Pyroptosis is a type of programmed cell death activated by lethal stimuli to cleave gasdermins (GSDMs) into N-terminal pore forming and C-terminal autoinhibitory domains. Pyroptosis leads to inflammation which can be harnessed for host defense during infection and to promote anti-tumor immunity. The post-cleavage interactions of the N-and C-terminal domains of GSDME are unknown. Pyroptosis-resistant fibroblasts were used to study the interaction partners of N/C-GSDME using the proximity approach BioID. The N-GSDME interactome revealed proteins associated with localization to the cell periphery and actin-based cell projections. We found previously established interactors of full-length GSDME (EGFR and SPTAN1), ZDHHC5 (essential for GSDMD membrane localization), and novel proteins, like SH3BP4. The C- GSDME interactome was mainly associated with the proteosome, except for RNA- polymerase associated protein RPAP3. These results further establish the mechanism and regulation of pyroptosis. Future research will investigate direct interactions to reveal new targets to modulate pyroptosis for therapeutic purposes.