SPP1+ macrophages in fibrosis

ABSTRACT: Fibrosis is a common end-stage pathological process in many chronic diseases and is characterized by excessive extracellular matrix (ECM) deposition and progressive tissue dysfunction. Effective antifibrotic therapies remain limited, and macrophages are increasingly recognized as key regulators of fibrogenesis. Recent multiorgan single-cell and spatial transcriptomic studies have identified a macrophages state characterized by high expression of secreted phosphoprotein 1 (SPP1), which is recurrently enriched in fibrotic niches. This review summarizes the regulation of macrophages biology by SPP1, the cellular origins and regulatory networks of SPP1+ macrophages, and the mechanisms through which these cells contribute to multiorgan fibrosis. These mechanisms include ECM remodeling, activation of fibroblasts and myofibroblasts, induction of epithelial-mesenchymal and endothelial-mesenchymal transition, and immunoregulatory autocrine and paracrine circuits. We further discussed emerging therapeutic strategies targeting SPP1 or SPP1+ macrophages and evaluated their potential as biomarkers for patient stratification and personalized antifibrotic therapy.