Targeting MRP4 in drug resistance and aspirin treatment failure: implications for precision medicine

Aspirin is widely used as an antiplatelet therapy for preventing and managing thrombotic complications in individuals at high risk. Nevertheless, growing evidence indicates that some patients continue to face cardiovascular events, suggesting impaired drug responsiveness or reduced sensitivity to aspirin. This review primarily aims to elucidate a new emerging molecular mechanism underlying this clinical outcome. Recent studies propose that aspirin induces PPARα-dependent overexpression of the Multidrug Resistance Protein 4 (MRP4) transporter, leading to increased extrusion of aspirin and reduced drug efficacy. Several findings support this mechanism: i) MRP4 is associated with resistance to several drugs; ii) it is highly expressed in platelets, which are notably affected by aspirin; iii) it transports organic anions such as aspirin, which has been demonstrated to be a substrate; and iv) aspirin enhances PPARα activity, leading to higher MRP4 gene transcription. Consequently, inhibition of MRP4-mediated aspirin efflux may enhance pharmacological efficacy and prevent platelet aggregation. This review also highlights the potential role of lifelong monitoring in patients on aspirin therapy using platelet function tests to identify those with high residual platelet reactivity (RPR) despite treatment. Such monitoring helps detect inadequate antiplatelet response, guiding clinicians in selecting the most appropriate and personalised therapy, thereby optimising treatment efficacy and reducing the risk of recurrent thrombosis. In conclusion, combining an MRP4 inhibitor with aspirin may represent a promising therapeutic strategy to overcome resistance mechanisms and improve clinical outcomes in patients who exhibit RPR on aspirin and MRP4 overexpression.