Li Min, Hu Longhui, Ke Qiao, Li Zhao, Ruan Chujun, Lu Hanjing, Liu Xiaoran
Emergency trauma College of Hainan Medical University, Haikou, China.
Emergency Department, Hainan Affiliated Hospital of Hainan Medical University (Hainan General Hospital), Haikou, China.
Commun Biol. 2025 Feb 3;8(1):159. doi: 10.1038/s42003-025-07531-z.
Acute lung injury (ALI), a frequent and severe complication of sepsis, is associated with significant mortality rates. Previous studies indicated that GLS2 plays a key role in promoting ferroptosis. However, its underlying mechanisms remain unclear. Here we show, there were elevated ferroptosis and increased expression levels of protein arginine methyltransferase 1 (PRMT1), early growth response 1 (EGR1), and glutaminase 2 (GLS2) in both in vitro and in vivo ALI models. Additionally, EGR1 was found to induce the transcription of GLS2, thereby promoting ferroptosis. We also discovered that the protein level of EGR1 was increased through enhanced stability, facilitated by PRMT1-mediated arginine methylation, and reduced ubiquitination degradation regulated by neural precursor cell expressed developmentally down-regulated protein 4 like (NEDD4L). The in vivo results confirmed that the knockdown of PRMT1 suppressed ferroptosis via the EGR1/GLS2 axis. Our findings suggest that PRMT1-mediated stabilization of EGR1 promoted sepsis induced ALI via GLS2, highlighting the therapeutic potential of targeting PRMT1 or EGR1 in the treatment of sepsis-induced ALI.
急性肺损伤（ALI）是脓毒症常见且严重的并发症，与显著的死亡率相关。先前的研究表明，GLS2在促进铁死亡中起关键作用。然而，其潜在机制仍不清楚。在此我们表明，在体外和体内ALI模型中，铁死亡均升高，且蛋白质精氨酸甲基转移酶1（PRMT1）、早期生长反应1（EGR1）和谷氨酰胺酶2（GLS2）的表达水平均增加。此外，发现EGR1可诱导GLS2的转录，从而促进铁死亡。我们还发现，PRMT1介导的精氨酸甲基化促进了EGR1稳定性增强，进而增加了EGR1的蛋白水平，并且神经前体细胞表达的发育下调蛋白4样蛋白（NEDD4L）调节的泛素化降解减少。体内结果证实，敲低PRMT1可通过EGR1/GLS2轴抑制铁死亡。我们的研究结果表明，PRMT1介导的EGR1稳定通过GLS2促进脓毒症诱导的ALI，突出了靶向PRMT1或EGR1在治疗脓毒症诱导的ALI中的治疗潜力。
