Does a REV-ERB Synthetic Agonist Hold Utility as a Protective Agent Against Chemotherapy-Induced Heart Failure?

Abstract

By 2040, the number of cancer survivors in the U.S. is expected to reach an unprecedented 26 million. Doxorubicin (Dox) is a frontline chemotherapy for various cancers, but cardiomyocyte damage is a common side effect. As a result, cancer survivors who received Dox face a 37% higher likelihood of developing heart failure post-treatment, and no therapy can substantially reduce that risk. REV-ERB is a nuclear hormone receptor that plays a critical role in cardiac function, and abundant evidence suggests that increasing its activity may be cardioprotective during chemotherapy treatment. To verify this hypothesis, we examined the clinical potential of a novel REV-ERB agonist, SLU-PP-1799 (1799) in a mouse model of induced cardiomyopathy. C57BL/6 mice were assigned to one of three groups (n = 8/group) and treated for 3 weeks: saline + vehicle (healthy control group), Dox + vehicle, and Dox + 1799. We evaluated the molecular changes associated with Dox-induced heart failure via qPCR. Our results show that 1799 attenuated the Dox-induced inflammatory response through the NLRP3 inflammasome and IL-6 pathway. Additionally, it modulated the Nox4 and Mtck genes, suggesting the possibility of an exercise-mimetic, adaptive response and mitochondrial preservation. These findings not only deepen our understanding of the cardioprotective role of REV-ERB but also highlight a novel therapeutic approach that could improve the quality of life for millions of cancer survivors.