The dual role of RIPK family in IBD: from cell death to therapeutic targeting.

The receptor-interacting serine/threonine-protein kinase (RIPK) family, particularly RIPK1, RIPK2, and RIPK3, functions as a central regulatory hub at the intersection of cell death and inflammatory signaling, critically shaping the pathogenesis of inflammatory bowel disease (IBD). These kinases exhibit context-dependent dual roles in maintaining intestinal homeostasis and driving mucosal inflammation. RIPK1 operates as a molecular switch, with its scaffold activity sustaining epithelial survival via the NF-κB and MAPK pathways, whereas its kinase activity promotes apoptosis and necroptosis under pathological conditions. RIPK2 acts as an essential adaptor downstream of nucleotide-binding oligomerization domain-containing protein 1/2 (NOD1/2), mediating antimicrobial host defense while contributing to excessive inflammation upon dysregulation. RIPK3, a core executor of necroptosis, also exerts kinase-independent immunomodulatory functions that influence tissue repair and inflammatory resolution. Dysregulation of RIPK signaling disrupts epithelial barrier integrity, amplifies inflammatory cascades, and engages in crosstalk with other programmed cell death modalities, such as pyroptosis, thereby exacerbating chronic intestinal injury. Therapeutic targeting of RIPK pathways has shown promise in preclinical models; however, achieving selective modulation that suppresses pathogenic signaling while preserving physiological functions remains a critical challenge. We propose that function-selective targeting of RIPKs, rather than complete inhibition, represents an essential direction for future IBD therapy.