSE100927 reproduced inflammatory response at the pathway level; ABCA1, CD36, IL1B, and TNF showed concordant expression changes. ABCA1, CD36, and IL1B were detected mainly in monocyte/macrophage and other myeloid populations. Inflammatory macrophages showed larger disease-control differences in inflammatory response and TNFA/NF-κB module scores. Among 70 overlapping BBR-atherosclerosis targets, PPARG was retained for further evaluation. The predicted BBR-PPARγ pose remained relatively stable during simulation. In mice, BBR and BNL lowered serum total cholesterol and low-density lipoprotein cholesterol, reduced hepatic IL-1β, IL-6, and TNF-α, and attenuated liver lipid deposition. Hepatic PPARγ increased significantly only in the BNL group. These findings delineate the myeloid cellular context of lipid- and inflammation-related signals in human plaques and show that BBR and BNL improve selected lipid and hepatic inflammatory measures in ApoE-/- mice. PPARG remains a candidate for functional investigation.