Unmasking Alarmins: How the Exposome Shapes IBD Through Redox Modifications

Abstract Alarmins are endogenous molecules released upon tissue damage that play a central role in maintaining epithelial barrier integrity and coordinating immune responses. In inflammatory bowel diseases (IBD), the interplay between intestinal epithelium and immune system is profoundly disrupted, yet the mechanisms governing alarmin functional diversity remain incompletely understood. Key alarmins, including IL-33, HMGB1, IL-1α, and S100 proteins, exhibit context-dependent and occasionally opposing functions, highlighting regulatory layers that are not yet fully understood in intestinal inflammation. Emerging evidence indicates that oxidative stress can reshape alarmin activity through oxidative post-translational modifications (Ox-PTMs), and other stress-associated mechanisms, thereby altering receptor engagement and downstream signalling pathways. Although many of these mechanisms involve redox-sensitive cysteine residues, others are indirectly driven by oxidative stress through pathways such as calcium dysregulation, proteolytic processing, and altered release mechanisms. However, these regulatory pathways remain poorly integrated into IBD pathophysiology. Environmental exposures comprising the exposome, including diet, smoking, and pollutants promote mucosal oxidative stress, epithelial barrier disruption, and dysregulated alarmin release. This positions oxidative stress as key interface linking environmental perturbation to context-dependent alarmin activation. In this review, we examine current evidence on the oxidative stress and stress-associated regulation of major alarmins in IBD. We propose a conceptual model in which alarmins act as redox-sensitive and stress-responsive sensors of the intestinal exposome, translating environmental perturbations into functional immune signalling changes. This perspective provides mechanistic insight into disease heterogeneity and highlights modified alarmins states as potential biomarkers and therapeutic targets for restoring mucosal homeostasis in IBD.