Ma Yan, Wang Yongjun, Chen Renzheng, Wang Yabin, Fang Yan, Qin Cheng, Wang Tianhu, Shen Xiaoying, Zhou Tingwen, Tian Lei, Sun Ting, Fan Li, Wang Xiaoning, Han Dong, Cao Feng
Chinese Military Medical School, National Clinical Research Center for Geriatric Diseases, The Second Medical Center, Chinese PLA General Hospital, 100853, Beijing, China.
Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China.
Signal Transduct Target Ther. 2025 May 14;10(1):157. doi: 10.1038/s41392-025-02245-4.
Doxorubicin (DOX) is the most effective chemotherapeutic for breast cancer, but it is usually associated with severe cardiotoxicity. Further investigation to alleviate its side effects is essential. The present study investigated the mechanism of the cross-organ communication between tumors and the heart and potential intervention targets. Morphological bubble-like protrusions were observed in both adult murine ventricular cardiomyocytes (AMVCs) and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) cocultured with breast cancer cells (BCCs), along with elevated expression of pyroptosis-related proteins. Exosomes (EXOs) from DOX-treated BCCs aggravated DOX-induced cardiotoxicity (DOXIC) in an orthotopic mouse model of breast cancer. Blocking miRNAs by knocking down Rab27a or inhibiting the release of EXOs in cancer tissue by Dicer enzyme knockout attenuated this additional injury effect. Exosomal miRNA sequencing revealed that miR-216a-5p is especially upregulated in EXOs from DOX-induced BCCs. Mechanistically, miR-216a-5p was upregulated by enhanced transcription mediated by DOX-induced AMP-dependent transcription factor 3 (ATF3) and packaged into EXOs by splicing factor 3b subunit 4 (SF3B4) in BCCs. Itchy E3 ubiquitin-protein ligase (ITCH) was identified as a novel downstream target mRNA of miR-216a-5p. ITCH negatively mediated thioredoxin-interacting protein (TXNIP) ubiquitination to activate the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome pathway, ultimately leading to cardiomyocyte pyroptosis. Our findings revealed novel cross-organ pathogenic communication between breast cancer and the heart through the exosomal miR-216a-5p-mediated ITCH/TXNIP/NLRP3 pathway, which drives cardiomyocyte pyroptosis. These findings suggest that targeting myocardial miR-216a-5p or blocking harmful EXOs from breast cancer is a potential therapeutic strategy for alleviating DOXIC.
多柔比星（DOX）是治疗乳腺癌最有效的化疗药物，但它通常与严重的心脏毒性相关。进一步研究减轻其副作用至关重要。本研究调查了肿瘤与心脏之间跨器官通讯的机制以及潜在的干预靶点。在与乳腺癌细胞（BCCs）共培养的成年小鼠心室心肌细胞（AMVCs）和人诱导多能干细胞衍生的心肌细胞（hiPSC-CMs）中均观察到形态学上的气泡样突起，同时焦亡相关蛋白的表达升高。来自多柔比星处理的BCCs的外泌体（EXOs）在乳腺癌原位小鼠模型中加重了多柔比星诱导的心脏毒性（DOXIC）。通过敲低Rab27a阻断微小RNA（miRNAs）或通过Dicer酶敲除抑制癌症组织中外泌体的释放可减轻这种额外的损伤作用。外泌体微小RNA测序显示，miR-216a-5p在多柔比星诱导的BCCs来源的外泌体中尤其上调。机制上，miR-216a-5p通过多柔比星诱导的AMP依赖转录因子3（ATF3）介导的转录增强而上调，并由BCCs中的剪接因子3b亚基4（SF3B4）包装到外泌体中。瘙痒E3泛素蛋白连接酶（ITCH）被鉴定为miR-216a-5p的一个新的下游靶标mRNA。ITCH负向介导硫氧还蛋白相互作用蛋白（TXNIP）的泛素化，以激活含NOD、LRR和吡啉结构域的蛋白3（NLRP3）炎性小体途径，最终导致心肌细胞焦亡。我们的研究结果揭示了乳腺癌与心脏之间通过外泌体miR-216a-5p介导的ITCH/TXNIP/NLRP3途径存在新的跨器官致病通讯，该途径驱动心肌细胞焦亡。这些发现表明，靶向心肌miR-216a-5p或阻断来自乳腺癌的有害外泌体是减轻DOXIC的一种潜在治疗策略。
