Scholarlink

Background <p>Ferroptosis and macrophage activation are key contributors to the development of acute kidney injury (AKI). Ferroptosis is accompanied by metabolic reprogramming and the release of soluble mediators, including metabolites, cytokines, and extracellular signals, which can propagate tissue damage and modulate immune responses. However, the metabolic profile of ferroptotic tubular epithelial cells and its impact on the immune microenvironment during ischemia–reperfusion injury (IRI) remains largely unexplored.</p> Methods <p>Using untargeted metabolomics, we found that ferroptotic cells secreted abnormally elevated levels of methylmalonic acid (MMA), and investigated the physiological role of MMA in acute kidney injury in mice. Furthermore, through transcriptomics and Western blotting, we explored the mechanism by which the ferroptosis-associated metabolite MMA promotes macrophage polarization.</p> Results <p>Here, untargeted metabolomics revealed a distinct metabolic secretome of ferroptotic tubular epithelial cells, with the level of MMA markedly elevated after IRI. Mechanistic studies demonstrated that MMA activated the PI3K/ Akt /NF-κB pathway in macrophages, driving M1 polarization and increasing the secretion of proinflammatory cytokines such as IL-6 and TNF-α, ultimately exacerbating acute kidney injury.</p> Conclusion <p>These findings reveal the mechanism of metabolite–immune crosstalk in AKI, and suggest that targeting the ferroptosis–macrophage axis may represent a therapeutic strategy to disrupt the vicious cycle of inflammation and tissue injury.</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

Methylmalonic acid as a ferroptosis-derived danger signal: activation of the PI3K–NF-κB pathway drives M1 macrophage polarization in renal ischemia–reperfusion injury

  • 期刊论文

  • 发表日期：

    2026年6月22日

查看全文
  • Huimeng Wang,
  • Jiajia Sun,
  • Xiaohu Li,
  • Hongxuan Ma,
  • Yongsheng Luo,
  • Minghui Qin,
  • Hao Zhang,
  • Haodong Bian,
  • Jinfeng Li

摘要

Background

Ferroptosis and macrophage activation are key contributors to the development of acute kidney injury (AKI). Ferroptosis is accompanied by metabolic reprogramming and the release of soluble mediators, including metabolites, cytokines, and extracellular signals, which can propagate tissue damage and modulate immune responses. However, the metabolic profile of ferroptotic tubular epithelial cells and its impact on the immune microenvironment during ischemia–reperfusion injury (IRI) remains largely unexplored.

Methods

Using untargeted metabolomics, we found that ferroptotic cells secreted abnormally elevated levels of methylmalonic acid (MMA), and investigated the physiological role of MMA in acute kidney injury in mice. Furthermore, through transcriptomics and Western blotting, we explored the mechanism by which the ferroptosis-associated metabolite MMA promotes macrophage polarization.

Results

Here, untargeted metabolomics revealed a distinct metabolic secretome of ferroptotic tubular epithelial cells, with the level of MMA markedly elevated after IRI. Mechanistic studies demonstrated that MMA activated the PI3K/ Akt /NF-κB pathway in macrophages, driving M1 polarization and increasing the secretion of proinflammatory cytokines such as IL-6 and TNF-α, ultimately exacerbating acute kidney injury.

Conclusion

These findings reveal the mechanism of metabolite–immune crosstalk in AKI, and suggest that targeting the ferroptosis–macrophage axis may represent a therapeutic strategy to disrupt the vicious cycle of inflammation and tissue injury.