Department of Hepatobiliary Surgery, Xi Jing Hospital, Air Force Medical University, Xi'an, 710032, China.
Inflamm Res. 2024 Nov;73(11):1961-1979. doi: 10.1007/s00011-024-01944-y. Epub 2024 Sep 18.
Although ferroptosis plays a crucial role in hepatic ischemia‒reperfusion injury (IRI), the molecular mechanisms underlying this process remain unclear. We aimed to explore the potential involvement of the receptor for activated C kinase 1 (RACK1) in hepatic IRI-triggered ferroptosis. Using hepatocyte-specific RACK1 knockout mice and alpha mouse liver 12 (AML12) cells, we conducted a series of in vivo and in vitro experiments. We found that RACK1 has a protective effect on hepatic IRI-induced ferroptosis. Specifically, RACK1 was found to interact with AMPKα through its 1-93 amino acid (aa) region, which facilitates the phosphorylation of AMPKα at threonine 172 (Thr172), ultimately exerting an antiferroptotic effect. Furthermore, the long noncoding RNA (lncRNA) ZNFX1 Antisense 1 (ZFAS1) directly binds to aa 181-317 of RACK1. ZFAS1 has a dual impact on RACK1 by promoting its ubiquitin‒proteasome-mediated degradation and inhibiting its expression at the transcriptional level, which indirectly exacerbates hepatic IRI-induced ferroptosis. These findings underscore the protective role of RACK1 in hepatic IRI-induced ferroptosis and showcase its potential as a prophylactic target for hepatic IRI mitigation.
尽管铁死亡在肝缺血再灌注损伤（IRI）中发挥着关键作用，但这一过程的分子机制尚不清楚。我们旨在探讨激活蛋白激酶 C 受体 1（RACK1）在肝 IRI 触发的铁死亡中的潜在作用。我们使用肝特异性 RACK1 敲除小鼠和 alpha 小鼠肝 12（AML12）细胞进行了一系列体内和体外实验。我们发现 RACK1 对肝 IRI 诱导的铁死亡具有保护作用。具体而言，发现 RACK1 通过其 1-93 个氨基酸（aa）区域与 AMPKα 相互作用，促进 AMPKα 在苏氨酸 172（Thr172）的磷酸化，最终发挥抗铁死亡作用。此外，长链非编码 RNA（lncRNA）ZNFX1 反义 1（ZFAS1）直接与 RACK1 的 aa181-317 结合。ZFAS1 通过促进其泛素-蛋白酶体介导的降解和抑制其转录水平的表达，对 RACK1 具有双重影响，这间接加剧了肝 IRI 诱导的铁死亡。这些发现强调了 RACK1 在肝 IRI 诱导的铁死亡中的保护作用，并展示了其作为肝 IRI 缓解的预防靶点的潜力。
