Scholarlink

<p>The concept of organ-organ communication in systemic diseases has gained significant traction. Despite accumulating evidence of liver-kidney crosstalk, the underlying regulatory mechanisms remain poorly understood. Here, we identify hepatokine fibrinogen-like protein 1 (FGL1) as a pivotal mediator driving liver-kidney communication in renal fibrosis. Integrative RNA sequencing and clinical analyses revealed FGL1 upregulation in the liver post-renal injury, with subsequent selective accumulation in fibrotic kidneys. Hepatocyte-specific knockout of FGL1 improved renal morphology, attenuated collagen deposition, and inhibited fibrosis markers in unilateral ureteral obstruction and adenine-induced mouse models. Conversely, FGL1 overexpression exacerbated renal fibrosis. Mechanistically, FGL1 binds to TGF-β receptor ALK5 and blocks its interaction with K48-linked polyubiquitin. Structural analyses identified critical residues in FGL1-ALK5 interaction. Hepatic FGL1 is transcriptionally regulated by STAT3, and activated by inflammatory cytokines (IL-6, IL-1β and TNF-α). Pharmacological inhibition by p-hydroxybenzaldehyde (screened out from 4080 compounds) or an anti-FGL1 monoclonal antibody significantly reduced renal fibrosis without hepatotoxicity. These findings establish FGL1 as a key mediator of pathogenic liver-kidney crosstalk and highlights therapeutic strategies to targeting organ-organ networks in renal fibrosis.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Hepatokine fibrinogen-like protein 1 drives liver-kidney crosstalk to promote renal fibrosis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月9日

查看全文
  • Wen-Hui Wu,
  • Li-Zeng Zhu,
  • Kang Liu,
  • Lin Cao,
  • Yuan-Ming Fan,
  • Ping Zhou,
  • Yue Zhang,
  • Gaoxiang Ma,
  • Jin-Feng Liu,
  • Bao-Lin Liu,
  • Lian-Wen Qi,
  • Qun Liu

摘要

The concept of organ-organ communication in systemic diseases has gained significant traction. Despite accumulating evidence of liver-kidney crosstalk, the underlying regulatory mechanisms remain poorly understood. Here, we identify hepatokine fibrinogen-like protein 1 (FGL1) as a pivotal mediator driving liver-kidney communication in renal fibrosis. Integrative RNA sequencing and clinical analyses revealed FGL1 upregulation in the liver post-renal injury, with subsequent selective accumulation in fibrotic kidneys. Hepatocyte-specific knockout of FGL1 improved renal morphology, attenuated collagen deposition, and inhibited fibrosis markers in unilateral ureteral obstruction and adenine-induced mouse models. Conversely, FGL1 overexpression exacerbated renal fibrosis. Mechanistically, FGL1 binds to TGF-β receptor ALK5 and blocks its interaction with K48-linked polyubiquitin. Structural analyses identified critical residues in FGL1-ALK5 interaction. Hepatic FGL1 is transcriptionally regulated by STAT3, and activated by inflammatory cytokines (IL-6, IL-1β and TNF-α). Pharmacological inhibition by p-hydroxybenzaldehyde (screened out from 4080 compounds) or an anti-FGL1 monoclonal antibody significantly reduced renal fibrosis without hepatotoxicity. These findings establish FGL1 as a key mediator of pathogenic liver-kidney crosstalk and highlights therapeutic strategies to targeting organ-organ networks in renal fibrosis.