TRIM47 drives cardiac ischemia/reperfusion injury by impairing mitochondrial function and fatty acid metabolism in male mice

E3 ubiquitin ligase Tripartite motif-containing 47 (TRIM47) is integral in modulating metabolic processes and cellular homeostasis. However, its pivotal role and underlying molecular mechanisms in cardiac ischemia/reperfusion (I/R) injury remain incompletely understood. Here, we show that TRIM47 is markedly upregulated in cardiomyocytes during cardiac I/R injury in an early growth response 1-dependent manner, and that its expression positively correlates with the severity of cardiac I/R injury. Gain- and loss-of-function studies reveal that cardiomyocyte-specific TRIM47 overexpression exacerbates, while TRIM47 knockout attenuates I/R-induced cardiac injury, structural remodeling and functional impairment in vivo and in vitro. Mechanistically, upregulated TRIM47 facilitates K63-linked ubiquitination of forkhead box O1 (FOXO1) at K210 site to induce its nuclear translocation, where it interacts with and inhibits the transcriptional activity of hepatocyte nuclear factor 4 alpha (HNF4α), thereby aggravating mitochondrial dysfunction, fatty acid oxidation defects and cardiac I/R injury. Moreover, therapeutic knockdown of TRIM47 after I/R injury is highly effective in preventing cardiac remodeling and dysfunction. Our findings identify the role of the TRIM47/FOXO1/HNF4α axis in I/R-induced mitochondrial dysfunction, metabolic disorders and cardiac injury, highlighting the therapeutic potential of targeting TRIM47 to treat cardiac I/R injury in male mice.