Project Summary/Abstract This application is being submitted in response to the Notice of Special Interest (NOSI) identified as “NOT-CA- 24-044”.The ultimate goal of this proposal is to address a fundamental gap in knowledge on the role of CCNE1 driving metabolism in uterine serous carcinoma (USC). The results from these studies could have a significant impact on the mechanistic understanding of the ~20-30% of USC tumors with CCNE1 amplification. This re- search plan focuses on assessing the homologous recombination (HR) proficiency of CCNE1hi USC and the contribution of nucleocytoplasmic acetyl-CoA metabolism and its associated histone acetylation to this pheno- type. Moreover, they will provide a more global understanding of metabolic reprogramming in CCNE1hi USC and identify novel therapeutic strategies to synergize with standard-of-care DNA damaging chemotherapies. The completion of the scientific aims of this proposal will not only provide new mechanistic insights into the interplay between the acetyl-CoA-mediated metabolic-epigenetic axis in USC, but will also establish targeting metabolism in this highly aggressive disease. The proposed research is of high impact because little is known about molec- ular mechanisms driving CCNEhi USC. Moreover, these studies have the potential to impact the management of CCNEhi USC.