Ultrasound-assisted extraction optimization of Fructus Tribuli polysaccharides: How stir-frying processing alters structures and enhances antihypertensive efficacy

• Optimized UAE of Fructus Tribuli polysaccharides (FP) via RSM achieved a high yield of 2.18%. • Stir-frying altered FP’s structure, increasing uronic acid content and narrowing MWD. • SFP exhibited superior antihypertensive efficacy over FP in SHRs. • SFP alleviated hypertension by modulating gut microbiota, increasing SCFAs. 5. SFP may alleviate hypertension by inhibiting the vascular LPS-TLR4/MyD88 pathway. Fructus Tribuli (FT), the dried ripe fruit of Tribulus terrestris L., is recognized for its antihypertensive properties, which are enhanced by stir-frying without adjuvants. However, research on its polysaccharides with therapeutic potential remains limited. This study optimized the ultrasound-assisted extraction (UAE) of FT polysaccharides (FP) using response surface methodology, yielding a maximum extraction yield of 2.182 ± 0.29% under the conditions of liquid–solid ratio 20:1 mL/g, 51 min, 62 °C, and precipitation ethanol concentration of 95%. Subsequently, FP and stir-fried FT polysaccharides (SFP) were isolated, and their structural differences and antihypertensive effects were systematically compared. Structural analysis revealed notable differences between FP and SFP. Furthermore, the extraction resulted in a higher polysaccharide yield for SFP. In spontaneously hypertensive rats, both FP and SFP attenuated hypertension and vascular injury, modulated gut microbiota, increased short-chain fatty acids, and enhanced intestinal barrier function effects that were more pronounced with SFP. Mechanistically, both polysaccharides inhibited the aortic TLR4/MyD88 pathway. These results suggest that stir-frying modifies polysaccharide structure, thereby improving gut microbiome regulation, barrier protection, and vascular outcomes, highlighting the value of processing in enhancing polysaccharide efficacy. Thus, stir-frying amplifies therapeutic effects through bioactive macromolecular remodeling, advancing the understanding of Traditional Chinese medicine processing principles.