ArticleScientific reports2026
The PI3K-Akt-CCND2 axis couples metabolic reprogramming with macrophage M1 polarization.
Article in Scientific reports, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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1 citing paper in PubMed.
- Extracellular vesicles mediate immune regulation in acute kidney injury.Frontiers in immunology · 2026Review
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9 authors.
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Abstract
Dysregulated macrophage M1 polarization is a core pathological feature of inflammatory disorders. However, the crosstalk between metabolic reprogramming and cell-cycle regulator Ccnd2 during macrophage polarization remains largely unclear. This study explored the role of the PI3K-Akt-Ccnd2 axis in LPS-induced macrophage inflammation and verified its therapeutic potential in sepsis-associated acute kidney injury (SA-AKI). In vitro experiments were performed using RAW264.7 macrophages (Sham, LPS, PI3K inhibitor + LPS, M-CSF alone, M-CSF + LPS, Ccnd2 inhibitor, Ccnd2 inhibitor + Akt activator). In vivo studies were conducted using a cecal ligation and puncture (CLP)-induced SA-AKI mouse model with M-CSF intervention. Transcriptomic/metabolomic profiling, Western blotting, qRT-PCR, flow cytometry, and histopathological analysis were applied. Renal function, systemic inflammation, and signaling pathway activation were evaluated. LPS triggered transcriptional reprogramming enriched in PI3K-Akt, cell-cycle, and inflammatory pathways, and downregulated Ccnd2 expression; M-CSF restored Ccnd2 via PI3K-Akt signaling, which was abolished by PI3K inhibition. Metabolomic analysis identified marked alterations in purine, glycerophospholipid, and amino acid metabolism in LPS-stimulated macrophages. LPS enhanced M1 polarization, whereas M-CSF or PI3K inhibition suppressed this effect. In CLP mice, M-CSF significantly reduced serum Cre/BUN levels, alleviated systemic inflammation and renal histopathological damage, and activated the renal PI3K-Akt-Ccnd2 axis; these renoprotective effects were reversed by PI3K inhibition. LPS-induced metabolic reprogramming cooperates with PI3K-Akt signaling to regulate Ccnd2, thereby coupling macrophage cell-cycle progression and M1 polarization. The PI3K-Akt-Ccnd2 axis modulates macrophage inflammation in vitro and ameliorates CLP-induced SA-AKI in vivo, representing a promising therapeutic target for sepsis and related inflammatory organ injury. The PI3K-Akt-Ccnd2 axis may represent a candidate for further investigation for sepsis and other inflammatory disorders.
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