Estrogen attenuates stiffness-driven fibrotic signaling via transcriptional regulation.

Fibrosis, marked by excessive extracellular matrix (ECM) accumulation, underlies functional decline in numerous diseases and often presents with sex-specific differences in severity. Although biochemical pathways have been widely studied, the contribution of mechanical cues-particularly ECM stiffness-to these disparities remains unclear. Here, we develop an integrative mechanobiological model to investigate how estrogen modulates stiffness-mediated fibrotic progression. The model reveals that ECM stiffness activates fibroblasts through two key pathways: a rapid nuclear translocation of mechanosensitive factors (MRTF and TAZ) and a delayed transforming growth factor β/Smad cascade, both of which enhance α-smooth muscle actin expression and matrix production. Moreover, we uncover a stiffness-induced "mechanical memory" effect, maintained through a miR-21/Smad feedback loop that sustains fibrotic signaling even after stiffness reduction. Estrogen, acting via estrogen receptor α, counteracts this process by promoting Smad degradation and interrupting the feedback loop, thereby dampening fibrosis. This work offers new insight into the mechanochemical regulation of sex-biased fibrosis and points to potential sex-specific therapeutic targets.