Carrier-Free Silibinin/Sorafenib Microparticles Alleviate Metabolic Dysfunction-Associated Steatotic Liver Disease by Modulating Fatty Acid Metabolism

Feifei Han,1,* Haiping Wang,1,2,* Li Wang,1 Limei Fan,1 Sibei Peng,1 Xiaoying Hou,1,2 Xiji Shu,1,2 Binlian Sun,1,2 Yuchen Liu1,2 1Cancer Institute, School of Medicine, Jianghan University, Wuhan, Hubei, 430056, People’s Republic of China; 2Hubei Key Laboratory of Cognitive and Affective Disorders, Jianghan University, Wuhan, Hubei, 430056, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuchen Liu, Email [email protected]: Metabolic dysfunction-associated steatotic liver disease (MASLD), characterized by excessive fat accumulation in the liver, is the most prevalent cause of chronic liver disease globally. The clinical use of pharmacological agents such as silibinin and sorafenib is limited due to poor water solubility, low bioavailability, and potential side effects, necessitating innovative therapeutic approaches.Methods: In this study, we developed self-assembled, carrier-free microparticles of silibinin and sorafenib (SIL-SOR-MPs) using magnetic stirring and evaluated their therapeutic effects on MASLD both in vitro and in vivo.Results: Compared to free SIL and free SOR, SIL-SOR-MPs significantly reduced lipid accumulation in HepG2 cells and effectively alleviated hepatic steatosis and liver damage in mice. Mechanistic investigations further showed that SIL-SOR-MPs more effectively down-regulated lipid synthesis genes and up-regulated genes involved in lipid oxidation.Discussion: In summary, our study highlights that carrier-free SIL-SOR-MPs demonstrate the ability to reverse the progression of MASLD and present a promising therapeutic strategy.Keywords: metabolic dysfunction-associated steatotic liver disease, silibinin, sorafenib, self-assembled carrier-free microparticles, fatty acid metabolism