Early-activated extracellular matrix proteins shape metabolic and spatial dynamics of the kidney fibrotic microenvironment

The fibrotic kidney microenvironment is shaped by cellular crosstalk, extracellular matrix (ECM) remodeling, metabolic reprogramming, and spatial heterogeneity. While late-stage ECM changes dominate fibrosis, the role of early-activated matrix proteins remains unclear. Here, we identified Ecm1 as an early regulator of kidney remodeling. Global Ecm1 knockout mice develop spontaneous fibrosis and early death, whereas Ecm1 levels markedly increase in biofluids during CKD. Targeting Ecm1 by AAV9-mediated knockdown or fibroblast-specific deletion substantially reduces renal fibrosis. Mechanistically, Ecm1 deletion disrupts the integrin α2β1-RhoC axis, suppressing Yap activity. Reduced Yap nuclear translocation and diminished Yap-Tead4 complex formation relieve Tead4-mediated repression of Pgc1α, enhancing mitochondrial OXPHOS and promoting repair. Spatial transcriptomics and proteomics confirm this mechano-metabolic pathway, revealing mitochondrial reprogramming in tubules that counteracts fibrotic progression. Notably, fibroblast Yap inactivation limits aberrant activation without impairing their OXPHOS. This selective ECM-mitochondrial crosstalk uncovers a mechano-metabolic pathway where mitochondrial shifts drive defense against kidney fibrosis.