Dietary supplement Forskolin improves MASLD through hepatocyte-macrophage crosstalk via the GLUT1/ABCF1-HNF4α axis

Nutritional interventions and bioactive supplements have attracted increasing attention as strategies for managing metabolic dysfunction-associated steatotic liver disease (MASLD). Among them, Forskolin (FSK), a bioactive diterpenoid derived from Coleus forskohlii, is widely used as a dietary supplement for weight management. This study investigated the hepatoprotective effects of FSK and the underlying metabolic mechanisms in MASLD. C57BL/6 mice were fed a high-fat diet (HFD) for 12 weeks to induce MASLD and received FSK or metformin (Met). AML12 and Raw264.7 were co-cultured and treated with FSK or phloretin (PHL). FSK reduced lipid droplet accumulation, de novo lipogenesis (DNL), and inflammatory activation in vitro and in vivo, and further attenuated collagen deposition in HFD-fed mice. Notably, FSK decreased the expressions of glucose transporter 1 (GLUT1) and ATP-binding cassette subfamily F member 1 (ABCF1), reduced glycolytic activity and ATP production, and attenuated aberrant nucleocytoplasmic shuttling of hepatocyte nuclear factor 4 alpha (HNF4α) in vitro and in vivo. These effects were abolished by GLUT1 or ABCF1 silencing. FSK also regulated the interactions among GLUT1, ABCF1, and HNF4α. Cellular thermal shift assay (CETSA) and molecular dynamics analysis further supported a potential interaction between FSK and GLUT1. FSK prevented lipid metabolic dysregulation through the GLUT1/ABCF1-HNF4α axis in AML12 induced by M1-polarized macrophages, particularly under oleic acid (OA) co-stimulation. FSK also inhibited inflammatory activation in macrophages induced by IL-1β derived from OA-stimulated AML12. Collectively, these findings support the potential of FSK as a functional dietary supplement for the management of MASLD.