Methylmalonic acid (MMA) acts as ferroptosis-derived danger signal, activating PI3K-NF-κB pathway and driving M1 macrophage polarization in renal IRI.

Acute Kidney Injury (AKI), particularly from renal ischemia-reperfusion injury (IRI), is a significant clinical challenge often leading to chronic kidney disease. Key drivers of AKI progression include ferroptosis (a form of iron-dependent cell death) and subsequent macrophage activation. While ferroptosis is known to involve metabolic reprogramming and the release of soluble mediators, the specific metabolic profile of ferroptotic tubular epithelial cells and its precise impact on the immune microenvironment during IRI has remained largely unknown, representing a critical gap in understanding AKI pathogenesis.

Researchers employed untargeted metabolomics to analyze the secretome of ferroptotic tubular epithelial cells, identifying abnormally elevated levels of methylmalonic acid (MMA). They then investigated the physiological role of MMA in a mouse model of acute kidney injury. Further mechanistic studies utilized transcriptomics and Western blotting to elucidate how this ferroptosis-associated metabolite promotes macrophage polarization. The study focused on the PI3K/Akt/NF-κB pathway in macrophages as a potential mediator of MMA's effects.

Untargeted metabolomics revealed a distinct metabolic secretome from ferroptotic tubular epithelial cells, with methylmalonic acid (MMA) levels markedly elevated after renal ischemia-reperfusion injury (IRI). Mechanistic investigations demonstrated that MMA directly activated the PI3K/Akt/NF-κB pathway within macrophages. This activation, in turn, drove M1 macrophage polarization, a phenotype associated with pro-inflammatory responses. The polarized M1 macrophages showed increased secretion of key proinflammatory cytokines, including IL-6 and TNF-α.