Targeting SERPINE1 suppresses cGAS-STING-mediated fibroblast senescence and attenuates intestinal inflammation in Crohn’s disease

Background Cellular senescence and the senescence-associated secretory phenotype (SASP) are recognized drivers of chronic inflammation. This study aims to characterize a specific senescent fibroblast subset and its role in reshaping the immune landscape of Crohn’s disease (CD). Methods Single-cell and bulk transcriptomic data from CD patients were analyzed to identify senescent cell populations and map intercellular communication networks. Mechanistic and functional validations were conducted utilizing macrophage-fibroblast co-culture systems and a dextran sulfate sodium (DSS)-induced colitis mouse model treated with the selective SERPINE1 inhibitor, TM5441. Results Transcriptomic profiling identified a localized, previously uncharacterized subpopulation of SERPINE1⁺ fibroblasts in inflamed CD tissues that exhibited high senescence scores, G1 cell-cycle arrest, and a pro-inflammatory secretory profile. Interaction analyses revealed that IL1RN⁺ macrophages induce this fibroblast senescence primarily via paracrine TNF-α signaling. Mechanistically, SERPINE1 sustains this senescent phenotype by promoting the activation of the cGAS-STING pathway. Importantly, targeted pharmacological inhibition of SERPINE1 using TM5441 significantly attenuated DSS-induced colitis and effectively suppressed cGAS-STING-mediated cellular senescence in vivo. Conclusion SERPINE1 acts as a central driver of pathogenic fibroblast senescence in the CD mucosal microenvironment by activating the cGAS-STING pathway. Consequently, pharmacological inhibition of SERPINE1 presents a promising therapeutic strategy for managing intestinal inflammation in Crohn's disease.