Heart failure is a leading cause of human mortality and morbidity without a cure. Protein degradation by the ubiquitin-proteasome system (UPS) and the autophagic-lysosomal pathway (ALP) is pivotal to cardiac protein quality control which acts to minimize the level and toxicity of misfolded proteins in cardiomyocytes. Protein quality control inadequacy resulting from UPS and ALP dysfunctions is implicated in the development of heart failure from a variety of heart diseases including pressure overload (PO) disorders. Proteasome inhibition activates ALP while ALP impairment can compromise UPS performance, suggesting an intricate interplay between UPS and ALP dysfunctions. However, such interplay in diseased hearts and its underlying mechanisms remain to be defined. Therefore the long term goal of this research project is to delineate the molecular basis of UPS-ALP crosstalk. Literature and our pilot studies suggest that NRF2 (nuclear factor- erythroid 2-related factor 2) and its target gene p62/SQSTM1 may act as a molecular link in the impairment of UPS performance by ALP insufficiency but this remains to be established in the heart. Hence, we propose to determine the role of the Nrf2-p62 axis in regulating ALP-UPS cross-talk in pressure overloaded hearts. The central hypothesis to be tested is that activation of the Nrf2-p62 axis plays a major mediating role in the impairment of UPS performance by ALP insufficiency in pressure overloaded hearts. We will pursue 2 specific aims. Aim 1 will determine the role of Nrf2 in the induction of cardiac UPS impairment and maladaptive remodeling by ALP impairment in PO hearts. Aim 2 will investigate the molecular mechanism by which Nrf2 exacerbates cardiac injury in ALP insufficient hearts, testing the hypothesis that induction of p62 by Nrf2 impairs UPS performance in ALP deficient hearts. This project will likely provide new mechanistic insight into UPS-ALP interplay in the heart and establish a new concept that enhancing ALP while activating Nrf2 is a better strategy than Nrf2 activation alone for treating heart disease.