Sorting nexin 3 exacerbates doxorubicin-induced cardiomyopathy via regulation of TFRC-dependent ferroptosis  

作　　者：Wenjing Yu Yuehuai Hu Zhiping Liu Kaiteng Guo Dinghu Ma Mingxia Peng Yuemei Wang Jing Zhang Xiaolei Zhang Panxia Wang Jiguo Zhang Peiqing Liu Jing Lu 

机构地区：[1]National and Local United Engineering Lab of Druggability and New Drugs Evaluation,School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510006,China [2]Guangdong Provincial Key Laboratory of New Drug Design and Evaluation,Guangdong Province Engineering Laboratory for Druggability and New Drug Evaluation,School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510006,China [3]School of Pharmacy,Jinan University,Guangzhou 510632,China [4]School of Pharmaceutical Sciences,Shandong First Medical University&Shangdong Academy of Medical Sciences,Taian 271016,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第12期4875-4892,共18页药学学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(82173808,U21A20419,82270500);Natural Science Foundation of Guangdong Province(2021B1515020100,China);Guangzhou Basic and Applied Basic Research Project(202206080007,China);Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(2017BT01Y093,China);Guangdong Provincial Key Laboratory of Construction Foundation(2017B030314030,China);Academic promotion program of Shandong First Medical University(2019LJ003,China).

摘　　要：The clinical utilization of doxorubicin(Dox)in various malignancies is restrained by its major adverse effect:irreversible cardiomyopathy.Extensive studies have been done to explore the prevention of Dox cardiomyopathy.Currently,ferroptosis has been shown to participate in the incidence and development of Dox cardiomyopathy.Sorting Nexin 3(SNX3),the retromer-associated cargo binding protein with important physiological functions,was identified as a potent therapeutic target for cardiac hypertrophy in our previous study.However,few study has shown whether SNX3 plays a critical role in Dox-induced cardiomyopathy.In this study,a decreased level of SNX3 in Dox-induced cardiomyopathy was observed.Cardiac-specific Snx3 knockout(Snx3-cKO)significantly alleviated cardiomyopathy by downregulating Dox-induced ferroptosis significantly.SNX3 was further demonstrated to exacerbate Dox-induced cardiomyopathy via induction of ferroptosis in vivo and in vitro,and cardiac-specific Snx3 transgenic(Snx3-cTg)mice were more susceptible to Dox-induced feroptosis and cardiomyopathy.Mechanistically,SNX3 facilitated the recycling of transferrin 1 receptor(TFRC)via direct interaction,disrupting iron homeostasis,increasing the accumulation of iron,triggering ferroptosis,and eventually exacerbating Dox-induced cardiomyopathy.Overall,these findings established a direct SNX3-TFRC-ferroptosis positive regulatory axis in Dox-induced cardiomyopathy and suggested that targeting SNX3 provided a new effective therapeutic strategy for Dox-induced cardiomyopathy through TFRCdependentferroptosis.

关 键 词：SNX3 Ferroptosis TFRC CARDIOMYOPATHY DOXORUBICIN Iron homeostasis Cell death Mitochondria 

分 类 号：R54[医药卫生—心血管疾病]