謝錦源HSIEH, CHIN-YUAN柯品榕KE, PIN-JUNGPIN-JUNGKE醫學檢驗暨生物技術學系碩士班2026-10-162030-06-2620252025-06-13https://handle.ncl.edu.tw/11296/w2j2rehttps://scholars.csmu.edu.tw/handle/123456789/22193心臟因能量需求高而對氧氣極為敏感，缺氧是缺血性心臟病、發紺性心臟病、肺部疾病的共同病理特徵，已被證實可誘發代謝重編程、活性氧（ROS）累積與細胞死亡，進而導致病理性心肌肥大與纖維化。訊號轉導與轉錄活化因子5（STAT5）可促進發炎反應並驅動心肌肥大；15-脂氧化酶（ALOX15）則透過誘導鐵依賴性細胞死亡（ferroptosis）加劇心肌損傷。秦皮乙素（Esculetin）為多種中草藥來源之香豆素（coumarin）衍生物，以良好的抗氧化與抗發炎能力聞名。本研究旨在探討 STAT5/ALOX15 介導之 ferroptosis 在缺氧誘導心肌重塑中的角色，並評估 Esculetin 作為潛在心臟保護劑之治療效果。為此，我們建立心肌纖維母細胞（H9c2 cardiomyoblasts）、新生大鼠心肌細胞（NRCMs）與心臟纖維母細胞（NRCFs）之長期缺氧模型，證實 ALOX15 介導之ferroptosis 會促進心肌肥大與纖維母細胞分化，進一步導致纖維化。由於 ALOX15 上游轉錄調控尚未闡明，我們透過資料庫預測 STAT5為其潛在轉錄因子，並證實 STAT5在缺氧下直接結合 ALOX15 啟動子促進其表現，參與心肌病理性重塑過程。後續亦證實，Esculetin 可有效抑制 STAT5 活化，從而減少 ALOX15表現，並降低其酵素活性，進而緩解心肌肥大與纖維化。綜上所述，本研究首度揭示 STAT5 調控 ALOX15 於心肌 ferroptosis中的關鍵角色，並證實Esculetin具STAT5/ALOX15雙重抑制效應，展現其作為缺氧誘導心臟損傷新興治療策略的潛力。Heart was highly sensitive to oxygen availability due to its high energy demand. Hypoxia, a common pathological feature of ischemic heart disease, cyanotic congenital heart disease, and pulmonary disorders has been shown to induce metabolic reprogramming, ROS accumulation, and cell death, ultimately leading to pathological cardiac hypertrophy and fibrosis. Signal transducer and activator of transcription 5 (STAT5) promoted inflammation and contributed to cardiac hypertrophy, while 15-lipoxygenase (ALOX15) exacerbated cardiac injury by triggering ferroptosis, an iron-dependent regulated form of cell death. Esculetin, a coumarin derivative derived from various Chinese medicinal herbs, was known for its potent antioxidant and anti-inflammatory properties. This study aimed to investigate the role of STAT5/ALOX15-mediated ferroptosis in hypoxia-induced cardiac hypertrophy and fibrosis and to evaluate the potential of Esculetin as a cardioprotective agent. To this end, we established hypoxia models using H9c2 cardiomyoblasts, neonatal rat cardiomyocytes (NRCMs), and neonatal rat cardiac fibroblasts (NRCFs). Our results demonstrated that ALOX15-mediated ferroptosis promoted cardiomyocyte hypertrophy and fibroblast-to-myofibroblast transition, thereby contributing to fibrosis and highlighting ALOX15 as a therapeutic target. Given that the upstream transcriptional regulation of ALOX15 remained unclear, we predicted STAT5 as a putative transcription factor and confirmed that STAT5 directly bound to the ALOX15 promoter under hypoxic conditions to enhance its expression, thus contributing to pathological remodeling. Furthermore, Esculetin was found to suppress STAT5 activation, reduce ALOX15 expression and enzymatic activity, and attenuate cardiac hypertrophy and fibrosis. In conclusion, this study was the first to reveal the critical role of STAT5 in regulating ALOX15 during cardiac ferroptosis and demonstrated that the herbal-derived compound Esculetin exerted dual inhibitory effects on the STAT5 and ALOX15, highlighting its potential as a novel therapeutic strategy for hypoxia-induced cardiac injury.STAT5ALOX15鐵依賴性細胞死亡心臟重構秦皮乙素ferroptosiscardiac remodelingEsculetinthesis