Elucidating the mechanistic interplay of AMPK and Nrf2 in MASLD: A focus on dietary phytochemical modulation of lipid and redox homeostasis

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major chronic liver disease with close ties to obesity, insulin resistance, and metabolic syndrome. It is characterized by excessive hepatic lipid accumulation in the absence of alcohol abuse or other liver complications. Dysregulated lipid metabolism in MASLD disrupts redox balance, leading to oxidative damage and inflammation. AMP-activated protein kinase (AMPK) is a major cellular energy regulator that controls the balance between lipid synthesis and breakdown among other functions. Nuclear erythroid 2-related factor 2 (Nrf2) is a master regulator of cellular redox balance by promoting the transcription of antioxidant genes. This review summarized MASLD pathogenesis, the roles of AMPK and Nrf2 in the context of MASLD and discussed the current knowledge on the phytochemical-mediated mechanisms of AMPK and Nrf2 interaction in MASLD management through mitigating lipid dysregulation, oxidative stress, and inflammation. Mechanisms include direct AMPK activation of Nrf2 and indirect preservation of Nrf2 by AMPK-mediated interference of negative Nrf2 regulators (Kelch-like ECH associated protein 1 (Keap1) and glycogen synthase kinase 3 β (GSK3β)). Therapeutic potential of phytochemicals such as polyphenols, carotenoids, saponins, alkaloids, phytosterol esters and polysaccharides have been demonstrated in vitro and in vivo. Future studies on clinical applications are needed.