中国组织工程研究

中国组织工程研究 ›› 2026, Vol. 30 ›› Issue (22): 5756-5769.doi: 10.12307/2026.133

• 组织构建实验造模 experimental modeling in tissue construction • 上一篇    下一篇

阿霉素诱导的心肌细胞铁死亡模型小鼠及心肌细胞中 piRNA CFAPIR 的作用

陶香宇，王  霜，李雨涵，曹济民，孙  腾   

  1. 山西医科大学细胞生理学教育部重点实验室，山西省细胞生理学重点实验室，山西医科大学基础医学院生理学系，山西省太原市   030001
  • 收稿日期:2025-03-11 接受日期:2025-08-08 出版日期:2026-08-08 发布日期:2025-12-27
  • 通讯作者: 孙腾，博士，副教授，博士生导师，山西医科大学细胞生理学教育部重点实验室，山西省细胞生理学重点实验室，山西医科大学基础医学院生理学系，山西省太原市 030001
  • 作者简介:陶香宇，女，1999年生，辽宁省阜新市人，汉族，山西医科大学在读硕士，主要从事心肌损伤的表观遗传学调控机制研究。
  • 基金资助:
    国家自然科学基金面上项目(82170294)，项目负责人：孙腾；国家自然科学基金青年科学基金项目(81800268)，项目负责人：孙腾；国家自然科学基金面上项目(82170523)，项目负责人：曹济民；中央引导地方科技发展资金项目(YDZJSX2022A061)，项目负责人：孙腾；山西省高等教育“百亿工程”科技引导专项(BYJL006)，项目负责人：孙腾

Effects of piRNA CFAPIR in doxorubicin-induced ferroptosis models of rat and human cardiomyocytes

Tao Xiangyu, Wang Shuang, Li Yuhan, Cao Jimin, Sun Teng   

  1. Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Key Laboratory of Cellular Physiology of Shanxi Province, Department of Physiology, School of Basic Medicine, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
  • Received:2025-03-11 Accepted:2025-08-08 Online:2026-08-08 Published:2025-12-27
  • Contact: Sun Teng, PhD, Associate professor, Doctoral supervisor, Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Key Laboratory of Cellular Physiology of Shanxi Province, Department of Physiology, School of Basic Medicine, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
  • About author:Tao Xiangyu, MS candidate, Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education, Key Laboratory of Cellular Physiology of Shanxi Province, Department of Physiology, School of Basic Medicine, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
  • Supported by:
    National Natural Science Foundation of China (General Program), No. 82170294 (to ST); National Natural Science Foundation of China for the Youth, No. 81800268 (to ST); National Natural Science Foundation of China (General Program), No. 82170523 (to CJM); The Central Leading Local Science and Technology Development Fund Project, No. YDZJSX2022A061 (to ST); Shanxi Province Higher Education “Billion Project” Science and Technology Guidance Project, No. BYJL006 (to ST)

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摘要：


文题释义：
CFAPIR：通过RNA深度测序筛选出piRNA413，其NCBI序列号为AB349597.1，长度21 nt，基因座为Mirlet7i，经过进一步的功能研究发现piRNA413调控了阿霉素诱导心肌细胞铁死亡，因此将其命名为心脏铁死亡相关piRNA(cardiac ferroptosis-associated piRNA)，简称CFAPIR。
铁死亡：一种程序性细胞死亡方式，区别于传统的细胞凋亡、坏死和自噬等细胞死亡方式，其核心机制为细胞内铁代谢失衡和活性氧过度积累，导致细胞膜脂质过氧化，最终引发细胞死亡。铁死亡与多种疾病的病理过程密切相关，在阿霉素诱导的心肌病中起关键作用。

背景：研究发现，铁死亡在阿霉素诱导心肌病中发挥关键作用，并发现piRNA413调控了阿霉素诱导心肌细胞铁死亡，将其命名为心脏铁死亡相关piRNA(简称CFAPIR)，但具体调控机制有待进一步阐明。
目的：探究piRNA CFAPIR在阿霉素诱导的心肌细胞铁死亡和心肌病中的作用和调控机制。
方法：①腹腔注射阿霉素诱导小鼠心肌病，心脏原位注射CFAPIR敲低慢病毒。监测和记录小鼠体质量和生存率，评估心功能、心脏体积和质量、炎症以及心脏纤维化程度。②阿霉素诱导AC16心肌细胞铁死亡，将CFAPIR抑制剂转染至细胞。检测细胞损伤、铁死亡(铁死亡标志物表达水平，铁离子、丙二醛和还原型谷胱甘肽的含量)以及线粒体功能障碍，检测CFAPIR对ABCB8表达水平的影响。
结果与结论：①在阿霉素诱导的心肌病动物模型(P < 0.000 1)和心肌细胞铁死亡模型(P < 0.01)中，CFAPIR的水平均显著上调。②在动物水平，敲低CFAPIR显著减轻了阿霉素引起的小鼠心脏毒性，包括抑制体质量减轻(P < 0.05)、提高生存率、改善心功能(P < 0.01)，减轻心脏萎缩(P < 0.05)，抑制乳酸脱氢酶活性增强(P < 0.05)，以及减轻心脏纤维化(P < 0.000 1)。③在细胞水平，敲低CFAPIR显著改善了阿霉素诱导的心肌细胞铁死亡，表现为细胞存活率增高(P < 0.05)，乳酸脱氢酶活性降低(P < 0.01)，铁死亡标志物xCT(P < 0.01)和谷胱甘肽过氧化物酶4(P < 0.001)表达水平上调，前列腺素内过氧化物合酶2的mRNA水平下调(P < 0.05)，铁超载减轻(P < 0.05)，丙二醛含量减少(P < 0.05)，还原型谷胱甘肽含量增多(P < 0.01)，活性氧积累减少(P < 0.01)，以及线粒体膜电位的升高(P < 0.05)。④敲低CFAPIR显著减弱阿霉素诱导的铁转运蛋白ABCB8表达水平降低(P < 0.05)。⑤结果表明，在阿霉素诱导心肌病的动物模型和细胞铁死亡模型中CFAPIR水平均显著上调，敲低CFAPIR显著改善了阿霉素诱导的心脏毒性和心肌细胞铁死亡，并且可能通过靶向线粒体铁转运蛋白ABCB8发挥作用。

