Stress hyperglycemia impairs FOXK2-dependent macrophage cardiac repair after myocardial infarction.

FOXK2 supports macrophage-mediated cardiac repair after myocardial infarction under stress hyperglycemia, and its reduced expression or loss worsens injury in hyperglycemic mice.

• Why it matters: Stress hyperglycemia predicts poor MI outcomes, but the macrophage and FOXK2-linked mechanisms driving impaired cardiac repair were unclear.
• What they did: FOXK2 expression was reduced in cardiac macrophages from hyperglycemic mice after MI and in peripheral blood mononuclear cells from MI patients with SHG; macrophage-specific FOXK2 deficiency aggravated injury. Under high glucose, FOXK2 was O-GlcNAcylated at T552 by O-GlcNAc transferase, promoting ubiquitin-proteasome degradation, while the T552A variant resisted degradation.
• The result: FOXK2 restrained pro-inflammatory cytokine expression by suppressing H3K27 acetylation, and targeting excessive FOXK2 O-GlcNAcylation may offer a therapeutic strategy for MI patients with SHG.