Protective effects of berberine on MASLD: regulation of glucose and lipid metabolism through PI3K/Akt and STING pathways

This study is aimed at exploring the therapeutic potential of berberine (BBR) in mitigating metabolic dysfunction-associated steatotic liver disease (MASLD) and at elucidating its mechanisms of action, with a focus on the modulation of glucose and lipid metabolism via the PI3K/Akt and STING signaling pathways. Male C57BL/6 J mice were fed a high-fat diet (HFD) to induce MASLD and subsequently treated with BBR or metformin. HepG2 cells were cultured in vitro, and palmitic acid (PA) was used to construct the cell model. Comprehensive analyses, including network pharmacology, transcriptome sequencing, and Western blotting, were conducted to identify critical pathways and molecular targets. Biochemical, histological, and molecular assays were performed to evaluate metabolic and inflammatory responses. BBR significantly attenuated HFD-induced hepatic steatosis, inflammation, and glucose intolerance. It effectively reduced lipid accumulation, enhanced insulin sensitivity, and modulated the expression of genes involved in lipid metabolism. Network pharmacology and transcriptome analysis highlighted the involvement of the PI3K/Akt and STING pathways. BBR activated PI3K/Akt signaling while suppressing the STING pathway, thereby reducing lipid accumulation in both in vivo and in vitro models. The inhibition of AKT negated the beneficial effects of BBR, underscoring the pivotal role of PI3K/Akt in regulating STING signaling. BBR ameliorates MASLD by activating the PI3K/Akt pathway and inhibiting the STING pathway, leading to improved glucose and lipid metabolism. These findings position BBR as a promising therapeutic candidate for the treatment of MASLD.