PCSK9 inhibitor cooperatively with high triglyceride induces adverse pregnancy outcomes by impairing mitochondrial function

The two monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9), namely evolocumab and alirocumab, were first approved by the U.S. Food and Drug Administration (FDA) in 2015. PCSK9 inhibitor (PCSK9i) has served as a viable new therapeutic option to lower cholesterol levels and associated cardiovascular events. However, a better understanding of safety issue of PCSK9i is necessarily needed. We present here an increased risk of adverse pregnancy outcomes, including stillbirths and embryonic defects, particularly neural tube defects, following PCSK9i treatment harnessing a high-fat diet-based mouse model. Proteomics of PCSK9i-treated neural stem cells uncovered that PCSK9i may disrupt mitochondrial function via succinic dehydrogenase complex subunit A (SDHA), which is a key enzyme in the mitochondrial respiratory chain. Furthermore, PCSK9i-induced SDHA deficiency combines with high triglyceride to drive the production of reactive oxygen species and subsequent apoptosis during embryonic development, which may account for the occurrence of adverse pregnancy outcomes. Our findings reveal the existence of a hitherto unknown risk of PCSK9i in pregnant women, as well as novel gene-environment interaction.