Lactate Dehydrogenase A Is a Novel Positive Regulator of Vascular Smooth Muscle Cell Ferroptosis During Aortic Dissection

<b><i>Aims:</i></b> Vascular smooth muscle cell (VSMC) ferroptosis is a pivotal event in the process of aortic dissection (AD), and a number of agents have a protective role against AD by inhibiting VSMC ferroptosis. While glycolysis is an ancient pathway related to almost all biological processes, its precise involvement in VSMC ferroptosis and AD remains unclear. <b><i>Results:</i></b> In this study, bioinformatics analysis revealed that glycolysis-related molecules and pathways were involved in VSMC ferroptosis and AD. We focused on the key enzyme of glycolysis, lactate dehydrogenase A (LDHA), and found that LDHA overexpression promoted ferroptosis and lipid peroxidation in cystine deprivation- or imidazole ketone erastin-treated VSMCs and vice versa. Clinical specimens showed a negative correlation between elevated LDHA levels in dissected aortae and ferroptosis-related molecules glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), and ferroptosis suppressor protein 1 (FSP1). In VSMC ferroptosis, LDHA overexpression led to the suppression of GPX4, SLC7A11, and FSP1. Furthermore, the interaction between LDHA and nuclear factor (erythroid-derived 2)-like 2 (NRF2) was identified, and the overexpression or agonist of NRF2 reversed the contribution of LDHA on VSMC ferroptosis and lipid peroxidation. <b><i>Innovation and Conclusion:</i></b> These results highlight a significant association between LDHA and VSMC ferroptosis in AD development mediated through NRF2. These findings present LDHA as a potential target for AD intervention by inhibiting its expression. <i>Antioxid. Redox Signal.</i> 42, 378-392.