Hydroxysafflor Yellow A Ameliorates Hyperlipidemia and Hepatic Steatosis via Gut-Liver Axis Modulation

Hydroxysafflor yellow A, the primary bioactive component derived from Safflower L., significantly reduces body weight gain, dyslipidemia, and hepatic steatosis in mice subjected to a high-fat diet, according to research published on Research Square. The metabolic disorder hyperlipidemia involves abnormally elevated circulating lipid levels that disrupt host metabolic homeostasis.

Laboratory Findings in Diet-Induced Metabolic Disorders

Research Square reported that mice fed a high-fat diet developed obesity-like symptoms, including increased body weight and elevated intraperitoneal glucose tolerance test levels. Treatment with low and high doses of hydroxysafflor yellow A over a four-week period significantly decreased the weight gain rate and diminished the rise in intraperitoneal glucose tolerance test levels. Food and water intake assessments indicated that the observed inhibitory effect on weight gain was not caused by a reduction in high-fat diet consumption. Furthermore, the model group exhibited elevated serum glucose levels alongside impaired liver and kidney functions, showing significant increases in alanine aminotransferase, aspartate aminotransferase, urea, creatinine, and uric acid. Hydroxysafflor yellow A treatment effectively mitigated these alterations.

Cellular Mechanisms and Gut Microbiota Restoration

Network pharmacology and in vivo and in vitro experiments investigated the lipid-lowering mechanisms of the compound. The main source states that hydroxysafflor yellow A reduced serum levels of total cholesterol, low-density lipoprotein cholesterol, alanine aminotransferase, aspartate aminotransferase, and lipopolysaccharide while enhancing hepatic superoxide dismutase activity and suppressing tumor necrosis factor-alpha, interleukin-6, and interleukin-1beta. 16S rRNA sequencing showed that the treatment restored gut microbiota homeostasis, increased beneficial bacteria such as Bacteroidota and Verrucomicrobiota, and upregulated intestinal barrier proteins zonula occludens-1 and occludin. Network pharmacology identified the PI3K/AKT/HIF-1alpha pathway as a key mediator. In vitro tests on palmitic acid-treated HepG2 cells demonstrated no cytotoxicity while reducing total cholesterol, triglycerides, and lipid droplets.

Research Square noted that histopathological analysis using oil red O staining revealed that hydroxysafflor yellow A markedly reduced lipid deposition and improved hepatic steatosis in hyperlipidemic mice in a dose-dependent manner. Epididymal fat examinations showed reduced adipocyte volume and density compared to untreated model mice, while high-dose treatment and atorvastatin markedly reduced total cholesterol and low-density lipoprotein cholesterol levels. The findings support the clinical potential of hydroxysafflor yellow A in managing metabolic diseases through gut-liver axis modulation and PI3K/AKT/HIF-1alpha pathways.