The role of lncRNA H19/Hmox1 axis regulating ferroptosis in anthracycline-induced cardiotoxicity

This study investigates the molecular mechanisms underlying anthracyclines (ANT)-induced cardiotoxicity, with a specific focus on ferroptosis regulated by the long non-coding RNA (lncRNA) H19/heme oxygenase-1 (Hmox1) signaling axis. A retrospective analysis was performed on 50 breast cancer patients who developed ANT-associated cardiac dysfunction. Clinical assessments included measurements of left ventricular ejection fraction (LVEF) and serum markers, such as cardiac troponin I (cTnI), creatine kinase-MB (CK-MB), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and serum iron levels. Serum analysis revealed a marked downregulation of lncRNA H19 and upregulation of Hmox1, both significantly correlated with impaired cardiac function and disrupted iron homeostasis. To further elucidate the mechanism, an Epirubicin (EPI)-induced injury model in HL-1 cardiomyocytes was established. EPI exposure led to suppression of lncRNA H19, upregulation of Hmox1, and induction of apoptosis and ferroptotic cell death. RNA-seq analysis identified potential downstream targets linking lncRNA H19 to iron metabolism via Hmox1 modulation. Functional assays demonstrated that overexpression of lncRNA H19 mitigated EPI-induced ferroptosis, while enforced expression of Hmox1 reversed these protective effects. Collectively, these findings identify the lncRNA H19/Hmox1 axis as a critical regulator of ferroptosis in ANT-induced cardiotoxicity and suggest it as a potential therapeutic target for mitigating cardiac injury in breast cancer patients undergoing anthracycline chemotherapy.

本研究探究了蒽环类药物（anthracyclines, ANT）诱导心肌毒性的分子机制，重点关注长链非编码RNA（long non-coding RNA, lncRNA）H19/血红素氧合酶-1（heme oxygenase-1, Hmox1）信号轴调控的铁死亡（ferroptosis）。本研究回顾性分析了50例发生蒽环类药物相关心功能不全的乳腺癌患者，临床评估指标包括左心室射血分数（left ventricular ejection fraction, LVEF），以及心肌肌钙蛋白I（cardiac troponin I, cTnI）、肌酸激酶同工酶MB（creatine kinase-MB, CK-MB）、N末端B型利钠肽原（N-terminal pro-B-type natriuretic peptide, NT-proBNP）与血清铁水平等血清标志物。血清检测结果显示，lncRNA H19表达显著下调，而Hmox1表达显著上调，二者均与心功能受损及铁代谢稳态紊乱显著相关。为进一步阐明其分子机制，本研究构建了表柔比星（Epirubicin, EPI）诱导的HL-1心肌细胞损伤模型。结果显示，表柔比星暴露可抑制lncRNA H19的表达、上调Hmox1水平，并诱导细胞凋亡与铁死亡性细胞死亡。RNA测序（RNA-seq）分析鉴定出了通过调控Hmox1、将lncRNA H19与铁代谢相关联的潜在下游靶点。功能实验证实，过表达lncRNA H19可缓解表柔比星诱导的铁死亡，而强制过表达Hmox1则会逆转上述保护作用。综上，本研究证实lncRNA H19/Hmox1信号轴是蒽环类药物诱导心肌毒性中铁死亡的关键调控因子，并提示其可作为接受蒽环类化疗的乳腺癌患者心肌损伤的潜在治疗靶点。