APOE and atherosclerosis: To rigorously test this hypothesis in vivo, the ApoE knockout mouse model is essential, as it spontaneously develops human-like hyperlipidemia and atherosclerosis, providing a robust platform to study hesperidin’s modulation of gut microbiota and BCAA metabolism in AS, this study aims to evaluate the anti-atherosclerotic effects of hesperidin and elucidate its mechanisms via the “gut microbiota–metabolite–host” axis, providing new insights into targeting the gut microbiome for AS prevention and treatment.