We previously observed that there was a protective effect of global CD38 deletion on cardiac ischemia-reperfusion and nonalcoholic fatty liver disease (NAFLD).19 It has been reported that CD38 deficiency upregulated IL-1β/TLR4/NLRP3/GSDMD signaling axis via the TLR1/ERK/NF-κB pathway, resulting in aggravated liver injury in the sepsis model of CD38KO mice.28,43 In our study, we demonstrated that myeloid-specific CD38 deletion greatly ameliorated HIRI in mice, strengthening the view that functional regulation of CD38/NAD+/SIRT1 axis may improve aseptic inflammation and tissue damage. Here, TLR4 is linked to metabolic dysfunction-associated steatotic liver disease.