Department of Emergency Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.
Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, Henan, 450052, China.
Adv Sci (Weinh). 2024 Oct;11(39):e2402710. doi: 10.1002/advs.202402710. Epub 2024 Aug 19.
Acetaminophen (APAP) overdose is a major cause of drug-induced liver injury. Sirtuins 5 (SIRT5) has been implicated in the development of various liver diseases. However, its involvement in APAP-induced acute liver injury (AILI) remains unclear. The present study aimed to explore the role of SIRT5 in AILI. SIRT5 expression is dramatically downregulated by APAP administration in mouse livers and AML12 hepatocytes. SIRT5 deficiency not only exacerbates liver injury and the inflammatory response, but also worsens mitochondrial oxidative stress. Conversely, the opposite pathological and biochemical changes are observed in mice with SIRT5 overexpression. Mechanistically, quantitative succinylome analysis and site mutation experiments revealed that SIRT5 desuccinylated aldehyde dehydrogenase 2 (ALDH2) at lysine 385 and maintained the enzymatic activity of ALDH2, resulting in the suppression of inflammation and mitochondrial oxidative stress. Furthermore, succinylation of ALDH2 at lysine 385 abolished its protective effect against AILI, and the protective effect of SIRT5 against AILI is dependent on the desuccinylation of ALDH2 at K385. Finally, virtual screening of natural compounds revealed that Puerarin promoted SIRT5 desuccinylase activity and further attenuated AILI. Collectively, the present study showed that the SIRT5-ALDH2 axis plays a critical role in AILI progression and might be a strategy for therapeutic intervention.
对乙酰氨基酚（APAP）过量是药物性肝损伤的主要原因。Sirtuins 5（SIRT5）已被牵连到各种肝病的发展中。然而，其在 APAP 诱导的急性肝损伤（AILI）中的作用尚不清楚。本研究旨在探讨 SIRT5 在 AILI 中的作用。APAP 给药后，SIRT5 在小鼠肝脏和 AML12 肝细胞中的表达显著下调。SIRT5 缺乏不仅加重了肝损伤和炎症反应，还加重了线粒体氧化应激。相反，在 SIRT5 过表达的小鼠中观察到相反的病理和生化变化。在机制上，定量琥珀酰化组分析和位点突变实验表明，SIRT5 在赖氨酸 385 处去琥珀酰化醛脱氢酶 2（ALDH2）并维持 ALDH2 的酶活性，从而抑制炎症和线粒体氧化应激。此外，ALDH2 赖氨酸 385 处的琥珀酰化消除了其对 AILI 的保护作用，SIRT5 对 AILI 的保护作用依赖于 K385 处的去琥珀酰化。最后，天然化合物的虚拟筛选表明，葛根素促进 SIRT5 去琥珀酰化酶活性，进一步减轻 AILI。总之，本研究表明 SIRT5-ALDH2 轴在 AILI 进展中起着关键作用，可能是一种治疗干预策略。
