Bicuculline ameliorates metabolic dysfunction-associated steatotic liver disease by inhibiting the nuclear factor-kappa B pathway and reducing lipid accumulation.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a prominent and pervasive global health challenge. Bicuculline (BIC), which is a key active component of the anti-MASLD prescription "Eight Zhes Decoction", has been preliminarily shown by our research team to have significant potential in treating MASLD. AIM: To determine BIC's efficacy in treating MASLD by regulating lipid metabolism and suppressing hepatic inflammation via nuclear factor-kappa B (NF-κB) pathway, identifying it as a therapeutic candidate. METHODS: This study explored the potential of BIC in preventing and treating MASLD using zebrafish, cellular (HepG2 and AML12), and mouse models. RESULTS: Our results indicate that BIC significantly reduces lipid accumulation and inflammation both in vivo and in vitro. Transcriptomic analysis suggested that the anti-MASLD effects of BIC are linked to the inhibition of the NF-κB pathway, which plays a critical role in mitigating inflammation and lipid deposition. CONCLUSION: This study is the first to demonstrate that BIC specifically alleviates lipid accumulation and hepatic steatosis in MASLD models via the NF-κB signaling pathway. Overall, BIC has emerged as a promising candidate for treating MASLD.