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

Background Hyperlipidemia is a major risk factor for cardiovascular diseases. Accumulating evidence has demonstrated that the gut microbiota-liver axis exerts a crucial regulatory effect on lipid metabolism. Hydroxysafflor yellow A (HSYA), a major bioactive compound derived from Carthamus tinctorius L., exhibits anti-inflammatory and antioxidant properties. However, its lipid-lowering effects and underlying mechanisms remain unclear. Methods High - fat diet (HFD)-induced hyperlipidemia mouse model and palmitic acid (PA)-induced HepG2 cells were used to evaluate the therapeutic effects of HSYA. We detected lipid metabolic parameters, hepatic and renal function indexes, serum lipid profiles, oxidative stress markers, and inflammatory cytokines in mice of each group. Oil Red O staining was applied to analyze hepatic lipid accumulation, while 16S rRNA sequencing was used to determine gut microbiota composition. The protein expression of the PI3K/AKT/HIF-1α pathway and lipid metabolism-related pathways were determined via Western blotting. Network pharmacology and gutMGene-based analyses validated potential targets and pathways, with molecular docking serving as supplementary confirmation. Results HSYA significantly ameliorated body weight gain abnormalities, dyslipidemia, and hepatic steatosis induced by high-fat diet in each group of mice. HSYA reduced the levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), alanine transaminase (ALT), and aspartate transaminase (AST) in murine serum; it enhanced antioxidant capacity by increasing the activity of superoxide dismutase (SOD) in murine liver, and suppressed inflammatory responses by downregulating the expression of TNF-α, IL-6, and IL-1β in murine serum. HSYA also restored gut microbiota homeostasis, increased the abundance of beneficial bacteria (e.g., Bacteroidota and Verrucomicrobiota), and improved intestinal barrier integrity by upregulating the expression of ZO-1 and occludin. Mechanistically, HSYA ameliorated hyperlipidemia primarily by modulating the PI3K/AKT/HIF-1α signaling pathway, accompanied by partial restoration of gut microbiota and intestinal barrier function. These findings were further supported by in vitro experiments and bioinformatics analyses. Conclusions HSYA alleviates HFD-induced dyslipidemia and hepatic steatosis by suppressing hepatic inflammation and lipogenesis via PI3K/AKT/HIF-1α signaling pathways and regulating the gut microbiota–gut barrier–liver axis. This study elucidates the underlying mechanisms of HSYA in ameliorating hyperlipidemia and hepatic steatosis, and offers experimental and theoretical evidence for its clinical potential in the treatment of metabolic disorders.