Macrophage FOXK2 promotes cardiac repair in myocardial infarction with stress hyperglycemia

Abstract Background Stress hyperglycemia (SHG) frequently occurs in patients with acute myocardial infarction (MI) and is a strong independent predictor of poor clinical outcomes, even in individuals without pre-existing diabetes. Although stress-induced hyperglycemia has been closely linked to exaggerated cardiac inflammation, the molecular mechanisms by which acute hyperglycemic stress disrupts inflammatory resolution and myocardial repair remain largely unclear. Methods and Results In this study, we identify the transcription factor FOXK2 as a critical molecular sensor linking hyperglycemic stress to maladaptive inflammatory responses during MI. FOXK2 expression was significantly reduced in cardiac macrophages from hyperglycemic mice following MI and in peripheral blood mononuclear cells from MI patients with SHG, with FOXK2 levels inversely correlating with infarct severity and cardiac dysfunction. Macrophage-specific deletion of FOXK2 markedly exacerbated myocardial injury, enhanced inflammatory cytokine production, and impaired post-infarction cardiac repair. Mechanistically, hyperglycemia promoted the interaction between FOXK2 and O-GlcNAc transferase (OGT), leading to site-specific O-GlcNAcylation of FOXK2 at threonine 552. This modification triggered K11-linked polyubiquitination and subsequent proteasomal degradation of FOXK2, thereby releasing a broad pro-inflammatory transcriptional program during MI. Integrated CUT&Tag and RNA-sequencing analyses demonstrated that FOXK2 normally restrains macrophage inflammatory activation by suppressing H3K27 acetylation at key inflammatory loci, with the IL-6/STAT3 signaling axis emerging as a prominently derepressed pathway in the absence of FOXK2. Mass spectrometry and functional validation further revealed that a FOXK2T552A mutant was resistant to hyperglycemia-induced degradation, confirming the functional importance of this modification site. To translate these mechanistic insights into therapeutic intervention, we developed a cell-penetrating peptide (Peptide-I) that disrupts the FOXK2–OGT interaction and stabilizes FOXK2 under hyperglycemic conditions. Administration of Peptide-I significantly attenuated cardiac inflammation, improved cardiac function, and enhanced myocardial repair in both acute SHG and chronic diabetic MI models. Conclusions These findings establish FOXK2 as a central molecular node integrating hyperglycemic stress with macrophage-driven inflammatory responses during MI and provide proof-of-concept that targeting FOXK2 O-GlcNAcylation may represent a novel therapeutic strategy for improving outcomes in MI complicated by stress hyperglycemia.