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心肌细胞定位蛋白CCDC25通过识别中性粒细胞胞外诱捕网（NET）DNA激活自噬流进而促进阿霉素心脏毒性

Cardiomyocyte-localized CCDC25 senses NET DNA to promote doxorubicin cardiotoxicity by activating autophagic flux

原文发布日期: 2025-05-29

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文章 :

心肌细胞定位蛋白CCDC25通过识别中性粒细胞胞外诱捕网（NET）DNA激活自噬流进而促进阿霉素心脏毒性

Cardiomyocyte-localized CCDC25 senses NET DNA to promote doxorubicin cardiotoxicity by activating autophagic flux

原文发布日期: 2025-05-29

英文摘要:

Cardiotoxicity restricts the clinical use of anthracyclines. Although recent evidence indicates that aberrant activation of the cytosolic DNA-sensing pathway mediates cardiotoxicity, the function of extracellular DNA remains unclear. Here we observe a substantial increase in circulating neutrophil extracellular trap (NET) DNA in individuals with lymphoma experiencing cardiotoxicity after anthracycline-containing treatment. Using mouse models and human organotypic myocardial slices, we demonstrate that doxorubicin induces HMGB1-dependent cardiac NET formation, thereby promoting cardiac remodeling and dysfunction. Mechanistically, extracellular NET DNA is recognized by the transmembrane protein CCDC25 on cardiomyocytes, and their cross-talk generates reactive oxygen species and activates autophagic flux, subsequently impairing cardiac function. Targeting CCDC25 significantly alleviates anthracycline cardiotoxicity and synergizes with the antitumor efficacy of doxorubicin in lymphoma and breast cancer models. Overall, our findings demonstrate a previously unrecognized role of NETs and CCDC25 in anthracycline cardiotoxicity and suggest that targeting CCDC25 could provide a dual therapeutic and cardioprotective advantage.

摘要翻译：

心脏毒性限制了蒽环类药物的临床应用。尽管近期证据表明胞质DNA传感通路的异常激活介导了心脏毒性，但细胞外DNA的功能仍不清楚。本研究发现，在接受含蒽环类药物治疗后出现心脏毒性的淋巴瘤患者体内，循环中性粒细胞胞外诱捕网（NET）DNA显著增加。通过小鼠模型和人源器官型心肌切片实验，我们证实阿霉素可诱导HMGB1依赖性的心脏NET形成，从而促进心脏重构和功能障碍。机制上，心肌细胞跨膜蛋白CCDC25识别细胞外NET DNA，二者相互作用产生活性氧并激活自噬流，最终导致心功能损伤。靶向CCDC25不仅能显著减轻蒽环类心脏毒性，在淋巴瘤和乳腺癌模型中还能协同增强阿霉素的抗肿瘤疗效。本研究首次揭示了NETs与CCDC25在蒽环类心脏毒性中的关键作用，表明靶向CCDC25可能产生兼具心脏保护与肿瘤治疗的双重获益。