Meshrkey Fibi, Ibrahim Somaya Y, Bagchi Rushita A, Richardson William J
Ralph E. Martin Department of Chemical Engineering, University of Arkansas, Fayetteville, AR 72701, USA.
PharmD Program, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Cells. 2025 Sep 20;14(18):1471. doi: 10.3390/cells14181471.
Anthracyclines are widely used chemotherapeutic agents with proven efficacy against a broad range of malignancies, but their clinical utility is limited by a well-documented, dose-dependent cardiotoxicity. While this toxicity has traditionally been attributed to direct cardiomyocyte injury, emerging evidence highlights the pivotal role of cardiac fibroblasts (CFs) in the development and progression of anthracycline-induced cardiotoxicity. This review examines the diverse effects of anthracycline focusing on doxorubicin (DOX) and CFs across the temporal phases of cardiac injury. DOX activates fibroblast-driven extracellular matrix remodeling and promotes fibrosis through enhanced collagen production and the induction of cellular senescence, thereby exacerbating early myocardial inflammation and dysfunction. Clinically, anthracycline cardiotoxicity may present as acute (within days), subacute (within weeks), or chronic progressive forms manifesting either early (within one year) or late (up to decades post-treatment). While early manifestations may be reversible with timely detection and management, late-phase cardiotoxicity is often irreversible, characterized by declining left ventricular ejection fraction and heart failure. A deeper understanding of the molecular and cellular contributions of CFs may uncover novel therapeutic targets to prevent or attenuate anthracycline-related cardiac damage.
蒽环类药物是广泛使用的化疗药物，已证实对多种恶性肿瘤有效，但其临床应用受到充分记录的剂量依赖性心脏毒性的限制。虽然这种毒性传统上归因于直接的心肌细胞损伤，但新出现的证据突出了心脏成纤维细胞（CFs）在蒽环类药物诱导的心脏毒性发生和发展中的关键作用。本综述探讨了蒽环类药物的多种作用，重点关注阿霉素（DOX）和心脏成纤维细胞在心脏损伤不同阶段的作用。DOX激活成纤维细胞驱动的细胞外基质重塑，并通过增强胶原蛋白生成和诱导细胞衰老促进纤维化，从而加剧早期心肌炎症和功能障碍。临床上，蒽环类药物心脏毒性可表现为急性（数天内）、亚急性（数周内）或慢性进行性形式，可在早期（一年内）或晚期（治疗后数十年）出现。虽然早期表现通过及时检测和处理可能可逆，但晚期心脏毒性往往不可逆，其特征是左心室射血分数下降和心力衰竭。对心脏成纤维细胞分子和细胞作用的更深入理解可能会揭示预防或减轻蒽环类药物相关心脏损伤的新治疗靶点。
