biostudies-literatureSun ZScience and Technology Commission of Shanghai Municipality (Shanghai Municipal Science and Technology Commission)Shanghai Science and Technology Development Foundation (Shanghai Science and Technology Development Fund)National Natural Science Foundation of China (National Science Foundation of China)1890https://www.ebi.ac.uk/biostudies/studies/S-EPMC11846980biostudies-literatureUnknown16(1)Dysfunctional NF-κB signaling is critically involved in inflammatory bowel disease (IBD). We investigated the mechanism by which RIPK1 and TRADD, two key mediators of NF-κB signaling, in mediating intestinal pathology using TAK1 IEC deficient model. We show that phosphorylation of TRADD by TAK1 modulates RIPK1-dependent apoptosis. TRADD and RIPK1 act cooperatively to mediate cell death regulated by TNF and TLR signaling. We demonstrate the pathological evolution from RIPK1-dependent ileitis to RIPK1- and TRADD-co-dependent colitis in TAK1 IEC deficient condition. Combined RIPK1 inhibition and TRADD knockout completely protect against intestinal pathology and lethality in TAK1 IEC KO mice. Furthermore, we identify distinctive microbiota dysbiosis biomarkers for RIPK1-dependent ileitis and TNature communicationsCooperation of TRADD- and RIPK1-dependent cell death pathways in maintaining intestinal homeostasis.PMC11846980920493033217075422JC14104002019SHZDZX028218810132370796Jing HLiu JJiang LZhang MSun WShan BSun ZXu JYuan JLi WPan HHou MZhang TWu RXie CYe JfalseCooperation of TRADD- and RIPK1-dependent cell death pathways in maintaining intestinal homeostasis.Dysfunctional NF-κB signaling is critically involved in inflammatory bowel disease (IBD). We investigated the mechanism by which RIPK1 and TRADD, two key mediators of NF-κB signaling, in mediating intestinal pathology using TAK1 IEC deficient model. We show that phosphorylation of TRADD by TAK1 modulates RIPK1-dependent apoptosis. TRADD and RIPK1 act cooperatively to mediate cell death regulated by TNF and TLR signaling. We demonstrate the pathological evolution from RIPK1-dependent ileitis to RIPK1- and TRADD-co-dependent colitis in TAK1 IEC deficient condition. Combined RIPK1 inhibition and TRADD knockout completely protect against intestinal pathology and lethality in TAK1 IEC KO mice. Furthermore, we identify distinctive microbiota dysbiosis biomarkers for RIPK1-dependent ileitis and T2025-01-01T00:00:00Z2025 Feb2025-04-18T12:53:05.811Z2025-04-04T00:51:58.658ZS-EPMC118469803998726110.1038/s41467-025-57211-z