Ufmylation Suppresses Unfolded Protein Response to Prevent Peripartum Cardiomyopathy

Ufmylation is a novel ubiquitin-like protein modification that plays a critical role in maintaining the homeostasis of different tissues, but its role in the heart remains poorly understood. Here, we showed that mice lacking UFM1 ligase 1 (UFL1), an enzyme essential for ufmylation, in the heart developed peripartum cardiomyopathy. Loss of UFL1 reversed pregnancy-induced adaptive cardiac transcriptome alterations. Moreover, loss of UFL1 triggered excessive endoplasmic reticulum stress, inhibited mitochondrial oxidative metabolism, and caused augmented mTOR signaling, leading to pronounced pathological remodeling and heart failure. These results demonstrate that ufmylation is essential for physiological cardiac remodeling and that disruption of ufmylation predisposes the heart to peripartum cardiomyopathy.