Macrophage heterogeneity in organ fibrosis in the era of single-cell omics

Organ fibrosis is the ultimate common pathway resulting from dysregulated tissue repair caused by chronic inflammation, it accounts for approximately 45% of global mortality, and there are currently no effective clinical treatments to reverse it. As the central immune cells in the fibrotic microenvironment, macrophages exhibit a high degree of phenotypic and functional heterogeneity that far exceeds the traditional M1/M2 dichotomy. Based on the latest evidence from single-cell transcriptomics and spatial transcriptomics, this review establishes a multidimensional framework for macrophage heterogeneity that encompasses cellular origin, disease stage, spatial microenvironment, and functional output. We compared the conserved and organ-specific characteristics of macrophage subsets in pulmonary, hepatic, renal, and cardiac fibrosis, highlighting that Secreted Phosphoprotein 1⁺ (SPP1⁺) Stroma-Associated Macrophages (MAMs) represent a conserved pro-fibrotic end-state and could serve as a candidate for a cross-organ therapeutic axis. In addition, we explored how metabolic reprogramming - such as the glycolysis-Pyruvate Kinase Isozyme Type M2 (PKM2) axis - determines the fate of macrophages and mediates their interactions with parenchymal cells, as well as the therapeutic potential of targeting macrophage metabolic pathways, phenotypic transitions, and the elimination of specific subpopulations. It aims to provide a theoretical basis for understanding the pathogenesis of fibrosis and developing precision treatment strategies based on macrophage heterogeneity.