Role of Scar‐Associated Macrophages in Organ Fibrosis Diseases

Fibrosis refers to the scarring and hardening of tissue resulting from the excessive deposition of extracellular matrix (ECM) proteins by myofibroblasts during chronic inflammatory responses, which can ultimately lead to organ failure and potentially death. Different states of macrophage activation are critical in regulating both the progression and regression of fibrosis. However, the conventional M1/M2 polarization model fails to accurately capture the dynamic and heterogeneous states of macrophages observed in vivo. As a result, an increasing number of studies have begun to classify macrophages based on their functional phenotypes. One specific subset of functionally distinct macrophages, termed scar-associated macrophages (SAMs), has been confirmed to play a significant regulatory role in organ fibrosis. This review provides a comprehensive summary of recent advances in understanding the role of SAMs in fibrotic diseases across multiple organs, including the liver, lungs, heart, and kidneys. It further explores the emerging conceptual framework of hot and cold fibrosis, highlighting the potential role of SAMs as central cellular mediators that sustain a positive feedback loop between inflammation and fibrosis in the "hot fibrosis" state. Building on these insights, this review also discusses future research directions aimed at developing targeted therapeutic strategies to modulate SAM activity and mitigate fibrosis in diverse organ systems.