辣椒素通过 SIRT3 依赖的机制抑制铁死亡和维持线粒体氧化还原稳态，减轻呼吸机引起的肺损伤。

BACKGROUND: Ventilator-induced lung injury (VILI) is one of the severe complications in the clinic concerning mechanical ventilation (MV). Capsaicin (CAP) has anti-inflammatory and inhibitory effects on oxidative stress, which is a significant element causing cellular ferroptosis. Nevertheless, the specific role and potential mechanistic pathways through which CAP modulates ferroptosis in VILI remain elusive. METHODS: VILI was established in vivo, and the pulmonary epithelial cell injury model induced by circulation stretching (CS) was established in vitro. Both mice and cells were pretreated with CAP. Transmission electron microscopy, ELISA, Western blot, immunofluorescence, RT-PCR, fluorescent probes, and other experimental methods were used to clarify the relationship between iron death and VILI in alveolar epithelial cells, and whether capsaicin alleviates VILI by inhibiting iron death and its specific mechanism. RESULTS: Ferroptosis was involved in VILI by utilizing in vivo models. CAP inhibited ferroptosis and alleviated VILI's lung damage and inflammation, and this protective effect of CAP was dependent on maintaining mitochondrial redox system through SITR3 signaling. In the CS-caused lung epithelial cell injury models, CAP reduced pathological CS-caused ferroptosis and cell injury. Knockdown SIRT3 reversed the role of CAP on the maintaining mitochondria dysfunction under pathological CS and eliminated its subsequent advantageous impacts for ferroptosis against overstretching cells. CONCLUSION: The outcomes showed that CAP alleviated ferroptosis in VILI via improving the activity of SITR3 to suppressing mitochondrial oxidative damage and maintaining mitochondrial redox homeostasis, illustrating its possibility as a novel therapeutic goal for VILI.

背景：呼吸机相关性肺损伤（VILI）是机械通气（MV）相关的临床严重并发症之一。辣椒素（CAP）具有抗炎和抑制氧化应激的作用，氧化应激是导致细胞铁死亡的重要因素。然而，CAP 调节 VILI 中铁死亡的确切作用和潜在机制途径仍不清楚。

方法：建立体内 VILI 模型，并建立体外循环拉伸（CS）诱导的肺上皮细胞损伤模型。用 CAP 预处理小鼠和细胞。采用透射电镜、ELISA、Western blot、免疫荧光、RT-PCR、荧光探针等实验方法，阐明肺泡上皮细胞中铁死亡与 VILI 的关系，以及辣椒素是否通过抑制铁死亡缓解 VILI 及其具体机制。

结果：利用体内模型证实铁死亡参与了 VILI。CAP 抑制铁死亡并减轻 VILI 的肺损伤和炎症，这种 CAP 的保护作用依赖于 SITR3 信号通过维持线粒体氧化还原系统来实现。在 CS 引起的肺上皮细胞损伤模型中，CAP 减少了病理 CS 引起的铁死亡和细胞损伤。敲低 SIRT3 逆转了 CAP 在病理 CS 下维持线粒体功能障碍的作用，并消除了其随后对过度拉伸细胞的铁死亡的有利影响。

结论：结果表明，CAP 通过提高 SITR3 的活性来抑制线粒体氧化损伤并维持线粒体氧化还原稳态，从而减轻 VILI 中的铁死亡，这表明其作为 VILI 新型治疗目标的可能性。