Licorice is a traditional and versatile herbal medicine and food. Glabridin (Gla) is a kind of isoflavone extracted from the licorice root, which has anti-obesity, anti-atherosclerotic, and antioxidative effects. Alcoholic liver disease (ALD) is a widespread liver disease induced by chronic alcohol consumption. However, studies demonstrating the effect of Gla on ALD are rare. The research explored the positive effect of Gla in C57BL/6J mice fed by the Lieber–DeCarli ethanol mice diet and HepG2 cells treated with ethanol. Gla alleviated ethanol-induced liver injury, including reducing liver vacuolation and lipid accumulation. The serum levels of inflammatory cytokines were decreased in the Gla-treated mice. The reactive oxygen species and apoptosis levels were attenuated and antioxidant enzyme activity levels were restored in ethanol-induced mice by Gla treatment. In vitro, Gla reduced ethanol-induced cytotoxicity, nuclear factor kappa B (NF-κB) nuclear translocation, and enhanced nuclear factor (erythroid-derived 2)-like 2 (Nrf2) nuclear translocation. Anisomycin (an agonist of p38 MAPK) eliminated the positive role of Gla on ethanol-caused oxidative stress and inflammation. On the whole, Gla can alleviate alcoholic liver damage via the p38 MAPK/Nrf2/NF-κB pathway and may be used as a novel health product or drug to potentially alleviate ALD.

Heart failure is the leading cause of death worldwide. Compound Danshen Dripping Pill (CDDP) or CDDP combined with simvastatin has been widely used to treat patients with myocardial infarction and other cardiovascular diseases in China. However, the effect of CDDP on hypercholesterolemia/atherosclerosis-induced heart failure is unknown. We constructed a new model of heart failure induced by hypercholesterolemia/atherosclerosis in apolipoprotein E (ApoE) and LDL receptor (LDLR) dual deficient (ApoE^-/-LDLR^-/-) mice and investigated the effect of CDDP or CDDP plus a low dose of simvastatin on the heart failure. CDDP or CDDP plus a low dose of simvastatin inhibited heart injury by multiple actions including anti-myocardial dysfunction and anti-fibrosis. Mechanistically, both Wnt and lysine-specific demethylase 4A (KDM4A) pathways were significantly activated in mice with heart injury. Conversely, CDDP or CDDP plus a low dose of simvastatin inhibited Wnt pathway by markedly up-regulating expression of Wnt inhibitors. While the anti-inflammation and anti-oxidative stress by CDDP were achieved by inhibiting KDM4A expression and activity. In addition, CDDP attenuated simvastatin-induced myolysis in skeletal muscle. Taken together, our study suggests that CDDP or CDDP plus a low dose of simvastatin can be an effective therapy to reduce hypercholesterolemia/atherosclerosis-induced heart failure.

Background: Atherosclerotic cardiovascular disease can progress despite intensive lipid lowering, highlighting the need to identify local mechanisms that remodel established plaques. Intermittent fasting may engage metabolic, circadian, and immune pathways relevant to this process. Methods: We used genome-wide association study structural equation modeling to construct circulatory plaque burden (CPB) and integrated multi-omic data to prioritize candidate pathways. We then tested intermittent fasting in a baseline-controlled Ldlr⁻/⁻ mouse induction–intervention model and evaluated the BMAL1–MERTK efferocytosis axis in macrophages. Results: Systems-genetic analyses linked systemic atherosclerotic burden to nutrient-response, circadian, and efferocytosis-related pathways. In mice, intermittent fasting reduced plaque size relative to both the ad libitum-fed and week-14 Baseline groups and improved structural features of plaque stability without additional endpoint lipid lowering. Aortic and single-cell analyses prioritized macrophage BMAL1–MERTK signaling. BMAL1 activated the Mertk promoter and occupied the tested promoter region. Mertk re-expression rescued the efferocytosis defect caused by Bmal1 knockdown, whereas MERTK inhibition reversed the benefit of BMAL1 overexpression. Conclusions: In this mouse model, intermittent fasting promoted remodeling of established atherosclerotic plaques, with macrophage BMAL1–MERTK signaling and efferocytosis identified as contributing mechanisms. These findings provide mechanistic insight and highlight this lifestyle-linked axis as a candidate for future translational investigation alongside established lipid-lowering therapy.