SIK2 antagonizes postinfarction cardiac repair by driving macrophage proinflammatory signaling and impairing efferocytosis via TRAF2 phosphorylation and K63 polyubiquitylation through P38 and NF-κB pathways.
SIK2 is notably up-regulated in monocytes/macrophages of patients with MI and animal models.
Macrophage-specific SIK2 deletion reduces infarct size and improves healing after myocardial infarction.
SIK2-knockout macrophages exhibit decreased proinflammatory factor expression and enhanced efferocytosis.
SIK2 associates with TRAF2 and promotes its phosphorylation and K63 polyubiquitylation, exacerbating inflammation and hindering efferocytosis.
Macrophage-specific SIK2 overexpression worsens cardiac changes after MI, and P38 inhibition reduces this detrimental effect.
Pharmacological inactivation of SIK2 substantially enhances cardiac repair after MI in mice.
This research suggests that a protein called SIK2, found in immune cells called macrophages, plays a harmful role after a heart attack. When someone has a myocardial infarction (MI, or heart attack), macrophages rush to the damaged heart tissue, where they can either drive harmful inflammation or help with repair and cleanup of dead cells. This study found that SIK2 levels rise sharply in macrophages during MI in both human patients and mouse models, and that high SIK2 activity pushes macrophages toward causing more inflammation while also impairing their ability to clean up dead and dying cells — a process called efferocytosis. When macrophages cannot efficiently clear dead cells, inflammation persists and heart healing is delayed. The researchers traced the molecular mechanism to a chain of events: SIK2 binds to another protein called TRAF2, chemically modifies it (through phosphorylation and a process called K63 polyubiquitylation), and this triggers two well-known inflammatory signaling pathways — P38 and NF-κB — to become overactive. When the scientists genetically removed SIK2 specifically from macrophages in mice, the animals had smaller heart attack scars and better recovery. Conversely, when SIK2 was artificially increased in macrophages, cardiac damage worsened. Blocking the P38 pathway downstream of SIK2 was able to reduce that damage, and a single mutation in SIK2 (called T175A) completely abolished the harmful effects, pinpointing the precise functional site. Importantly, giving mice a drug that pharmacologically inhibits SIK2 after a heart attack also substantially improved cardiac repair, suggesting that existing or new SIK2-targeting drugs could one day be explored as a way to improve recovery from heart attacks in people. This research presents SIK2 and its interaction with TRAF2 as potential targets for therapies aimed at reducing heart damage and improving healing after MI.
Rong W, Xu Z, Shao S, Deng Q, Li M, Wei J, et al.. (2026). SIK2 antagonizes postinfarction cardiac repair by driving macrophage proinflammatory and impairing efferocytosis.. Science advances. https://doi.org/10.1126/sciadv.adw6624