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TNFAIP3-interacting protein 1 (TNIP1; also known as ABIN-1) is a ubiquitin-binding protein that suppresses death-receptor- or Toll-like receptor-mediated apoptosis and necroptosis; however, it remains unclear whether ABIN-1 is capable of regulating pyroptosis. In the present study, we found that, in mouse embryonic fibroblasts and macrophages, ABIN-1 deficiency sensitized cells to poly(I:C) + TAK1 inhibitor 5Z-7-oxozeaenol-induced pyroptosis besides apoptosis and necroptosis. The sensitizing effect of ABIN-1 deficiency on pyroptosis depended on caspase-8 and its adaptor molecule FAS-associated death domain protein. In a mouse model of polymicrobial sepsis, myeloid-specific deletion of Abin-1 rendered mice more sensitive to pyroptosis, apoptosis and necroptosis, and exacerbated disease severity. Interestingly, ABIN-1 deficiency triggered gasdermin-E-mediated pyroptosis in mouse embryonic fibroblasts, but induced gasdermin-D-mediated pyroptosis in macrophages, both in a caspase-8-dependent manner. Furthermore, we demonstrated that, upon poly(I:C) + 5Z-7-oxozeaenol stimulation, ABIN-1 deficiency facilitates FAS-associated death domain protein recruitment to caspase-8; thus, the mechanism by which ABIN-1 downregulates caspase-8 activity is conserved in tumor necrosis factor receptor type 1 and Toll-like receptor 3 signaling-induced cell death. Together, our work identifies a previously unrecognized role for ABIN-1 as a negative regulator of pyroptosis in addition to apoptosis and necroptosis, suggesting that ABIN-1 represents a promising molecule to halt or reverse progression of refractory inflammatory disorders whose pathogenesis involves multiple forms of programmed cell death., (© 2025 Federation of European Biochemical Societies.)