This study investigates the endothelial protective activity of flavokawain A (FKA) against
oxidative stress induced by ochratoxin A (OTA), which acts as a mycotoxin, and its primary mecha-
nisms in in vitro models. Reactive oxygen species, in general, regulate oxidative stress that signifi-
cantly contributes to the pathophysiology of endothelial dysfunctions. OTA exerts toxicity through
inflammation and the accumulation of ROS. This research is aimed at exploring the defensive function
of FKA against the endothelial injury triggered by OTA through the Nrf2 pathway regulated by
PI3K/AKT. OTA exposure significantly increased the nuclear translocation of NFκB, whereas we
found a reduction in inflammation via NFκB inhibition with FKA treatment. FKA increased the PI3K
and AKT phosphorylation, which may lead to the stimulation of antioxidative and antiapoptotic
signaling in HUVECs. It also upregulated the phosphorylation of Nrf2 and a concomitant expression
of antioxidant genes, such as HO-1, NQO-1, and γGCLC, depending on the dose under the oxidative
stress triggered by OTA. Knockdown of Nrf2 through small interfering RNA (siRNA) impedes the
protective role of FKA against the endothelial toxicity induced by OTA. In addition, FKA enhanced
Bcl2 activation while suppressing apoptosis marker proteins. Therefore, FKA is regarded as a po-
tential agent against endothelial oxidative stress caused by the deterioration of the endothelium.
The research findings showed that FKA plays a key role in activating the p-PI3K/p-AKT and Nrf2
signaling pathways, while suppressing caspase-dependent apoptosis.