Sci Adv. 2026 Oct 16. 12(42):
eadw6624
Wu-Wei Rong,
Zi-Qi Xu,
Shuai Shao,
Qian-Wan Deng,
Meng-Yao Li,
Jin-Qiu Wei,
Yi-Hang Yang,
Jia-Jia Zhao,
Wen-Hui Zhai,
Zhi-Wen Shang,
Zhi Zhang,
Wen-Yi Yang,
Shao-Wen Liu,
Ping-Jin Gao,
Xiao-Dong Li,
Ji-Guang Wang.
Macrophages play a key role in cardiac injury and repair after myocardial infarction (MI). Salt-inducible kinase 2 (SIK2), a member of the adenosine monophosphate-activated protein kinase family, is notably up-regulated in monocytes/macrophages of patients with MI and animal models. In this study, we investigated the role of SIK2 in macrophage-mediated inflammation and efferocytosis following MI. Macrophage-specific SIK2 deletion reduces infarct size and improves healing post-MI. Furthermore, SIK2-knockout macrophages decrease proinflammatory factor expression and enhance efferocytosis, thereby increasing repair factors expression. SIK2 associates with tumor necrosis factor receptor-associated factor 2 (TRAF2), promoting its phosphorylation and K63 polyubiquitylation, which exacerbates inflammation and hinders efferocytosis via the P38 and nuclear factor κB pathways. In contrast, the SIK2T175A mutation exhibits no effect. Macrophage-specific SIK2 overexpression worsens cardiac changes after MI, whereas P38 inhibition reduces this effect. In addition, pharmacological inactivation of SIK2 substantially enhances cardiac repair after MI in mice. These findings highlight the crucial role of macrophage SIK2 in the regulation of inflammation and efferocytosis via TRAF2 polyubiquitination in MI, thereby presenting potential therapeutic targets.