Curcusone D improves metabolic dysfunction associated steatotic liver disease via activation of the AMPK signaling.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide with limited effective clinical treatments. Previous high-throughput drug screening identified Curcusone D as a promising candidate for MASLD treatment. This study aimed to validate its therapeutic effects and underlying molecular mechanism. In vivo efficacy was evaluated in high-fat and high-cholesterol (HFHC) diet-fed mice, while in vitro hepatocyte models were used for mechanistic verification. The results demonstrated that Curcusone D significantly improved liver function, reduced serum pro-inflammatory cytokines, and suppressed hepatic inflammation and fibrosis in MASLD mice. It also markedly reversed excessive lipid accumulation and inhibited inflammatory responses in hepatocytes. Mechanistically, Curcusone D specifically activated the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. Pharmacological inhibition of AMPK fully abolished the protective effects of Curcusone D against HFHC-induced hepatic steatosis, insulin resistance, inflammation and fibrosis. In conclusion, Curcusone D ameliorates MASLD progression via AMPK pathway activation, serving as a novel and druggable natural candidate for future MASLD clinical therapy.