Objective: To discuss the effect of free Heme on sepsis induced immunosuppression model mice based on the regulation on macrophage PANoptosis by NLR family pyrin domain containing 12 (NLRP12). Methods: The sepsis mice model was constructed, and divided into Model group, Heme group, Heme+empty plasmid group (Heme+si-NC), and Heme+NLRP12 low expression plasmid group (Heme+si-NLRP12 group), each with 12 mice. Another 12 mice with only exposed cecum without ligation or puncture were considered as the sham surgery group (Control). The levels of inflammatory factors in serum were detected by ELISA. The ratio of CD4+/CD8+ in the blood was detected by flow cytometry, the pathological changes of lung tissue were detected by HE staining, the apoptosis of cells was detected by TUNEL staining, and the expression level of pan-apoptosis-related proteins in lung tissue was detected by Western blot. To further clarify the mechanism by which Heme regulates NLRP12, sepsis cell models were induced by LPS-infected mouse bone marrow-derived macrophages (BMDM), and they were divided into LPS group, LPS+Heme group, LPS+Heme+si-NC group, and LPS+Heme+si-NLRP12 group. Take the normally cultivated BMDM as the Control group. The levels of inflammatory factors in the supernatant of BMDM were detected by ELISA, the cell viability was detected by CCK-8, the apoptosis rate was detected by TUNEL, and the expression levels of pan-apoptosis-related proteins were detected by Western blot. Results: Compared with the Model group, the Heme group could further increase the levels of serum inflammatory factors, aggravate lung tissue injury and cell apoptosis, promote the progression of cell pan-apoptosis, while the CD4+/CD8+ ratio was reduce (P<0.05). Compared with the Heme+si-NC group, the pathological damage of lung tissue and the process of pan-apoptosis in the Heme+si-NLRP12 group were alleviated, the levels of serum inflammatory factors and the apoptosis rate of lung tissue cells decreased, while the ratio of CD4+/CD8+ was increased (P<0.05). Cell experiments showed that the cell survival rate in the LPS group decreased significantly, while the process of cell pan-apoptosis and the levels of inflammatory factors in the supernatant were increased (P<0.05). Compared with the LPS group, the apoptosis rate, the process of pan-apoptosis and the levels of inflammatory factors further increased in the LPS+Heme group(P<0.05). Compared with the LPS+Heme+si-NC group, the cell survival rate in the LPS+Heme+si-NLRP12 group increased significantly, while the process of cell pan-apoptosis and the levels of inflammatory factors in the supernatant were decreased (P<0.05). Conclusion: Heme may induce macrophage PANoptosis by upregulating NLRP12, thereby enhancing immune suppression in sepsis.