Zhu Junjie, Jin Zhouxiang, Wang Jie, Wu Zhaohang, Xu Tianpeng, Tong Gaozan, Shen Enzhao, Fan Junfu, Jiang Chunhui, Wang Jiaqi, Li Xiaokun, Cong Weitao, Lin Li
School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou 325000, PR China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China.
Department of Hepatobiliary Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, PR China.
J Adv Res. 2025 Mar;69:477-494. doi: 10.1016/j.jare.2024.04.004. Epub 2024 Apr 9.
Sepsis, a systemic immune syndrome caused by severe trauma or infection, poses a substantial threat to the health of patients worldwide. The progression of sepsis is heavily influenced by septic liver injury, which is triggered by infection and cytokine storms, and has a significant impact on the tolerance and prognosis of septic patients. The objective of our study is to elucidate the biological role and molecular mechanism of fibroblast growth factor 21 (FGF21) in the process of sepsis.
This study was undertaken in an attempt to elucidate the function and molecular mechanism of FGF21 in therapy of sepsis.
Serum concentrations of FGF21 were measured in sepsis patients and septic mice. Liver injury was compared between mice FGF21 knockout (KO) mice and wildtype (WT) mice. To assess the therapeutic potential, recombinant human FGF21 was administered to septic mice. Furthermore, the molecular mechanism of FGF21 was investigated in mice with myeloid-cell specific HIF-1α overexpression mice (LyzM-Cre) and myeloid-cell specific Atg7 knockout mice (Atg7).
Serum level of FGF21 was significantly increased in sepsis patients and septic mice. Through the use of recombinant human FGF21 (rhFGF21) and FGF21 KO mice, we found that FGF21 mitigated septic liver injury by inhibiting the initiation and propagation of inflammation. Treatment with rhFGF21 effectively suppressed the activation of proinflammatory macrophages by promoting macroautophagy/autophagy degradation of hypoxia-inducible factor-1α (HIF-1α). Importantly, the therapeutic effect of rhFGF21 against septic liver injury was nullified in LyzM-Cre mice and Atg7 mice.
Our findings demonstrate that FGF21 considerably suppresses inflammation upon septic liver injury through the autophagy/ HIF-1α axis.
脓毒症是一种由严重创伤或感染引起的全身性免疫综合征，对全球患者的健康构成重大威胁。脓毒症的进展受到脓毒性肝损伤的严重影响，脓毒性肝损伤由感染和细胞因子风暴引发，对脓毒症患者的耐受性和预后有重大影响。我们研究的目的是阐明成纤维细胞生长因子21（FGF21）在脓毒症过程中的生物学作用和分子机制。
本研究旨在阐明FGF21在脓毒症治疗中的功能和分子机制。
检测脓毒症患者和脓毒症小鼠血清中FGF21的浓度。比较FGF21基因敲除（KO）小鼠和野生型（WT）小鼠的肝损伤情况。为评估治疗潜力，给脓毒症小鼠注射重组人FGF21。此外，在髓系细胞特异性缺氧诱导因子-1α（HIF-1α）过表达小鼠（LyzM-Cre）和髓系细胞特异性自噬相关蛋白7（Atg7）基因敲除小鼠中研究FGF21的分子机制。
脓毒症患者和脓毒症小鼠血清中FGF21水平显著升高。通过使用重组人FGF21（rhFGF21）和FGF21基因敲除小鼠，我们发现FGF21通过抑制炎症的起始和传播减轻脓毒性肝损伤。rhFGF21治疗通过促进缺氧诱导因子-1α（HIF-1α）的巨自噬/自噬降解有效抑制促炎巨噬细胞的激活。重要的是，rhFGF21对脓毒性肝损伤的治疗作用在LyzM-Cre小鼠和Atg7小鼠中无效。
我们的研究结果表明，FGF21通过自噬/HIF-1α轴在脓毒性肝损伤时显著抑制炎症。
