Metabolic-associated fatty liver disease now affects roughly one-third of adults globally, yet approved pharmacological options remain limited. A mechanistic study in Phytomedicine provides molecular-level evidence that a traditional Chinese herbal preparation may work through a specific longevity-linked protein, potentially repositioning a centuries-old remedy within modern hepatology.
Using a 12-week high-fat diet mouse model of MAFLD, researchers evaluated three doses of Bupleurum chinense decoction (0.325, 0.65, and 1.3 g/kg/day) against pioglitazone as an active comparator. At the highest dose, Bc produced dose-responsive reductions in circulating triglycerides, alanine aminotransferase, and aspartate aminotransferase — markers of both dyslipidemia and hepatocellular injury. RNA sequencing of liver tissue pointed to Sirtuin 6 (SIRT6) as a primary molecular target. Liver-specific SIRT6 knockout mice were then used to confirm target dependency. Bioactive constituents were screened through the TCMSP database, refined by molecular docking, molecular dynamics simulations, and microscale thermophoresis to verify binding affinity and structural stability at the SIRT6 active site. An in vitro model using oleic and palmitic acid-challenged primary mouse hepatocytes corroborated the lipid-lowering and antioxidant effects.
SIRT6 is a NAD⁺-dependent deacylase already implicated in glucose homeostasis, fatty acid oxidation, and inflammatory gene suppression — overlapping pathways that make it an attractive MAFLD target. This study is notable for its multi-layered validation strategy, moving from whole-animal RNA-seq through knockout confirmation to biophysical binding assays, which is more rigorous than typical botanical pharmacology work. Limitations are meaningful, however: all data derive from rodent models, and translation to human MAFLD remains unproven. Bc is a complex botanical mixture, so isolating which constituent drives the SIRT6 interaction — and at achievable human tissue concentrations — requires clinical pharmacokinetic work. Still, the SIRT6 mechanism aligns this herb with emerging small-molecule SIRT6 activators under pharmaceutical development, making it an incremental but scientifically credible addition to the MAFLD research landscape.
