|本期目录/Table of Contents|

[1]李雪航,晏秋梅,张欣,等.MST1/2抑制剂对DOX心脏毒性的影响及作用机制研究[J].天津医科大学学报,2026,32(02):146-152.[doi:10.20135/j.issn.1006-8147.2026.02.0146]
　LI Xuehang,YAN Qiumei,ZHANG Xin,et al.The effects and mechanisms of MST1/2 inhibitor on doxorubicin-induced cardiotoxicity[J].Journal of Tianjin Medical University,2026,32(02):146-152.[doi:10.20135/j.issn.1006-8147.2026.02.0146]
点击复制

MST1/2抑制剂对DOX心脏毒性的影响及作用机制研究(PDF)

《天津医科大学学报》[ISSN:1006-8147/CN:12-1259/R]

卷:
32卷
期数:
2026年02期
页码:
146-152
栏目:
基础医学
出版日期:
2026-03-20

文章信息/Info

Title:
The effects and mechanisms of MST1/2 inhibitor on doxorubicin-induced cardiotoxicity
文章编号:
1006-8147(2026)02-0146-07
作者:
李雪航1; 晏秋梅2; 张欣3; 白英玉2; 李晓祥4; 王晓虹1; 陈雄文2
（1.天津医科大学基础医学院，天津300070；2.天津医科大学药学院，天津300070；3.中国医科大学附属第一医院感染性疾病一科，沈阳110001；4.安徽省新星药物开发有限责任公司，合肥230001）
Author(s):
LI Xuehang1; YAN Qiumei2;  ZHANG Xin3;  BAI Yingyu2;  LI Xiaoxiang4;  WANG Xiaohong1;  CHEN Xiongwen2
（1. School of Basic Medical Sciences，Tianjin Medical University， Tianjin 300070， China； 2. School of Pharmacy， Tianjin Medical University， Tianjin 300070， China； 3.Department of Infectious Diseases I， The First Affiliated Hospital of China Medical University， Shenyang 110001， China； 4. Anhui Xinxing Pharmaceutical Development Co.， Ltd.， Hefei 230001， China）
关键词:
阿霉素; MST1/2抑制剂; 心肌细胞萎缩; 肌纤维; 自噬
Keywords:
Doxorubicin;  MST1/2 inhibitor;  cardiomyocyte atrophy;  myofibril;  autophagy
分类号:
R96
DOI:
10.20135/j.issn.1006-8147.2026.02.0146
文献标志码:
A
摘要:
目的：探讨MST1/2抑制剂（MSTi） 对阿霉素（DOX）心脏毒性的治疗作用及机制。方法：C57BL/6小鼠经生理盐水或者MSTi预处理5 d后，每隔1 d腹腔注射5 mg/kg DOX或者生理盐水（共4次），将小鼠随机分为4组：Con+DMSO组、Con+MST1/2抑制剂组、DOX+DMSO组、DOX+MST1/2抑制剂组，以造模时间划分为慢性效应组（末次DOX注射后观察至28 d）和急性效应组（末次DOX注射后观察24 h）。慢性效应组在末次注射后每周采用超声心动图检测心脏功能。动物处死后收集心脏组织，进行实时荧光定量PCR、Western blotting、组织切片HE染色、心肌肌钙蛋白T（cTnT）免疫荧光，检测心肌组织mRNA和自噬标志蛋白微管相关蛋白轻链3（LC3）蛋白表达、心肌细胞横截面积、心肌纤维水平与排列。结果：与Con+DMSO组相比，DOX+DMXO组小鼠的生存率降低40%（χ2=8.418，df=3，P<0.05），MST1/2抑制剂治疗后提高20%（χ2=1.645，df=1，P=0.1997）；DOX+DMSO组小鼠左心室射血分数低于Con+DMSO组，MST1/2抑制剂治疗后明显升高（t=3.510，P<0.05）；DOX+DMSO组心房利钠肽（ANP）和脑利钠肽（BNP）显著升高，MST1/2抑制剂治疗后明显下降（ANP：t=3.553，P<0.05；BNP：t=2.993，P<0.05）；DOX+DMSO组出现心肌细胞横截面积减少、心肌纤维蛋白减少且排列紊乱，MST1/2抑制剂治疗后得到改善。分子水平检测结果显示，DOX+DMSO组心肌组织中自噬相关蛋白LC3的转化水平明显上升，LC3-Ⅱ/LC3-Ⅰ比值高于对照组（t=3.491，P<0.05）。经MST1/2抑制剂治疗干预后，该比值较DOX+DMSO组下降，但差异没有统计学意义（P>0.05）。结论：MST1/2抑制剂通过抑制DOX诱导的自噬过度激活，减少心肌纤维蛋白降解，缓解心肌细胞萎缩，改善心脏功能并提高生存率。
Abstract:
