Single-cell omics reframes fibrosis therapy as precision targeting of macrophage subtypes and niches, with SPP1-positive macrophages emerging as a cross-organ target and metabolic checkpoints offering additional therapeutic handles.

Therapeutic strategies are moving away from broad macrophage depletion toward precision approaches that selectively deplete profibrotic macrophages, silence SPP1 in specific subtypes, and employ nanoengineered or reprogramming therapies to modulate macrophage phenotypes.

SPP1-positive (osteopontin-expressing) macrophages are a conserved pro-fibrotic end-state across lung, kidney, heart, and liver, suggesting a shared therapeutic target across organs.

A single-cell RNA sequencing study builds an immune atlas of human myocardial infarction to map myeloid cell heterogeneity and their roles in inflammation and tissue repair.

Trajectory and regulatory analyses reveal dynamic macrophage differentiation and subtype-specific transcriptional programs, indicating evolving roles during myocardial infarction.

analyses of 44,574 high-quality cells across 24 cell types show enriched macrophages in infarcted regions with higher proliferative activity and activation of immune pathways.

Cell–cell communication analyses position C1 S100A4+ macrophages as central hubs interacting with endothelial cells, fibroblasts, and other immune cells via CXCL, MHC-II, and TNF pathways, underscoring their role in post-MI inflammatory remodeling.

Macrophage origin matters: tissue-resident macrophages versus bone marrow–derived monocyte–macrophages have distinct transcriptional programs and roles in fibrosis.

Spatial analysis shows scar-associated macrophages clustering near myofibroblasts to form niches sustained by factors like M-CSF, with macrophage positioning influencing remodeling outcomes.

Metabolic reprogramming drives macrophage fate, with glycolysis and PKM2/HIF-1α promoting inflammatory states, while metabolites such as succinate can have organ-specific pro-fibrotic or protective effects.

Four transcriptionally distinct macrophage subtypes (C0 GPNMB+, C1 S100A4+, C2 IL1B+, C3 EGR1+) exist, with C1 S100A4+ macrophages being dominant, highly proliferative, and expressing inflammatory mediators like IL1B, CCL3, and CXCL8.

Across lung, liver, kidney, and heart, macrophages drive and sustain fibrosis while also having the potential to reverse it, supporting a multidimensional view of macrophage heterogeneity beyond M1/M2 polarization.