Aim To explore the mechanism of oxidized lipoprotein(a) (oxLp(a) inducing pyroptosis of vascular endothelial cells. Methods After incubating human umbilical vein endothelial cells (HUVEC) with 100 mg/L oxLp(a) for 24 hours, Western blot and RT-qPCR was used to detect pyroptosis related proteins, pro-inflammatory cytokines, mitochondrial related proteins NRF1, NRF2, PGC-1α and mitochondrial gene cytochrome b (CYTB), ELISA was used to detect the levels of inflammatory factors, scanning electron microscopy was used to detect cell membrane rupture, transmission electron microscopy was used to detect mitochondrial morphology, Hoechst33342/PI staining was used to detect cell apoptosis, MitoSOX probe was used to detect mitochondrial reactive oxygen species (mtROS), Flu-4AM probe was used to detect calcium ions, JC-1 probe was used to detect mitochondrial membrane potential (MMP), and Calcein AM staining was used to detect mitochondrial permeability transition pore (mPTP). Transfecting HUVEC with CYTB overexpressing lentivirus and analyzing its effects on oxLp(a) induced pyroptosis and mitochondrial function. ResultsAfter treatment with oxLp(a), the expression of NLRP3, pro-Caspase-1, Caspase-1, GSDMD and GSDMD-N proteins related to pyroptosis were significantly increased (P＜0.05); the protein and mRNA levels of CYTB and pro-inflammatory cytokine IL-1β, IL-18 were significantly increased (P＜0.05). Small pores appeared on the cell membrane, the percentage of PI stained positive cells significantly increased (P＜0.05). OxLp(a) significantly inhibited the expression of mitochondrial related proteins NRF1, NRF2 and PGC-1α, and the expression of mitochondrial gene CYTB, promoted an increase in mtROS generation, Ca²＋ overload, a decrease in ATP levels, a decrease in MMP, an increase in mPTP values, and abnormal mitochondrial morphology. After transfection with pHelper 2.0 lentivirus vector overexpressing CYTB, it was found that oxLp(a) induced HUVEC pyroptosis and mitochondrial morphological and functional abnormalities were partially reversed by overexpression of CYTB. Conclusion oxLp(a) promotes mitochondrial morphological and functional abnormalities and induces HUVEC pyroptosis by downregulating CYTB.