Yu Qiwen, Yang Dongjing, Ran Binli, Pan Jie, Song Yaodong, Cui Mengwei, He Qianqian, Mei Chaopeng, Wang Haifeng, Li Huihui, Li Guanghui, Meng Yinuo, Wang Fazhan, Guo Wenzhi, Zhu Changju, Chen Sanyang
Department of Emergency Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
Henan Medical Key Laboratory of Emergency and Trauma Research, Zhengzhou, 450052, Henan, China.
Int J Biol Sci. 2025 Jul 11;21(10):4663-4682. doi: 10.7150/ijbs.114510. eCollection 2025.
Liver ischemia-reperfusion injury (LIRI) is an important cause of the clinical prognosis of liver transplantation. Despite Sirtuin 4 (SIRT4) is involved in various post-translational modifications, its role in LIRI is unclear. This research aimed to investigate the influence of SIRT4 on the pathogenesis of LIRI. To this end, SIRT4 knockout (KO) and liver-specific overexpression mice, as well as alpha mouse liver 12 (AML12) cells, were employed. We showed that SIRT4 expression was downregulated in mice with LIRI or AML12 cells exposed to hypoxia-reoxygenation (H/R) injury, as well as in the liver tissue of liver transplant patients. SIRT4 KO exacerbated liver injury and ferroptosis; conversely, liver-specific SIRT4 overexpression in mice produced the opposite results. Furthermore, the ferroptosis inhibitor ferrostatin-1 mitigated the exacerbation of liver injury and ferroptosis caused by SIRT4 KO. Mechanistically, SIRT4 interacted with peroxiredoxins 3 (PRDX3) and deacetylated it at lysine 92, leading to the inhibition of ferroptosis. Furthermore, the protective effect of SIRT4 on LIRI was dependent on PRDX3 deacetylation at lysine 92. Additionally, liver-targeted lipid nanoparticles (LNPs)-sirt4 mRNA alleviated LIRI and ferroptosis in mice. Taken together, our findings highlight the SIRT4-PRDX3 axis as a key regulator and potential therapeutic target for LIRI.
肝缺血再灌注损伤（LIRI）是肝移植临床预后的一个重要原因。尽管沉默调节蛋白4（SIRT4）参与各种翻译后修饰，但其在LIRI中的作用尚不清楚。本研究旨在探讨SIRT4对LIRI发病机制的影响。为此，采用了SIRT4基因敲除（KO）和肝脏特异性过表达小鼠，以及α小鼠肝脏12（AML12）细胞。我们发现，在患有LIRI的小鼠、暴露于缺氧复氧（H/R）损伤的AML12细胞以及肝移植患者的肝组织中，SIRT4表达下调。SIRT4基因敲除加剧了肝损伤和铁死亡；相反，小鼠肝脏特异性SIRT4过表达产生了相反的结果。此外，铁死亡抑制剂铁抑素-1减轻了SIRT4基因敲除引起的肝损伤和铁死亡的加剧。机制上，SIRT4与过氧化物酶3（PRDX3）相互作用并使其在赖氨酸92处去乙酰化，从而抑制铁死亡。此外，SIRT4对LIRI的保护作用依赖于PRDX3在赖氨酸92处的去乙酰化。此外，肝脏靶向脂质纳米颗粒（LNPs）-sirt4 mRNA减轻了小鼠的LIRI和铁死亡。综上所述，我们的研究结果突出了SIRT4-PRDX3轴作为LIRI的关键调节因子和潜在治疗靶点。
