Hydroxysafflor yellow A alleviates high fat diet induced hyperlipidemia and improves host intestinal environment via hepatic signaling regulation

Hyperlipidemia is a metabolic disorder characterized by abnormally elevated circulating lipid levels and is closely associated with host metabolic homeostasis. In this study, we integrated network pharmacology, in vivo and in vitro experiments to investigate the lipid-lowering effects and mechanisms of hydroxysafflor yellow A (HSYA), the major bioactive component of Carthamus tinctorius L. HSYA significantly ameliorated HFD-induced metabolic abnormalities, including body weight gain, dyslipidemia, and hepatic steatosis, reduced serum levels of total cholesterol (TC), low-density lipoprotein cholesterol, alanine aminotransferase, aspartate aminotransferase, and lipopolysaccharide, enhanced hepatic superoxide dismutase activity, and suppressed tumor necrosis factor-α, interleukin-6, and interleukin-1β. 16S rRNA sequencing revealed that HSYA restored gut microbiota homeostasis, increased beneficial bacteria such as Bacteroidota and Verrucomicrobiota, and upregulated intestinal barrier proteins zonula occludens-1 and occludin. Network pharmacology indicated close associations among HSYA, hyperlipidemia, gut microbiota, and metabolites, and identified the PI3K/AKT/HIF-1α pathway as a key mediator, with gut microbiota and intestinal barrier restoration as related mechanisms. In vitro, HSYA exhibited no cytotoxicity and reduced TC, triglycerides (TG), and lipid droplets in palmitic acid-treated HepG2 cells, confirming its metabolic benefits. Thus, HSYA may alleviate HFD-induced dyslipidemia and hepatic steatosis through PI3K/AKT/HIF-1α and gut–liver axis modulation, supporting its clinical potential in metabolic diseases.