Metabolic dysfunction-associated steatotic liver disease (MASLD) poses a global health challenge, yet effective therapies are hindered by limited efficacy of synthetic medications and poor druggability of natural bioactive compounds. Here, we report an engineered therapeutic strategy for MASLD that overcomes the gastrointestinal (GI) instability of a soy-derived peptide, soystatin (SP), through structural optimization and live probiotic delivery. Firstly, we developed two protease-resistant peptide analogs of SP, SP2 and SP9, which maintain potent bile acids micellar-disruptive capacities in the degradative environment of the GI tract. These peptides significantly reduced serum and hepatic lipids while resolving hepatic steatosis, which is superior to that of cholestyramine at the same dose and equivalent weight, the first-line cholesterol-lowering and traditional sequestrant. Additionally, pharmacokinetic analysis documented that these peptides exhibited gut-localized with negligible systemic exposure. Further investigations revealed that SP2 and SP9 work via a dual-hit lipid-lowering mechanism. Physically, like cholestyramine, they block intestinal cholesterol absorption by impairing micelle formation. Biologically, they reprogram hepatic lipid metabolism by activating the peroxisome proliferatoractivated receptor signaling pathway and fatty acid beta-oxidation, while modulating the bile acid pool linked to altered gut microbiome. These peptides may also mitigate the oxidative hepatocellular damage via the down-regulation of oxidative phosphorylation. Finally, we engineered a gut-colonizing Lactobacillus plantarum WCSF1 strain to continuously secrete SP2 and SP9-repeats in situ, significantly attenuating MASLD activity scores and improving lipid profiles. Our results demonstrate that coupling optimized bioactive peptides with engineered probiotic chassis provides a promising strategy for the long-term management of chronic metabolic liver diseases.
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