Phytic acid-based nanomedicine against mTOR represses lipogenesis and immune response for metabolic dysfunction-associated steatohepatitis therapy  

作　　者：Fenghua Xu Shoujie Zhao Yejing Zhu Jun Zhu Lingyang Kong Huichen Li Shouzheng Ma Bo Wang Yongquan Qu Zhimin Tian Junlong Zhao Lei Liu 

机构地区：[1]State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Xijing Hospital of Digestive Diseases,Air Force Medical University,Xi’an,Shaanxi 710032,China [2]Key Laboratory of Modern Teaching Technology,Ministry of Education,Shaanxi Normal University,Xi’an,Shaanxi 710062,China [3]Department of General Surgery,Tangdu Hospital,Air Force Medical University,Xi’an,Shaanxi 710038,China [4]Department of Thoracic Surgery,Tangdu Hospital,Air Force Medical University,Xi’an,Shaanxi 710038,China [5]Key Laboratory of Special Functional and Smart Polymer Materials of Ministry of Industry and Information Technology,School of Chemistry and Chemical Engineering,Northwestern Polytechnical University,Xi’an,Shaanxi 710072,China [6]State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers,Department of Medical Genetics and Developmental Biology,Air Force Medical University,Xi’an,Shaanxi 710032,China [7]Department of Pediatrics,Tangdu Hospital,Air Force Medical University,Xi’an,Shaanxi 710000,China

出　　处：《Life Metabolism》2024年第6期33-49,共17页生命代谢（英文）

基　　金：supported by the National Natural Science Foundation of China(82373409,82173143,and 82173082);the Top Young Talents Project of“Special Support Program for High Level Talents”in Shaanxi Province(TZ0422,2020−2025);the 2023 program for training talented pilots upon graduation(LHRCYB23009);support from the National Key Research and Development Program of China(2021YFB3500904);the Key Research and Development Program of Shaanxi(2024SF-YBXM-439);the support from the Fundamental Research Funds for the Central Universities(D5000210635 and D5000210829).

摘　　要：Metabolic dysfunction-associated steatohepatitis(MASH)is one of the most common chronic liver diseases and is mainly caused by metabolic disorders and systemic inflammatory responses.Recent studies have indicated that the activation of the mammalian(or mechanistic)target of rapamycin(mTOR)signaling participates in MASH progression by facilitating lipogenesis and regulating the immune microenvironment.Although several molecular medicines have been demonstrated to inhibit the phosphorylation or activation of mTOR,their poor specificity and side effects limit their clinical application in MASH treatment.Phytic acid(PA),as an endogenous and natural antioxidant in the liver,presents significant anti-inflammatory and lipid metabolism-inhibiting functions to alleviate MASH.In this study,considering the unique phosphate-rich structure of PA,we developed a cerium-PA(CePA)nanocom-plex by combining PA with cerium ions possessing phosphodiesterase activity.CePA intervened in the S2448 phosphorylation of mTOR through the occupation effect of phosphate groups,thereby inhibiting the inflammatory response and mTOR-sterol regulatory element-binding protein 1(SREBP1)regulation axis.The in vivo experiments suggested that CePA alleviated MASH progression and fat accumulation in high-fat diet-fed mice.Mechanistic studies validated that CePA exerts a liver-targeted mTOR repressive function,making it a promising candidate for MASH and other mTOR-related disease treatments.

关 键 词：metabolism inhibiting ENDOGENOUS 

分 类 号：R575[医药卫生—消化系统]