Sinigrin, a bioactive compound from cruciferous vegetables, ameliorates MASLD by activating AMPK/SIRT1/PGC-1α to enhance fatty acid beta-oxidation.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide, but effective therapeutic strategies for its early stage are still lacking. Sinigrin, a natural glucosinolate found in cruciferous vegetables known for its anti-inflammatory and antioxidant properties, has an unclear role and mechanism in MASLD. This study aimed to evaluate the therapeutic potential of Sinigrin and elucidate its mechanisms of action. We employed a high-fat diet (HFD)-induced mouse model and a palmitic acid (PA)-treated HepG2 cell model. A combination of techniques, including biochemical assays, histopathology, qPCR, and western blotting, was used to evaluate the effects and mechanisms of Sinigrin. The functional importance of AMPK was assessed using the pharmacological AMPK inhibitor Compound C (CC) and shRNA-mediated AMPK knockdown, while the involvement of the SIRT1/PGC-1α axis was further evaluated using the SIRT1 inhibitor EX527. Sinigrin treatment significantly ameliorated metabolic disorders, hepatic steatosis, systemic inflammation, and oxidative stress in MASLD models. It markedly enhanced fatty acid β-oxidation by activating the AMPK/SIRT1/PGC-1α pathway and improved mitochondrial function. Meanwhile, Sinigrin suppressed ferroptosis by enhancing Nrf2-mediated antioxidant and anti-ferroptotic responses. Furthermore, the essential role of AMPK was firmly established by the finding that its pharmacological blockade with CC largely abolished Sinigrin's beneficial effects. Collectively, our findings demonstrate that Sinigrin alleviates MASLD by enhancing fatty acid β-oxidation via the AMPK/SIRT1/PGC-1α axis while concurrently inhibiting ferroptosis through enhancement of Nrf2-mediated antioxidant defense.