Astragalus Polysaccharide Alleviates Hyperlipidemia via the miR‐128‐3p/NRF2/Antioxidant Pathway

Hyperlipidemia, a common metabolic disorder marked by elevated serum lipids like total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C), raises risks for cardiovascular diseases, atherosclerosis, nonalcoholic fatty liver disease, and diabetes. Conventional treatments like statins have limitations, including liver damage and resistance, driving interest in natural compounds with multi-target, low-toxicity effects. This study assessed Astragalus polysaccharide (APS), a traditional Chinese medicine component with antioxidant and metabolic-regulatory properties, for its therapeutic effects on hyperlipidemic rats and its mechanism via the miR-128-3p/NRF2/antioxidant pathway. SD rats were grouped into normal, model, simvastatin, and APS. Except normal, all received high-fat diet for 8 weeks to induce hyperlipidemia. Then, APS (700 mg/kg) or simvastatin (6.7 mg/kg) was administered via gavage for 8 weeks; controls received saline. Serum indices were monitored periodically; pancreatic and hepatic tissues were analyzed histologically and molecularly. In vitro, lipid accumulation was induced in BRL and HepG2 cells with oleic/palmitic acids (2:1). Optimal APS dose/time was determined by CCK-8; lipid and oxidative markers were measured. A high-fat diet caused hyperlipidemia, elevating lipids, body weight, and energy intake. APS reduced glucose/lipid levels, and transaminase activity and improved pancreatic/hepatic pathology, including β-cell function. APS lowered MDA and miR-128-3p while boosting T-SOD and hepatic NRF2. In cells, APS reversed lipid buildup and oxidative stress. APS mitigates hyperlipidemia via the miR-128-3p/NRF2/antioxidant pathway, providing a multi-target strategy for lipid metabolism, oxidative stress, and organ protection. This supports natural interventions for hyperlipidemia, especially with glucose/organ issues, meriting clinical exploration.