Inhibition of ASCT2 induces hepatic stellate cell senescence with modified proinflammatory secretome through an IL-1α/NF-κB feedback pathway to inhibit liver fibrosis

作     者：Feixia Wang Zhanghao Li Li Chen Ting Yang Baoyu Liang Zili Zhang Jiangjuan Shao Xuefen Xu Guoping Yin Shijun Wang Hai Ding Feng Zhang Shizhong Zheng Feixia Wang;Zhanghao Li;Li Chen;Ting Yang;Baoyu Liang;Zili Zhang;Jiangjuan Shao;Xuefen Xu;Guoping Yin;Shijun Wang;Hai Ding;Feng Zhang;Shizhong Zheng

作者机构：Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia MedicaSchool of PharmacyNanjing University of Chinese MedicineNanjing 210023China Department of General SurgeryNanjing Hospital Affiliated to Nanjing University of Chinese MedicineNanjing 210003China Department of AnesthesiologyNanjing Hospital Affiliated to Nanjing University of Chinese MedicineNanjing 210003China College of Traditional Chinese MedicineShandong University of Traditional Chinese MedicineJinan 250035China 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2022年第12卷第9期

页      面：3618-3638页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 10[医学] 100602[医学-中西医结合临床] 

基　　金：financially supported by the National Natural Science Foundation of China (81870423, 82173874 and 82073914) the Major Project of the Natural Science Research of Jiangsu Higher Education Institutions (19KJA310005, China) the Open Project of Chinese Materia Medica First-Class Discipline of Nanjing University of Chinese Medicine (2020YLXK022 and 2020YLXK023, China) the Open Project of Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica (JKLPSE202005, China) the Qing Lan Project of Jiangsu Higher Institutions (Young and Middle-Aged Academic Leader, China) the Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX20_1493, China) 

主　　题：Hepatic stellate cells Senescence SASP ASCT2 Precursor IL-1α NF-κB Atractylenolide III Liver fibrosis 

摘      要：Senescence of activated hepatic stellate cells(aHSCs) is a stable growth arrest that is implicated in liver fibrosis regression.Senescent cells often accompanied by a multi-faceted senescence-associated secretory phenotype(SASP).But little is known about how alanine-serine-cysteine transporter type-2(ASCT2),a high affinity glutamine transporter,affects HSC senescence and SASP during liver fibrosis.Here,we identified ASCT2 is mainly elevated in aHSCs and positively correlated with liver fibrosis in human and mouse fibrotic livers.We first discovered ASCT2 inhibition induced HSCs to senescence in vitro and in vivo.The proinflammatory SASP were restricted by ASCT2 inhibition at senescence initiation to prevent paracrine migration.Mechanically,ASCT2 was a direct target of glutaminolysisdependent proinflammatory SASP,interfering IL-1α/NF-κB feedback loop via interacting with precursor IL-1α at Lys82.From a translational perspective,atractylenolide Ⅲ is identified as ASCT2 inhibitor through directly bound to Asn230 of ASCT2.The presence of -OH group in atractylenolide Ⅲ is suggested to be favorable for the inhibition of ASCT2.Importantly,atractylenolide Ⅲ could be utilized to treat liver fibrosis mice.Taken together,ASCT2 controlled HSC senescence while modifying the proinflammatory SASP.Targeting ASCT2 by atractylenolide Ⅲ could be a therapeutic candidate for liver fibrosis.