甲基丙二酸作为铁死亡危险信号激活PI3K-NF-κB通路驱动M1巨噬细胞极化加重肾缺血再灌注损伤

Abstract

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.