Abstract Body (Do not enter title and authors here): Cancer survivors treated with doxorubicin (Dox) are 37% more likely to develop heart failure post-treatment, highlighting the urgent need for adjuvant therapies. REV-ERB, a nuclear receptor essential for cardiac function, has shown cardioprotective effects through enhanced mitochondrial function. Notably, SR9009, a first-generation REV-ERB agonist, has been found to substantially alleviate cardiac histopathology induced by Dox. However, SR9009 has an extremely poor pharmacokinetic profile and documented off-target effects. Moreover, current understanding is primarily based on histopathological and molecular analyses, leaving ambiguity regarding the relationship between these changes and improvements in cardiac function. To address this, we tested the effects of PEL-007, a novel REV-ERB agonist with improved potency and efficacy, in a mouse model of Dox-induced cardiotoxicity. First, naïve C57BL/6 mice were treated with various doses of PEL-007 for 5 days, and expression of REV-ERB target genes was assessed. Next, to test the effect on mitochondrial function, we performed a Mito Stress Test in neonatal rat ventricular myocytes (NRVMs) treated with PEL-007 or vehicle. Finally, in a mouse model of Dox-induced cardiomyopathy, animals were assigned to saline + vehicle, Dox + vehicle, or Dox + PEL-007 groups (n=8/group), with echocardiography used to assess function pre- and post-treatment. To explore potential mechanisms through which PEL-007 may exert cardioprotection, we compared transcript levels of master transcription factors and rate-limiting enzymes involved in the molecular pathways related to Dox-induced cardiotoxicity via qPCR. Additionally, we performed H&E staining to evaluate tissue-level inflammation. As expected, PEL-007 significantly repressed REV-ERB targets Bmal1 and Nfil3 in a dose-dependent manner, confirming target engagement. Strikingly, beyond all expectations, it also elevated all aspects of the Mito Stress Assay: basal respiration, ATP production, maximal respiration, and spare respiratory capacity (Ps < 0.0005). Unlike the Dox + vehicle group, Dox + PEL-007 mice maintained ejection fraction (P > 0.05). Consistent with functional results, we found a significant elevation of pro-inflammatory transcripts by Dox, which was completely prevented by PEL-007. Taken together, our findings suggest that PEL-007 could safeguard the heart during chemotherapy treatment both on a molecular and a functional level, calling for further exploration.