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The Spike Protein of SARS-CoV-2 Impairs Lipid Metabolism and Increases Susceptibility to Lipotoxicity: Implication for a Role of Nrf2


Coronavirus disease 2019 (COVID-19) patients show lipid metabolic alterations, but the
mechanism remains unknown. In this study, we aimed to investigate whether the Spike protein of
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) impairs lipid metabolism in
host cells. We generated a Spike cell line in HEK293 using the pcDNA vector carrying the Spike
gene expression cassette. A control cell line was generated using the empty pcDNA vector. Gene
expression profiles related to lipid metabolic, autophagic, and ferroptotic pathways were
investigated. Palmitic acid (PA)-overload was used to assess lipotoxicity-induced necrosis. As
compared with controls, the Spike cells showed a significant increase in lipid depositions in cell
membranes as well as dysregulation of expression of a panel of molecules involving lipid
metabolism, autophagy, and ferroptosis. The Spike cells showed an upregulation of nuclear
factor erythroid 2-related factor 2 (Nrf2), a multifunctional transcriptional factor, in response to
PA. Furthermore, the Spike cells exhibited increased necrosis in response to PA-induced
lipotoxicity compared to control cells in a time- and dose-dependent manner via ferroptosis,
which could be attenuated by the Nrf2 inhibitor trigonelline. We conclude that the Spike protein
impairs lipid metabolic and autophagic pathways in host cells, leading to increased susceptibility
to lipotoxicity via ferroptosis which can be suppressed by a Nrf2 inhibitor. This data also
suggests a central role of Nrf2 in Spike-induced lipid metabolic impairments.