Neuraminidase 1 Exacerbated Glycolytic Dysregulation and Cardiotoxicity by Destabilizing SIRT1 through Interactions with NRF2 and HIF1α

Despite significant therapeutic advances, cumulative DOX-induced cardiotoxicity (DIC) events remain unacceptably high. Recent evidence has underscored the critical role of impaired glycolytic metabolism in cardiovascular damage. Neuraminidase 1 (NEU1), a member of the neuraminidase family, catalyzes the hydrolysis of terminal sialic acids from glycoconjugates. Here, it is aimed to characterize the role of NEU1 on defective glycolysis during DIC. Mouse models with cardiac-specific genetic modifications of Neu1, Nrf2, and SIRT1 underwent functional analyses, and RNA Sequencing to clarify NEU1's role in glycolytic metabolism during DIC. It is discovered that NEU1 is highly expressed after DOX exposure and positively correlated with defective glycolysis phenotypes. Cardiomyocyte-specific deficiency of Neu1 ameliorated impaired glycolytic metabolism and DIC, whereas overexpression of Neu1 in cardiomyocytes exacerbated these pathological phenotypes. Mechanistically, the upregulation of Neu1 is attributed to HIF1α's transcriptional repression, which necessitated the collaboration of NRF2. Additionally, the C-terminal region of NEU1 physically interacted with SIRT1, facilitating its lysosomal-mediated degradation and contributing to the aberrant glycolytic phenotype. The pharmacological or genetic manipulation of NRF2 and HIF1α remarkably abolished DOX-induced NEU1 upregulation, compromised glucose metabolism, and DIC progression. Collectively, NEU1 as a key regulator of cardiac glycolysis is established, offering new therapeutic avenues for DIC through maintaining metabolic flexibility.

cardiotoxicity; doxorubicin; glycolysis; metabolic homeostasis; neuraminidase 1.