Targeting cell death in Crohn's disease: from mechanisms to medicines

Crohn's disease (CD) is a chronic inflammatory granulomatous disease that can damage the gastrointestinal tract. Existing treatment methods often fail to achieve satisfactory clinical effects. Although the pathogenesis of CD has not been fully elucidated, increasing evidence suggests that programmed cell death plays a key role in disease progression. This article comprehensively reviews 12 different mechanisms of cell death related to the pathogenesis of CD: apoptosis, necroptosis, pyroptosis, parthanatos, ferroptosis, autophagy-dependent cell death, cuproptosis, oxeiptosis, entotic cell death, netotic cell death, lysosome-dependent cell death, and alkaliptosis. On this basis, the article discusses targeted therapeutic strategies to regulate these cell death pathways, with a particular emphasis on their translational potential in clinical applications. Our analysis of existing studies concludes that autophagy, regulated by ATGs, is crucial in CD, and its dysregulation is associated with genetic factors (ATG16L1, IRGM, NOD2) and the mTOR signaling pathway, suggesting that autophagy may serve as a therapeutic target. Apoptosis and pyroptosis mediated by caspases and gasdermin, respectively, as well as ferroptosis and copper death, are all involved in the pathogenesis of CD, highlighting potential therapeutic strategies through the regulation of these pathways and cell death mechanisms (Graphical abstract 1).