Free Radic Biol Med. 2026 Jan 29:S0891-5849(26)00075-4. doi: 10.1016/j.freeradbiomed.2026.01.055. Online ahead of print.
ABSTRACT
Myocardial infarction (MI) stands as a leading contributor to global cardiovascular morbidity and mortality, defined by ischemic myocardial cell death and subsequent impairment of cardiac function. The tripartite motif (TRIM) protein family has been shown to regulate myocardial ischemia-reperfusion injury. As a key member of the TRIM protein family, tripartite motif-containing protein 28 (TRIM28) exhibits dysregulated expression in the heart during MI yet its pathophysiological role remains to be fully elucidated. This study aimed to investigate the functional roles and underlying mechanisms of TRIM28 in MI. We observed a significant upregulation of TRIM28 in ischemic myocardium and hypoxic cardiomyocytes. Genetic knockout of TRIM28 ameliorated cardiac function and attenuated apoptosis in MI mice, whereas its overexpression exacerbated contractile dysfunction, and promoted cardiomyocyte apoptosis and mitochondrial injury. Mechanistically, TRIM28 directly interacts with activating transcription factor 5 (ATF5) and suppresses its SUMOylation, thereby enhancing the ubiquitin-mediated degradation of ATF5, inhibiting the mitochondrial unfolded protein response (UPRmt), and ultimately culminating in increased apoptosis. Via molecular docking, we identified a TRIM28-targeting compound, Oolonghomobisflavan B (OFB), which attenuated post-MI apoptosis and facilitated cardiac function recovery. Collectively, these findings demonstrate that TRIM28 acts as a critical regulator of MI progression, and OFB holds therapeutic potential as a candidate drug.
PMID:41619820 | DOI:10.1016/j.freeradbiomed.2026.01.055