Objective To investigate the effect of free Heme on sepsis-induced immunosuppression model mice based on regulation of macrophage PANoptosis by NLR family pyrin domain containing 12 (NLRP12). Methods A sepsis mouse model was constructed and the mice were divided into Model, Heme, Heme+empty plasmid (Heme+si-NC), and Heme+NLRP12 low-expression plasmid groups (Heme+si-NLRP12) (n= 12 mice per group). Another 12 mice with exposed cecum without ligation or puncture were considered as the sham surgery group (Sham). Serum levels of inflammatory factors were detected by enzyme-linked immunosorbent assay (ELISA). The CD4⁺/ CD8⁺ratio in the blood was detected by flow cytometry, pathological changes in lung tissue were detected by hematoxylin / eosin staining, apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining, and expression levels of PANoptosis-related proteins in lung tissue were detected by Western blot. To clarify the mechanism by which heme regulates NLRP12, sepsis cell models were induced using lipopolysaccharide (LPS)- infected mouse bone marrow-derived macrophages (BMDM). Model mice were divided into LPS, LPS+Heme, LPS+Heme+si-NC group, and LPS+Heme+si-NLRP12 groups, with mice administered normally cultivated BMDMs as the Control group. Levels of inflammatory factors in the BMDM supernatant were detected by ELISA, cell viability was detected by Cell Counting Kit-8 assay, apoptosis rate was detected by TUNEL staining, and expression levels of PANoptosis-related proteins were detected by Western blot. Results Compared with the Model group, rats in the heme group showed increased serum levels of inflammatory factors, aggravated lung tissue injury and cell apoptosis, and progression of cell PANoptosis, while the CD4⁺/ CD8⁺ratio was reduced (P<0. 05). Compared with the Heme+si-NC group, pathological lung tissue damage and the process of PANoptosis were alleviated in the Heme+si-NLRP12 group, serum levels of inflammatory factors, and the apoptosis rate of lung tissue cells were decreased, while theCD4⁺/ CD8⁺ratio was increased ( P<0. 05). Cell experiments showed that the cell survival rate was significantly decreased in the LPS group, while the process of cell PANoptosis and levels of inflammatory factors in the supernatant were increased (P<0. 05). Compared with the LPS group, the apoptosis rate, process of PANoptosis, and levels of inflammatory factors were further increased in the LPS+Heme group (P<0. 05). Compared to the LPS+Heme+si-NC group, the LPS + Heme + si-NLRP12 group exhibited significantly increased cell viability, reduced apoptosis and supernatant inflammatory factor levels, along with decreased expression of NLRP12, Bax, Caspase-8, p-RIPK3, and GSDMD-N(P<0. 05). Conclusions Heme may induce macrophage PANoptosis by upregulating NLRP12, thereby enhancing immune suppression in sepsis.