曲妥珠单抗（Trz）诱导的心脏毒性（TIC）是靶向抗癌药物最常见的不良反应之一。尽管氧化应激、炎症、线粒体功能障碍、细胞凋亡和铁死亡等机制被确定为潜在导致TIC的机制，但热凋亡和坏死凋亡在TIC中的作用尚未研究。研究表明，通过使用多奈哌齐阻断乙酰胆碱酯酶功能在各种心脏病中具有保护效果。然而，目前尚不清楚多奈哌齐是否对具有TIC的大鼠具有抗心脏毒性的效果。我们假设多奈哌齐通过减轻线粒体功能障碍、炎症、氧化应激和心肌细胞死亡，改善左心室（LV）功能。 雄性Wistar大鼠随机分为对照组和Trz组（Trz 4 mg/kg/day, 7 天，腹腔注射）。Trz组大鼠被分成两组，一组饮用水（Trz组），一组口服给予多奈哌齐5 mg/kg/day（Trz+DPZ组）共7 天。评估心脏功能、心率变异性（HRV）和生化参数。Trz处理组大鼠表现出LV功能受损、HRV降低、线粒体功能障碍和炎症和氧化应激增加，导致细胞凋亡、铁死亡和热死亡。多奈哌齐联合治疗有效降低了TIC的这些不良反应，从而改善了LV功能。体外研究表明，多奈哌齐的细胞保护作用被毒性乙酰胆碱受体（mAChR）拮抗剂所抑制。 多奈哌齐通过减轻线粒体功能障碍、氧化应激、炎症和心肌细胞死亡的作用对抗TIC，从而通过mAChR激活改善LV功能。这表明多奈哌齐可能是一种新的TIC干预策略。©2023年，费茨因斯蒂北医学研究所。

Trastuzumab (Trz)-induced cardiotoxicity (TIC) is one of the most common adverse effects of targeted anticancer agents. Although oxidative stress, inflammation, mitochondrial dysfunction, apoptosis, and ferroptosis have been identified as potential mechanisms underlying TIC, the roles of pyroptosis and necroptosis under TIC have never been investigated. It has been shown that inhibition of acetylcholinesterase function by using donepezil exerts protective effects in various heart diseases. However, it remains unknown whether donepezil exerts anti-cardiotoxic effects in rats with TIC. We hypothesized that donepezil reduces mitochondrial dysfunction, inflammation, oxidative stress, and cardiomyocyte death, leading to improved left ventricular (LV) function in rats with TIC.Male Wistar rats were randomly assigned to be Control or Trz groups (Trz 4 mg/kg/day, 7 days, I.P.). Rats in Trz groups were assigned to be co-treated with either drinking water (Trz group) or donepezil 5 mg/kg/day (Trz + DPZ group) via oral gavage for 7 days. Cardiac function, heart rate variability (HRV), and biochemical parameters were evaluated.Trz-treated rats had impaired LV function, HRV, mitochondrial function, and increased inflammation and oxidative stress, leading to apoptosis, ferroptosis, and pyroptosis. Donepezil co-treatment effectively decreased those adverse effects of TIC, resulting in improved LV function. An in vitro study revealed that the cytoprotective effects of donepezil were abolished by a muscarinic acetylcholine receptor (mAChR) antagonist.Donepezil exerted cardioprotection against TIC via attenuating mitochondrial dysfunction, oxidative stress, inflammation, and cardiomyocyte death, leading to improved LV function through mAChR activation. This suggests that donepezil could be a novel intervention strategy in TIC.© 2023. The Feinstein Institute for Medical Research.