Lupin protein hydrolysate ameliorates MASLD: identification and in silico validation of peptides targeting the KEAP1–NRF2 axis

Abstract

The rising prevalence of obesity and its comorbidities, including metabolic dysfunction–associated steatotic liver disease (MASLD), requires novel preventive strategies, such as functional foods. Lupinus angustifolius protein hydrolysates (LPH) exhibits potent immunomodulatory and antioxidant properties, underscoring their potential to mitigate metabolic dysfunction. This study evaluated the effects of LPH on a diet-induced obese mouse model of MASLD. LPH supplementation significantly reduced body and liver weight, attenuated hepatic steatosis, and normalized lipid accumulation and triglyceride levels. Furthermore, LPH enhanced antioxidant capacity by upregulating Nrf2 and increasing SOD, GPx, and CAT activities. LPH also modified the liver transcriptome towards an anti-obesogenic profile, modulating genes involved in lipid metabolism (e.g., Cd36 and Ldlr ), adipokine signaling, and oxidative stress. Interestingly, proteomic and in silico approaches identified bioactive peptides with predicted potential to target the NRF2-KEAP1 axis, providing a plausible mechanistic hypothesis. Collectively, these findings support the therapeutic potential of LPH in the context of MASLD.