代谢功能障碍相关脂肪性肝病的机制、靶点及治疗药物:现状与挑战OA

Metabolic dysfunction-associated steatotic liver disease(MASLD)and its progressive condition-metabolic dysfunction-associated steatohepatitis(MASH)-are posing a significant challenge to human health worldwide.This disease is characterized by high prevalence,natural progression,and complex pathogenic mechanisms.In recent years,the incidence of MASLD has been increasing.What's worse,its progression to end-stage liver disease can impact the patient's prognosis.Despite the two drugs(resmetirom and semaglutide)approved by the U.S.Food and Drug Administration(FDA)for this indication,therapies currently available fail to meet real-world clinical needs,ameliorate such symptoms as the advanced liver fibrosis in MASLD or to prevent the occurrence of major compli-cations.In particular,the personalized treatments for the MASLD with different pathological characteris-tics at different stages need to be made available.The heterogeneity and complex pathological process involving intertwined multiple mechanisms of MASLD make single-target drugs ineffective for all related cases,pointing to a pressing need to develop drugs with new mechanisms and new targets and to find new intervention methods.This paper reviews the progress in the pathogenic mechanisms,intervention targets,and therapeutic drugs(including chemotherapeutic drugs,cell therapy drugs and gene therapy drugs)concerning MASLD/MASH in general and chemotherapeutic drugs and stem cell-based thera-peutic drugs in particular.This review also analyzes the issues and challenges facing chemical drugs and stem cells and their exosomes for treatment of MASLD/MASH,and asserts that the combination of different single-target drugs or the development of multi-target drugs may be the priority of research on MASLD/MASH.Mesenchymal stem cells and their exosomes show good prospects as a novel means of intervention or a supplement to clinical treatment for MASLD/MASH.However,its heterogeneity,sta-bility,long-term safety,and reliability of efficacy need to be verified.