Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou First People's Hospital, Hangzhou, China.
Zhejiang University School of Medicine, Hangzhou, China.
Nat Commun. 2024 Oct 3;15(1):8578. doi: 10.1038/s41467-024-52379-2.
Fibroblast growth factor 21 (FGF21) is essential for modulating hepatic homeostasis, but the impact of FGF21 on liver graft injury remains uncertain. Here, we show that high FGF21 levels in liver graft and serum are associated with improved graft function and survival in liver transplantation (LT) recipients. FGF21 deficiency aggravates early graft injury and activates arachidonic acid metabolism and regional inflammation in male mouse models of hepatic ischemia/reperfusion (I/R) injury and orthotopic LT. Mechanistically, FGF21 deficiency results in abnormal activation of the arachidonate 15-lipoxygenase (ALOX15)/15-hydroxy eicosatetraenoic acid (15-HETE) pathway, which triggers a cascade of innate immunity-dominated pro-inflammatory responses in grafts. Notably, the modulating role of FGF21/ALOX15/15-HETE pathway is more significant in steatotic livers. In contrast, pharmacological administration of recombinant FGF21 effectively protects against hepatic I/R injury. Overall, our study reveals the regulatory mechanism of FGF21 and offers insights into its potential clinical application in early liver graft injury after LT.
成纤维细胞生长因子 21（FGF21）对于调节肝脏稳态至关重要，但 FGF21 对肝移植物损伤的影响尚不确定。在这里，我们表明，肝移植物和血清中高 FGF21 水平与肝移植（LT）受者的移植物功能和存活改善相关。FGF21 缺乏会加重肝缺血/再灌注（I/R）损伤和原位 LT 雄性小鼠模型中的早期移植物损伤，并激活花生四烯酸代谢和局部炎症。在机制上，FGF21 缺乏导致花生四烯酸 15-脂氧合酶（ALOX15）/15-羟基二十碳四烯酸（15-HETE）途径的异常激活，从而触发移植物中固有免疫主导的促炎反应级联。值得注意的是，FGF21/ALOX15/15-HETE 途径的调节作用在脂肪变性肝脏中更为显著。相比之下，重组 FGF21 的药理给药可有效防止肝 I/R 损伤。总体而言，我们的研究揭示了 FGF21 的调节机制，并为其在 LT 后早期肝移植物损伤中的潜在临床应用提供了新的见解。
