Berberine and nanoliposomal berberine improved selected lipid and hepatic inflammatory measures in ApoE-/- mice, with PPARG identified as a candidate target through integrated transcriptomic, single-cell, and network pharmacology analyses delineating the myeloid cellular context of lipid- and inflammation-related signals in human plaques.
Key Findings
Results
Atherosclerotic plaques in GSE43292 showed enrichment of inflammatory response, TNFA signaling via NF-κB, cholesterol homeostasis, and fatty acid metabolism pathways.
Paired GSE43292 samples were used to characterize plaque-associated transcriptomic changes
Four major pathway categories were enriched: inflammatory response, TNFA signaling via NF-κB, cholesterol homeostasis, and fatty acid metabolism
GSE100927 was used as a reproducibility dataset and reproduced inflammatory response at the pathway level
ABCA1, CD36, IL1B, and TNF showed concordant expression changes across both datasets
Results
Key atherosclerosis-associated genes ABCA1, CD36, and IL1B were detected predominantly in monocyte/macrophage and other myeloid cell populations in single-cell data.
GSE159677 single-cell RNA sequencing dataset was used to resolve cellular distribution of plaque-associated genes
ABCA1, CD36, and IL1B localized mainly to monocyte/macrophage and other myeloid populations
Inflammatory macrophages showed larger disease-control differences in inflammatory response and TNFA/NF-κB module scores compared to other cell types
Results
Network pharmacology identified 70 overlapping BBR-atherosclerosis targets, with PPARG retained as the primary candidate for further structural and functional evaluation.
Network pharmacology was used to prioritize berberine-atherosclerosis candidate targets
70 overlapping targets between BBR and atherosclerosis were identified
PPARG was selected among these 70 candidates for further evaluation
Molecular docking and 100-nanosecond molecular dynamics simulations were used to evaluate the BBR-PPARγ interaction structurally
The predicted BBR-PPARγ binding pose remained relatively stable during the 100-ns simulation
Results
Both berberine (BBR) and nanoliposomal berberine (BNL) lowered serum total cholesterol and LDL cholesterol in high-fat diet-fed ApoE-/- mice.
ApoE-/- mice were fed a high-fat diet and treated with BBR or BNL, with atorvastatin as a comparator
Both BBR and BNL reduced serum total cholesterol and low-density lipoprotein cholesterol
Both formulations also attenuated liver lipid deposition
Atorvastatin was included as a positive comparator treatment
Results
Both BBR and BNL reduced hepatic inflammatory markers IL-1β, IL-6, and TNF-α in ApoE-/- mice.
Hepatic levels of IL-1β, IL-6, and TNF-α were reduced by both BBR and BNL treatment
This finding aligns with the human plaque transcriptomic data implicating TNFA/NF-κB and inflammatory response pathways
Reductions were observed at the hepatic level specifically, supporting a liver-centered inflammatory effect
Results
Hepatic PPARγ protein or expression increased significantly only in the nanoliposomal berberine (BNL) group, not in the conventional BBR group.
Hepatic PPAR γ increased significantly only in the BNL group
Conventional BBR treatment did not produce a significant increase in hepatic PPARγ
This differential effect suggests the nanoliposomal formulation may improve bioavailability or tissue delivery of berberine relevant to PPARγ modulation
PPARG was identified as a candidate for functional investigation based on this and the network pharmacology findings
What This Means
This research suggests that berberine, a natural compound found in several plants, may help address two key features of atherosclerosis (artery-clogging plaque disease): abnormal fat metabolism and chronic inflammation. The researchers first analyzed gene activity data from human atherosclerotic plaques and found that genes involved in inflammation, cholesterol handling, and fat metabolism were consistently altered in plaque tissue compared to healthy tissue. Using single-cell data, they traced these changes primarily to immune cells called macrophages, which are known to play a central role in plaque development. They then used computational tools to identify berberine's potential molecular targets, finding 70 genes shared between berberine's known effects and atherosclerosis biology, with a protein called PPARγ emerging as a top candidate. Computer simulations suggested berberine can physically bind to PPARγ in a stable way.
In animal experiments using mice prone to atherosclerosis and fed a high-fat diet, both regular berberine and a newer nanoparticle-encapsulated form (nanoliposomal berberine, or BNL) reduced blood levels of total cholesterol and LDL ('bad') cholesterol, decreased inflammatory proteins in the liver, and reduced fat accumulation in liver tissue. Notably, only the nanoliposomal form significantly increased PPARγ levels in the liver, suggesting that the delivery method matters for how the compound works at a molecular level.
This research suggests that berberine — particularly in a nanoliposomal formulation — may have beneficial effects on both lipid levels and inflammation relevant to atherosclerosis, and that PPARγ is a plausible molecular target worth investigating further. The study integrates human genomic data with animal experiments to provide biological context, though the findings are preliminary and further research would be needed to understand how these results might translate to human therapeutic applications.
Yao D, Wang X, Li Y, Wang Y, Mao X, Wang Y, et al.. (2026). Berberine-associated lipid-inflammatory regulation in atherosclerosis: an integrative transcriptomic, single-cell, and in vivo study.. Functional & integrative genomics. https://doi.org/10.1007/s10142-026-02019-3