Cellular senescence in Crohn's disease: a double-edged sword in intestinal fibrosis.

Abstract

Cellular senescence represents a pivotal yet paradoxical determinant in the pathogenesis of intestinal fibrosis associated with Crohn's disease (CD). While acute senescence may facilitate tissue repair and limit fibrogenesis, the chronic accumulation of senescent cells drives persistent inflammation and excessive extracellular matrix (ECM) deposition, ultimately leading to irreversible fibrotic strictures. This review systematically delineates the triggers of cellular senescence within the CD microenvironment-including oxidative stress, telomere dysfunction, endoplasmic reticulum stress, and genotoxic damage-and elucidates the roles of diverse senescent cell types (myo-/fibroblasts, endothelial, epithelial, and immune cells) in fibrotic progression. Central to this process is the senescence-associated secretory phenotype (SASP), which acts as a core mediator linking senescence to fibrosis through paracrine activation, ECM imbalance, immune modulation, and stem cell dysfunction. We further discuss emerging therapeutic strategies targeting senescent cells, such as senolytics and senomorphics, and highlight the translational potential of senescence-directed interventions in mitigating intestinal fibrosis. Understanding the dual roles of cellular senescence offers novel insights into the mechanisms of CD-related fibrogenesis and paves the way for innovative antifibrotic therapies.