Abstract / Summary
Abstract With the increasing rates of cesarean section (CS), cesarean section scar defect (CSD) has become an escalating clinical concern due to uterine dysfunction and reduced fertility. However, the biological basis of CSD remains poorly understood, particularly the mechanisms of impaired uterine repair after CS and the causes of failure in conventional repair surgeries. This study integrates metabolomics, transcriptomics, a newly developed mouse model, and functional assays to elucidate the complex interplay between senescence and fibrosis in CSD. Our findings identify upregulation of the PGES/prostaglandin E2 (PGE2) axis as a key upstream event that disrupts uterine healing. Elevated PGE2 preferentially induces early senescence of macrophages, which transmit pro-senescent signals to uterine fibroblasts through IL-1β/IL-1R signaling. This sequential senescence cascade drives excessive fibroblast activation and progressive fibrosis, ultimately impairing uterine structure and function. In mouse CS models, inhibition of the PGES/PGE2 pathway and anti-aging strategies significantly attenuate fibrosis and restore coordinated myometrial and endometrial repair. Our findings uncover a macrophage–fibroblast senescence relay to fibrotic scar formation in CSD and provide a translational rationale for targeting PGE2 signaling and senescence to improve uterine repair after CS.