The SPP1-CD44 Signaling Axis Orchestrates Macrophage Metabolism to Promote Early Inflammation in Acute Kidney Injury

The extent of the inflammatory response in the early stages of acute kidney injury (AKI) significantly influences renal damage, repair, and ultimately prognosis. Macrophages are key drivers of early inflammation in AKI, and their metabolic reprogramming is closely associated with their pro-inflammatory polarization. However, the mechanisms underlying this process remain incompletely understood. In this study, we combined single-cell RNA sequencing, metabolomics, and gene-editing approaches to, investigate how injured renal tubular epithelial cells regulate macrophage metabolism and phenotype in ischemia-reperfusion injury (IRI)-induced AKI. We found that injured proximal tubular cells secrete high levels of secreted phosphoprotein 1 (SPP1), which binds to CD44, a receptor abundantly expressed on infiltrating macrophages, thereby activating the downstream PI3K/AKT signaling pathway. This activation induces nuclear translocation of PKM2, a key metabolic enzyme, which drives glycolytic metabolic reprogramming in macrophages and promotes their polarization toward a pro-inflammatory phenotype. In vitro and in vivo functional experiments further confirmed that blocking the SPP1-CD44 axis, using siRNA, neutralizing antibodies, or conditional knockout strategies, effectively alleviates renal IRI in mice, reduces macrophage infiltration, and diminishes the inflammatory response. Overall, this study delineates a novel mechanism in which injured tubular cell-derived SPP1 communicates with macrophage CD44 to regulate immunometabolism and inflammatory polarization via the PI3K/AKT-PKM2 signaling module at the single-cell and metabolic levels. These findings provide both a potential therapeutic target and a mechanistic framework for the prevention and treatment of AKI.