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<p>A frequent final step in the development of chronic kidney disease is renal fibrosis, which involves a complex molecular network made up of innate immune effectors, cell death, and immunological inflammation. The interaction of three fundamental mechanisms—autophagy/ferroptosis, neutrophil extracellular traps, and the immune-inflammatory microenvironment—is the main topic of this review. M1 macrophages initiate inflammation at the immune-inflammatory level in the early phases of damage, whereas M2 macrophages directly encourage fibrosis in the later stages by secreting molecules like TGF-β. Their polarization process is carefully controlled by signaling pathways like HIF-1α and NF-κB. A new mediator between acute and chronic injuries, neutrophil extracellular traps directly damage tissues by releasing toxic components and can activate macrophages and fibroblasts. Ferroptosis damages renal tubular epithelial cells through iron dependent lipid peroxidation, and its upstream iron autophagy becomes a crucial bridge connecting autophagy and ferroptosis through NCOA4 mediated ferritin degradation. These processes work together to create a well-coordinated network: ferroptosis-released damage compounds trigger NLRP3 inflammasomes; neutrophil extracellular traps encourage M2 macrophage polarization; and the inflammatory agent TGF-β can increase the expression of genes linked to autophagy. Together, these interactions create a vicious cycle of fibrosis, inflammation, and cell death. A thorough examination of this molecular network will offer fresh theoretical underpinnings and therapeutic guidance for the creation of multi-target synergistic treatment approaches.</p>

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The inflammatory–autophagy–NETs axis in renal fibrosis: mechanistic crosstalk and pathological feed-forward amplification loops

  • 期刊论文

  • 发表日期：

    2026年4月28日

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  • Haixu Chen,
  • Yu Lin,
  • Changying Guo,
  • Feng Li

摘要

A frequent final step in the development of chronic kidney disease is renal fibrosis, which involves a complex molecular network made up of innate immune effectors, cell death, and immunological inflammation. The interaction of three fundamental mechanisms—autophagy/ferroptosis, neutrophil extracellular traps, and the immune-inflammatory microenvironment—is the main topic of this review. M1 macrophages initiate inflammation at the immune-inflammatory level in the early phases of damage, whereas M2 macrophages directly encourage fibrosis in the later stages by secreting molecules like TGF-β. Their polarization process is carefully controlled by signaling pathways like HIF-1α and NF-κB. A new mediator between acute and chronic injuries, neutrophil extracellular traps directly damage tissues by releasing toxic components and can activate macrophages and fibroblasts. Ferroptosis damages renal tubular epithelial cells through iron dependent lipid peroxidation, and its upstream iron autophagy becomes a crucial bridge connecting autophagy and ferroptosis through NCOA4 mediated ferritin degradation. These processes work together to create a well-coordinated network: ferroptosis-released damage compounds trigger NLRP3 inflammasomes; neutrophil extracellular traps encourage M2 macrophage polarization; and the inflammatory agent TGF-β can increase the expression of genes linked to autophagy. Together, these interactions create a vicious cycle of fibrosis, inflammation, and cell death. A thorough examination of this molecular network will offer fresh theoretical underpinnings and therapeutic guidance for the creation of multi-target synergistic treatment approaches.