https://orcid.org/0009-0001-2216-9283 (陶香宇) 


中国组织工程研究杂志出版内容重点：干细胞；骨髓干细胞；造血干细胞；脂肪干细胞；肿瘤干细胞；胚胎干细胞；脐带脐血干细胞；干细胞诱导；干细胞分化；组织工程

关键词: piRNA, CFAPIR, 阿霉素诱导心肌病, 铁死亡, 线粒体功能障碍, 铁转运蛋白ABCB8

Abstract: BACKGROUND: Ferroptosis plays a critical role in doxorubicin-induced cardiomyopathy; however, its specific regulatory mechanisms require further elucidation. Piwi-interacting RNA 413 (piRNA413) regulates ferroptosis in doxorubicin-induced cardiomyocytes, designated as cardiac ferroptosis-associated piRNA (CFAPIR). However, the specific regulatory mechanism needs to be further elucidated.
OBJECTIVE: To investigate the role and regulatory mechanism of piRNA CFAPIR in doxorubicin-induced cardiomyocyte ferroptosis and cardiomyopathy.
METHODS: (1) Intraperitoneal injection of doxorubicin was used to induce cardiomyopathy in mice. The myocardium was in situ injected with CFAPIR knocking down lentivirus. The body mass and survival rate of mice were monitored and recorded; cardiac function, heart volume and mass, inflammation, and fibrosis were evaluated. (2) Doxorubicin was used to induce ferroptosis in AC16 cardiomyocytes. CFAPIR inhibitor was transfected into cardiomyocytes. Cell injury and ferroptosis were assessed by measuring ferroptosis markers, intracellular iron level, malondialdehyde content, and reduced glutathione level, along with evaluating mitochondrial dysfunction. Additionally, the effect of CFAPIR on ABCB8 expression levels was analyzed.
RESULTS AND CONCLUSION: (1) The level of CFAPIR was significantly up-regulated in both doxorubicin-induced cardiomyopathy animal model (P < 0.000 1) and the cardiomyocyte ferroptosis model (P < 0.01). (2) At the animal level, CFAPIR knockdown markedly attenuated doxorubicin-induced cardiotoxicity, including the prevention of body mass loss (P < 0.05), improvement in survival rate, preservation of cardiac function (P < 0.01), reduction of cardiac atrophy (P < 0.05), inhibition of elevated lactate dehydrogenase activity (P < 0.05), and mitigation of cardiac fibrosis (P < 0.000 1). (3) At the cellular level, CFAPIR knockdown significantly improved doxorubicin-induced ferroptosis in cardiomyocytes, as evidenced by enhanced cell viability (P < 0.05), reduced lactate dehydrogenase activity (P < 0.01), upregulation of ferroptosis markers xCT (P < 0.01) and glutathione peroxidase 4 (P < 0.001), downregulation of prostaglandin-endoperoxide synthase 2 mRNA expression (P < 0.05), alleviation of iron overload (P < 0.05), decreased malondialdehyde levels (P < 0.05), restoration of reduced glutathione content (P < 0.01), reduced reactive oxygen species accumulation (P < 0.01), and improvement in mitochondrial membrane potential (P < 0.05). (4) CFAPIR knockdown significantly mitigated the doxorubicin-induced downregulation of the iron transport protein ABCB8 (P < 0.05). In conclusion, CFAPIR expression is markedly elevated in both the animal model of doxorubicin-induced cardiomyopathy and the cardiomyocyte ferroptosis model. CFAPIR knockdown significantly alleviates doxorubicin-induced cardiotoxicity and cardiomyocyte ferroptosis, potentially by targeting the mitochondrial iron transport protein ABCB8.

Key words: piRNA, CFAPIR, doxorubicin-induced cardiomyopathy, ferroptosis, mitochondrial dysfunction, iron transporter ABCB8

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