The PI3K-Akt-CCND2 axis orchestrates macrophage M1 polarization through metabolic reprogramming: mechanistic and therapeutic insights

Background Sepsis is a life-threatening syndrome driven by dysregulated macrophage polarization, in which excessive M1 polarization exacerbates systemic inflammation and organ injury. However, the mechanisms underlying the interplay between metabolic reprogramming and cell-cycle regulators such as Ccnd2 during macrophage polarization in sepsis remain poorly understood. This study investigates the role of Ccnd2 and its regulatory network in LPS-induced macrophage inflammation, with a focus on the PI3K–Akt signaling axis and associated metabolic alterations. Methods RAW264.7 macrophages were divided into four experimental groups: sham, LPS, PI3K inhibitor + LPS, and M-CSF–pretreated + LPS. Transcriptomic (RNA-seq) and metabolomic (LC-MS/MS) profiling were performed to identify differentially expressed genes and metabolites. Western blotting and qRT-PCR were used to validate expression levels of Ccnd2, PI3K, Akt, and P27. Flow cytometry was employed to assess M1 polarization, and KEGG enrichment analysis was conducted to explore transcriptome–metabolome regulatory networks. Results Transcriptomic analysis indicated significant enrichment of pathways related to PI3K–Akt signaling, cell cycle, and inflammatory cascades following LPS stimulation. Ccnd2 expression was downregulated in the LPS-treated group but markedly upregulated in the M-CSF–pretreated group—an effect abolished by PI3K inhibition. Metabolomic profiling revealed distinct metabolic reprogramming in LPS-stimulated macrophages, with notable alterations in purine metabolism, glycerophospholipid metabolism, and amino acid homeostasis. Flow cytometry demonstrated that LPS enhanced M1 polarization, whereas M-CSF co-treatment reversed this effect. PI3K inhibition suppressed both Ccnd2 expression and M1 polarization, suggesting a functional connection between Ccnd2-mediated cell-cycle progression and inflammatory polarization. Conclusion This study delineates a novel regulatory network in which LPS-induced metabolic reprogramming synergizes with PI3K–Akt signaling to modulate Ccnd2 expression, thereby coordinating macrophage cell-cycle progression and M1 polarization. The PI3K–Akt–Ccnd2 axis represents a promising therapeutic target for sepsis and other inflammatory disorders, offering potential for combined metabolic and immune interventions to reprogram macrophage polarization and mitigate inflammatory injury.