Duo Hong, Yang Yanwei, Luo Jun, Cao Yumeng, Liu Qian, Zhang Jiarui, Du Siqi, You Jian, Zhang Guqing, Ye Qifa, Pan Huaqin
National Quality Control Center for Donated Organ Procurement, Hubei Key Laboratory of Medical Technology on Transplantation, Hubei Clinical Research Center for Natural Polymer Biological Liver, Hubei Engineering Center of Natural Polymer-Based Medical Materials, Zhongnan Hospital of Wuhan University, Institute of Hepatobiliary Diseases of Wuhan University, Transplant Center of Wuhan University, Wuhan, Hubei, China.
Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Clinical Research Center of Hubei Critical Care Medicine, Wuhan, 430071, China.
Cell Death Discov. 2025 Jul 1;11(1):290. doi: 10.1038/s41420-025-02578-7.
Sepsis-associated acute kidney injury (SA-AKI) is a critical condition characterized by high morbidity and mortality rates, particularly in intensive care settings. This study focuses on RP105, a pattern recognition receptor, exploring its role in moderating the mechanisms of oxidative stress and ferroptosis during SA-AKI, offering insights into its potential as a therapeutic target. SA-AKI model was established using RP105 knockout (KO) and wild-type (WT) mice through cecal ligation and puncture (CLP). Comprehensive evaluations included the assessment of ferroptosis markers and the expression levels of pro-inflammatory cytokines. RP105 expression was markedly reduced in the kidneys following CLP induction, correlating with worsened renal outcomes. Compared to the Sham group, RP105 mice displayed heightened renal damage, increased levels of oxidative stress markers, and enhanced lipid peroxidation. Notably, the deficiency of RP105 led to increased macrophage infiltration and a shift towards pro-inflammatory phenotypes, which further potentiated ferroptosis and exacerbated renal tissue damage. By influencing macrophage behavior and mitigating inflammatory responses. RP105 deficiency exacerbates macrophage-induced inflammation, oxidative stress, and ferroptosis, forming a vicious cycle that leads to more severe renal injury. These findings underscore the pivotal role of RP105 in mitigating oxidative stress and suppressing ferroptosis in the context of SA-AKI through regulation of the HO-1/SLC7A11/GPX4 axis. By preventing macrophage polarization toward a pro-inflammatory phenotype, RP105 alleviates inflammatory responses and tissue damage, highlighting its potential as a therapeutic target. Thus, RP105 emerges as a promising therapeutic candidate for mitigating sepsis-induced renal damage.
脓毒症相关急性肾损伤（SA-AKI）是一种危急病症，其发病率和死亡率都很高，在重症监护环境中尤为如此。本研究聚焦于模式识别受体RP105，探索其在SA-AKI期间调节氧化应激和铁死亡机制中的作用，以深入了解其作为治疗靶点的潜力。通过盲肠结扎和穿刺（CLP），使用RP105基因敲除（KO）小鼠和野生型（WT）小鼠建立SA-AKI模型。综合评估包括对铁死亡标志物和促炎细胞因子表达水平的评估。CLP诱导后，肾脏中RP105的表达显著降低，这与肾脏预后恶化相关。与假手术组相比，RP105基因敲除小鼠表现出更严重的肾脏损伤、氧化应激标志物水平升高和脂质过氧化增强。值得注意的是，RP105的缺乏导致巨噬细胞浸润增加并向促炎表型转变，这进一步增强了铁死亡并加剧了肾组织损伤。通过影响巨噬细胞行为和减轻炎症反应，RP105缺乏加剧了巨噬细胞诱导的炎症、氧化应激和铁死亡，形成恶性循环，导致更严重的肾损伤。这些发现强调了RP105在SA-AKI背景下通过调节HO-1/SLC7A11/GPX4轴减轻氧化应激和抑制铁死亡中的关键作用。通过防止巨噬细胞向促炎表型极化，RP105减轻了炎症反应和组织损伤，突出了其作为治疗靶点的潜力。因此，RP105有望成为减轻脓毒症诱导的肾损伤的治疗候选药物。
