SAMHD1 promotes cardiac repair post myocardial infarction by targeting NR4a1 to regulate macrophage metabolic reprogramming

• SAMHD1 expression is upregulated in cardiac macrophages post-MI and is closely associated with inflammatory markers following myocardial infarction. • Macrophage-specific SAMHD1 deficiency exerts a protective effect in the heart post-MI. • SAMHD1 deficiency mediates macrophage polarization toward a reparative phenotype by regulating mitochondrial metabolism in macrophages. • SAMHD1 deficiency promotes the conversion of macrophages to a reparative phenotype by downregulating NR4a1 expression in macrophages, thereby affecting mitochondrial metabolism. • SAMHD1 deficiency mediates NR4a1 ubiquitination and degradation by upregulating Pparγ expression and promoting the interaction between Pparγ and NR4a1. Myocardial infarction (MI) is one of the leading causes of high mortality worldwide. Accumulating evidence suggests that macrophages emerge as the predominant immune population within the post-MI cardiac environment, serving as critical modulators that coordinate inflammatory cascades during myocardial repair. The main objective of this study was to explore the effects of sterile alpha motif and HD domain-containing protein 1 (SAMHD1) on myocardial remodeling post-MI and to elucidate its potential mechanism. We used MI mouse model ligation of the left anterior descending coronary artery (LAD) to investigate the role of SAMHD1 in MI. To assess the role of SAMHD1 in MI, we generated both macrophage-specific knockout and overexpression mice. To investigate the mechanisms by which SAMHD1 regulates MI progression, we employed transcriptomics sequencing and nontargeted metabolomics. SAMHD1 was significantly upregulated in mouse cardiac macrophages on day 3 post-MI and was closely associated with immune responses. We found that SAMHD1 deficiency facilitated myocardial repair. We found that SAMHD1 deficiency confers cardioprotection through metabolic reprogramming mechanisms: increased mitochondrial oxidative phosphorylation capacity coupled with increased production of the anti-inflammatory metabolite itaconic acid and suppression of the pentose phosphate pathway and lactate biosynthesis. We found that these metabolic shifts facilitated macrophage differentiation by promoting a transition toward reparative macrophage populations. Furthermore, SAMHD1 deficiency drives macrophage phenotypic switching through the transcriptional suppression of NR4a1. More importantly, we have shown that SAMHD1 deficiency promotes the interaction between NR4a1 and Pparγ, which facilitates NR4a1 ubiquitination-dependent degradation. Our study revealed that macrophage-specific SAMHD1 deletion confers post-MI cardioprotection. More importantly, we demonstrated that NR4a1, a downstream target of SAMHD1, mediates the cardioprotective effects of SAMHD1 deficiency post-MI by regulating the remodeling of macrophage energy metabolism to promote the macrophage reparative phenotype.