Cell Rep. 2026 Oct 28;45(11):118203. doi: 10.1016/j.celrep.2026.118203. Online ahead of print.
ABSTRACT
Stress hyperglycemia (SHG) predicts poor outcomes after myocardial infarction (MI), but the underlying mechanisms remain unclear. Here, we identify FOXK2 as a key regulator of macrophage-mediated cardiac repair. FOXK2 expression was reduced in cardiac macrophages from hyperglycemic mice after MI and in peripheral blood mononuclear cells from patients with MI with SHG, whereas macrophage-specific FOXK2 deficiency aggravated cardiac injury. Under high-glucose conditions, FOXK2 was glycosylated at T552 by O-GlcNAc transferase, promoting its ubiquitin-proteasome-dependent degradation. Mass spectrometry and functional assays showed that the FOXK2T552A variant resisted hyperglycemia-induced degradation. Integrated CUT&Tag and RNA-seq analyses revealed that FOXK2 restrained pro-inflammatory cytokine expression by suppressing H3K27 acetylation. Thus, our findings identify FOXK2 as a critical regulator that supports cardiac repair during hyperglycemia, and targeting excessive FOXK2 O-GlcNAcylation may offer a therapeutic strategy for patients with MI and SHG.
PMID:42949915 | DOI:10.1016/j.celrep.2026.118203