Qing-Xin-Jie-Yu Granule inhibits ferroptosis and stabilizes atherosclerotic plaques by regulating the GPX4/xCT signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Qing-Xin-Jie-Yu Granule (QXJYG) is an integrated traditional Chinese medicine formula used to treat atherosclerotic (AS) cardiovascular diseases. A randomized controlled trial found that QXJYG reduced cardiovascular events and experiments also verified that QXJYG attenuated AS by remodeling the intestinal flora. AIM OF THE STUDY: To determine whether QXJYG would attenuate AS and plaque vulnerability by regulating ferroptosis in high-fat diet-induced atherosclerotic ApoE-/- mice and to investigate the effects of QXJYG on macrophage ferroptosis in RAS-selective lethal 3 (RSL3)-induced J744A.1 cells. METHODS: AS models in ApoE-/- mice and RSL3-induced ferroptosis in J744A.1 cells were established to measure the protective and anti-ferroptotic effects of QXJYG in vivo and in vitro. The glutathione peroxidase 4 (GPX4)/cystine glutamate reverse transporter (xCT) signal pathway was examined by immunohistochemistry and western blotting. RESULTS: QXJYG attenuated AS progression and plaque vulnerability. Characteristic morphological changes of ferroptosis in the QXJYG-treated animals were rare. Total iron was significantly lower in the QXJYG group than in the model group (P < 0.05); QXJYG suppressed the lipid peroxidation (LPO) levels (malondialdehyde), enhanced the antioxidant capacity (superoxide dismutase and glutathione), and reduced inflammatory factors (interleukin [IL]-6, IL-1ß, tumor necrosis factor-α) associated with ferroptosis. Expression of GPX4/xCT in aorta tissues was remarkably increased in the QXJYG group. QXJYG inhibited ferroptosis in J744A.1 macrophages disturbed using RSL3. The Fe2+, LPO, and reactive oxygen species levels were lower in the QXJYG group than in the RSL3 group (P < 0.05). The QXJYG group showed higher expression of the GPX4/xCT signal pathway. CONCLUSION: QXJYG inhibits ferroptosis in vulnerable AS plaques partially via the GPX4/xCT signaling pathway.

Chinese Herbal Medicines and Active Metabolites: Potential Antioxidant Treatments for Atherosclerosis.

Atherosclerosis is a complex chronic disease that occurs in the arterial wall. Oxidative stress plays a crucial role in the occurrence and progression of atherosclerotic plaques. The dominance of oxidative stress over antioxidative capacity generates excess reactive oxygen species, leading to dysfunctions of the endothelium and accelerating atherosclerotic plaque progression. Studies showed that Chinese herbal medicines and traditional Chinese medicine (TCM) might regulate oxidative stress; they have already been used to treat diseases related to atherosclerosis, including stroke and myocardial infarction. This review will summarize the mechanisms of oxidative stress in atherosclerosis and discuss studies of Chinese herbal medicines and TCM preparations treating atherosclerosis, aiming to increase understanding of TCM and stimulate research for new drugs to treat diseases associated with oxidative stress.