Macrophage-to-myofibroblast transition in renal fibrosis: controversy, context dependence, and therapeutic implications

This is the authors' abstract. We don't add key points for this paper.

Myofibroblasts are the principal effector cells of renal interstitial fibrosis (RIF), but the relative contribution of proposed cellular sources remains disputed. Macrophage-to-myofibroblast transition (MMT) has been inferred from marker co-expression, single-recombinase lineage tracing, and functional perturbation, whereas high-specificity dual-recombinase tracing in unilateral ureteral obstruction identified resident fibroblasts as the predominant myofibroblast source and detected no appreciable macrophage contribution. We therefore distinguish three evidentiary categories: lineage-confirmed MMT, MMT-like macrophage remodeling, and broader profibrotic macrophage activation. We compare co-expression phenotyping, lineage-tracing systems, single-cell and spatial omics, and in vitro induction; organize candidate mechanisms into a causal hierarchy centered on TGF-β1/Smad3-Src-Pou4f1; and assess disease context and therapeutic implications. Current evidence does not support MMT as a universal or quantitatively dominant source. Whether a small MMT-like population exerts disproportionate local effects remains a testable hypothesis, not an established conclusion. We close with falsifiable experiments designed to define where, when, and by which criteria macrophage-derived fibrogenic states can be demonstrated in RIF.