EPIC-1042 alleviates cerebral ischemic/reperfusion injury through TAX1BP1-induced mitophagy

Abstract

Post ischemia-reperfusion (I/R) injury, an upregulation in Polymerase I and transcript release factor (PTRF) expression is observed. PTRF is implicated in the regulation of various cellular processes within neuronal cells, thereby exacerbating the deleterious effects of I/R injury. EPIC-1042 is a small molecule pharmacological agent that exhibits specificity in binding to PTRF. Therefore, this study aimed to explore whether EPIC-1042 could be used as a treatment for I/R injury. To achieve this goal, we observed brain injury in mice following EPIC-1042 pre-administration, and then transitioned to therapeutic administration. After observing the pre-protective and therapeutic effects of the drug, proteomic analysis revealed that the expression of TAX1BP1 continued to decline in a time-dependent manner, while EPIC-1042 was able to inhibit this decline. However, the function of TAX1BP1 in ischemic stroke is not yet fully understood. Subsequent experiments confirmed that the addition of EPIC-1042 resulted in an enhancement of mitophagy. Silencing the expression of TAX1BP1 abrogated the drug's effects, indicating that EPIC-1042 exerts a protective function by promoting mitophagy via TAX1BP1 mediation. We further investigated the synergistic effects of EPIC-1042 and edaravone by administering the two drugs in combination, observing an enhanced therapeutic efficacy compared to the administration of each drug alone. Subsequently, we optimized the administration protocol for the two drugs by utilizing liposome encapsulation for both drugs. This approach enabled us to achieve significant therapeutic outcomes while reducing both the dosage and frequency of administration, thereby demonstrating the potential for clinical translation of EPIC-1042.