Abstract <p>Myocardial infarction (MI) is a leading global health issue with high morbidity and mortality. It is primarily triggered by thrombosis and often complicated by unpredictable events such as hemorrhage, ischemia-reperfusion injury, and coronary restenosis. A series of cellular and molecular events, including apoptosis, autophagy, inflammation, and ferritin deposition, are involved in the pathogenesis of acute MI. Therefore, a more comprehensive understanding of the molecular mechanisms is crucial for identifying novel therapeutic targets and developing more effective strategies for the prevention and treatment of MI. The Toll-like receptor (TLR) family plays a critical role in both innate and adaptive immune responses and is a key component of the first line of defense against microbial infections. Bioinformatic and experimental evidence suggests that activation of the TLR2-TLR4 signaling axis is essential in mediating the inflammatory response following MI. Furthermore, bioinformatics analysis has revealed that DUX4 acts as a shared transcriptional regulator of TLR2 and TLR4 in MI. This study demonstrates that the expression of TLR2 and TLR4 can be mediated by DUX4. Animal experiments show that DUX4 enhances cardiac function in MI mice by regulating TLR2 and TLR4 expression and inhibiting lipid metabolic signaling pathways.</p>