Objective： To investigate the therapeutic effects and underlying mechanisms of a mammalian sterile 20-like kinase 1/2 inhibitor （MSTi） on doxorubicin （DOX）-induced cardiotoxicity. Methods： C57BL/6 mice were pretreated with saline or MSTi for 5 days， followed by intraperitoneal injections of DOX （5 mg/kg） or saline every other day for four times. Mice were randomly divided into four groups： Con+DMSO group， Con+MST1/2 inhibitor group， DOX+DMSO group and DOX+MST1/2 inhibitor group. The modeling time was divided into chronic effect group （observed until 28 days after the last DOX injection） and acute effect group （observed for 24 hours after the last DOX injection）.For the chronic effect groups， cardiac function was monitored weekly by echocardiography after the last injection. After animal euthanization and heart tissue collection，real-time fluorescence quantitative PCR， Western blotting， hematoxylin-eosin （HE） staining， and cardiac troponin T （cTnT） immunofluorescence were used to assess mRNA expression， the autophagy marker microtubule-associated protein light chain 3 （LC3） protein expression， cardiomyocyte cross-sectional area， and myocardial fiber level and alignment. Results： Compared with the Con+DMSO group， the DOX+DMSO group exhibited a 40% reduction in survival rate （χ2=8.418， df=3， P<0.05） whereas treatment with an MST1/2 inhibitor resulted in a 20% increase （χ2=1.645， df=1， P=0.1997）. Compared with Con+DMSO group， left ventricular ejection fraction was reduced in the DOX+DMSO group， and significantly improved after treatment with MST1/2 inhibitor （t=3.510，P<0.05）. Atrial natriuretic peptide （ANP） and brain natriuretic peptide （BNP） levels were markedly elevated in the DOX+DMSO group and decreased following treatment with MST1/2 inhibitors （ANP：t=3.553，P<0.05； BNP： t=2.993，P<0.05）. Histological abnormalities， including reduced cardiomyocyte cross-sectional area， decreased myocardial fibrillar content， and disorganized fiber alignment in the DOX+DMSO group， were ameliorated by treatment with MST1/2 inhibitors. Molecular detection results showed that the conversion level of autophagy-related protein LC3 in the myocardial tissue of the DOX+DMSO group increased significantly， and the LC3-Ⅱ/LC3-Ⅰ ratio was higher than that of the control group （t=3.491，P<0.05）. After MST1/2 inhibitor treatment intervention， this ratio decreased compared to the DOX+DMSO group， but the difference was not statistically significant（P>0.05）. Conclusion： MST1/2 inhibitor can reduce myocardial fibrin degradation， alleviate myocardial cell atrophy， improve cardiac function， and increase survival rate by inhibiting DOX-induced autophagy overactivation.

