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<p>Renal fibrosis is a major driver of chronic kidney disease (CKD) progression, yet targeted therapies remain limited due to incomplete understanding of key molecular mechanisms. While IL-1-mediated inflammation and mitochondrial dysfunction are recognized contributors, the precise links between IL-1 signaling, fibrosis, and mitochondrial homeostasis are unclear. Here, we investigated the therapeutic effects of recombinant human IL-1 receptor antagonist (rhIL-1Ra) in both acute (UUO) and chronic (5/6Nx) mouse models of kidney injury, as well as in vitro TGF-β1-stimulated kidney cells. rhIL-1Ra significantly attenuated renal fibrosis, inflammation, and functional impairment in vivo. Mechanistically, rhIL-1Ra suppressed TGF-β1-induced expression of the E3 ubiquitin ligase RNF182, which we show mediates MFN2 ubiquitination and degradation, leading to mitochondrial dysfunction. Inhibition of RNF182 by rhIL-1Ra stabilized MFN2, preserved mitochondrial respiration and ATP production, and reduced oxidative stress. Rescue experiments confirmed the centrality of the RNF182-MFN2 axis in fibrotic and mitochondrial injury. Our findings reveal a novel IL-1R/RNF182/MFN2 pathway linking inflammation to mitochondrial and fibrotic pathology, supporting RNF182 as a promising target and rhIL-1Ra as a potential therapy for CKD.</p>

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IL‑1 receptor antagonism attenuates renal fibrosis via RNF182‑driven MFN2 destabilization and mitochondrial dysfunction

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月29日

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  • Bo Yang,
  • Qing Shao,
  • Wei Wang,
  • Maoting Li,
  • Fanzhou Zeng,
  • Xuezi Fu,
  • Jun Liu,
  • Cheng Xue,
  • Nanmei Liu

摘要

Renal fibrosis is a major driver of chronic kidney disease (CKD) progression, yet targeted therapies remain limited due to incomplete understanding of key molecular mechanisms. While IL-1-mediated inflammation and mitochondrial dysfunction are recognized contributors, the precise links between IL-1 signaling, fibrosis, and mitochondrial homeostasis are unclear. Here, we investigated the therapeutic effects of recombinant human IL-1 receptor antagonist (rhIL-1Ra) in both acute (UUO) and chronic (5/6Nx) mouse models of kidney injury, as well as in vitro TGF-β1-stimulated kidney cells. rhIL-1Ra significantly attenuated renal fibrosis, inflammation, and functional impairment in vivo. Mechanistically, rhIL-1Ra suppressed TGF-β1-induced expression of the E3 ubiquitin ligase RNF182, which we show mediates MFN2 ubiquitination and degradation, leading to mitochondrial dysfunction. Inhibition of RNF182 by rhIL-1Ra stabilized MFN2, preserved mitochondrial respiration and ATP production, and reduced oxidative stress. Rescue experiments confirmed the centrality of the RNF182-MFN2 axis in fibrotic and mitochondrial injury. Our findings reveal a novel IL-1R/RNF182/MFN2 pathway linking inflammation to mitochondrial and fibrotic pathology, supporting RNF182 as a promising target and rhIL-1Ra as a potential therapy for CKD.