Nrf1 coordinates proteasome and autophagy to maintain cardiac proteostasis

To maintain proteostasis, cardiomyocytes depend on coordinated protein quality control pathways, including the ubiquitin-proteasome system and autophagy. Mechanisms that activate these pathways hold therapeutic potential for heart disease.

Here, we demonstrate that transient activation of nuclear factor erythroid 2–like 1 (Nfe2l1, also known as Nrf1), a transcriptional regulator of proteasome activity, specifically in cardiomyocytes during ischemia/reperfusion (I/R) injury improves cardiac function. In addition to regulating the proteasome, we identify a critical role for Nrf1 in activating autophagy, which is essential for its cardioprotective effects. Through multi-omics analyses, we define both transcriptional and post-transcriptional functions of Nrf1 that underlie its cardioprotective activity.