Therapeutic Effects and Mechanisms of Fucoidan on Dyslipidemia in Obese Mice.

Dyslipidemia, characterized by abnormal levels of serum lipids such as cholesterol and triglycerides, is a significant risk factor for metabolic disorders. Fucoidan, a marine sulfated polysaccharide, has shown anti-inflammatory and lipid-modulating properties, but its mechanism of action in high-fat diet (HFD)-induced dyslipidemia remains unclear. In this study, treatment with fucoidan (50 mg/kg/day) did not alter HFD-driven weight gain or food intake, but significantly decreased serum total cholesterol (TC). Although serum high-density lipoprotein cholesterol (HDL-C) was also decreased, this change may reflect normalization of HFD-induced cholesterol homeostasis in mice. Moreover, fucoidan treatment reduced hepatic triglyceride and TC, accompanied by decreasing lipid droplets in the liver, indicating fucoidan is critical for improving HFD-induced hepatic lipid accumulation. RNA-seq analysis revealed that fucoidan reverses HFD-induced downregulation of Defa24, Slc34a1, and Nnt, and may contribute to maintain hepatic metabolic homeostasis. Network pharmacology identified TNFα as a candidate key target, and molecular docking suggested a potential interaction between fucoidan and TNFα. Furthermore, fucoidan suppressed HFD-driven upregulation of TNFα and its downstream target Pla2g2f in vivo and attenuated TNFα-induced Pla2g2f expression in RAW264.7 cells. Collectively, these findings suggest that the protective effects of fucoidan against HFD-induced dyslipidemia are associated with regulation of cholesterol metabolism and suppression of TNFα-Pla2g2f-associated inflammatory signaling, supporting its potential application in dyslipidemia management.