参考文献/References:

[1] SCHWARTZ S M. Epidemiology of cancer[J]. Clin Chem， 2024， 70（1）： 140-149.
[2] CHEN Y， SHI S， DAI Y. Research progress of therapeutic drugs for doxorubicin-induced cardiomyopathy[J]. Biomed Pharmacother， 2022， 156： 113903.
[3] EWER M S， EWER S M. Cardiotoxicity of anticancer treatments： what the cardiologist needs to know[J]. Nat Rev Cardiol， 2010， 7（10）： 564-575.
[4] MCGOWAN J V， CHUNG R， MAULIK A， et al. Anthracycline chemotherapy and cardiotoxicity[J]. Cardiovasc Drugs Ther， 2017， 31（1）： 63-75.
[5] CHEN D S， YAN J， YANG P Z. Cardiomyocyte atrophy， an underestimated contributor in doxorubicin-induced cardiotoxicity[J]. Front Cardiovasc Med， 2022， 9： 812578.
[6] XIA P， CHEN J， LIU Y， et al. Doxorubicin induces cardiomyocyte apoptosis and atrophy through cyclin-dependent kinase 2-mediated activation of forkhead box O1[J]. J Biol Chem， 2020， 295（13）： 4265-4276.
[7] WU Z， GUAN K L. Hippo signaling in embryogenesis and development[J]. Trends Biochem Sci， 2021， 46（1）： 51-63.
[8] TANG W， LI M， YANGZHONG X， et al. Hippo signaling pathway and respiratory diseases[J]. Cell Death Discov， 2022， 8（1）： 213.
[9] RUSSELL J O， CAMARGO F D. Hippo signalling in the liver： role in development， regeneration and disease[J]. Nat Rev Gastroenterol Hepatol， 2022， 19（5）： 297-312.
[10] IBAR C， IRVINE K D. Integration of hippo-YAP signaling with metabolism[J]. Dev Cell， 2020， 54（2）： 256-267.
[11] KWON Y. YAP/TAZ as molecular targets in skeletal muscle atrophy and osteoporosis[J]. Aging Dis， 2024， 16（1）： 299-320.
[12] SCHIRONE L， VECCHIO D， VALENTI V， et al. MST1 mediates doxorubicin-induced cardiomyopathy by SIRT3 downregulation[J].Cell Mol Life Sci， 2023， 80（9）： 245.
[13] MAEJIMA Y， ZABLOCKI D， NAH J， et al. The role of the Hippo pathway in autophagy in the heart[J]. Nat Cardiovasc Res， 2022， 118（17）： 3320-3330.
[14] FAN F， HE Z， KONG L L， et al. Pharmacological targeting of kinases MST1 and MST2 augments tissue repair and regeneration[J]. Sci Transl Med， 2016， 8（352）：352ra108.
[15] CHLEBOWSKI R T. Adriamycin （doxorubicin） cardiotoxicity： a review[J]. West J Med， 1979， 131（5）： 364-368.
[16] SHE G， DU J C， WU W， et al. Hippo pathway activation mediates chemotherapy-induced anti-cancer effect and cardiomyopathy through causing mitochondrial damage and dysfunction[J]. Therano-stics， 2023， 13（2）： 560-577.
[17] DE SOUZA T F， SILVA T Q A C， COSTA F O， et al. Anthracycline therapy is associated with cardiomyocyte atrophy and preclinical manifestations of heart disease[J]. JACC Cardiovasc Imaging， 2018， 11（8）： 1045-1055.
[18] CHRISTIDI E， BRUNHAM L R. Regulated cell death pathways in doxorubicin-induced cardiotoxicity[J]. Cell Death Dis， 2021， 12（4）： 339.
[19] DIKIC I. Proteasomal and autophagic degradation systems[J]. Annu Rev Biochem， 2017， 86： 193-224.

相似文献/References:

备注/Memo

备注/Memo:
作者简介 李雪航（2000-），女，硕士在读，研究方向：药学；通信作者：王晓虹，E-mail：xiaohongwang@tmu.edu.cn ；陈雄文，E-mail：xiongwenchen@tmu.edu.cn。
更新日期/Last Update: 2026-03-20