3.3.3 Antiferroptosis may be a new target for hypertension treatment in the future
Nrf2 can activate the transcription of target antioxidant genes and play a key role in the oxidation reduction reaction regulation of hypertension95. Studies have found that inhibiting Nrf2 can promote oxidative stress and inflammation, and further aggravate hypertension in mice96. On the contrary, it promoted Nrf2 signaling pathway transduction and alleviated renal ferroptosis and lipid peroxidation in hypertensive state97. It was also found that activation of Nrf2 inhibited the progression of hypertension in hypertensive mice 12-14 days after infusion of Ang II98 . At present, studies on Nrf2 in the development and progression of hypertension are limited. Whether Nrf2 can protect hypertension by regulating related mechanisms to inhibit ferroptosis needs more research to determine.
It was also found that ferrostatin-1 administration could reverse the ferroptosis of VSMCs induced by high hydrostatic pressure7, while also significantly ameliorating hypertension and endothelial ferroptosis induced by lenvatinib in mice13 . This suggests that ferrostatin-1 may alleviate hypertension by inhibiting ferroptosis of VSMCs and endothelial cells, but it has not been applied in the clinic so far, and more in-depth and comprehensive research exploration of ferrostatin-1 is needed to ensure its safety and efficacy.
Elabela (ELA) is a novel endogenous ligand of the Apelin receptor (APJ) that regulates oxidative stress and plays a protective role in cardiovascular and cerebrovascular diseases. Zhang et al89. found that ELA could significantly inhibit the up-regulation of iron levels and lipid peroxidation in Ang II-induced hypertensive mice. Further studies found that ELA inhibited cardiac microvascular endothelial cell ferroptosis by regulating the IL-6/STAT3/GPX4 signaling pathway. It has also been shown that ELA binds to APJ and alleviates neuronal ferroptosis after ischemic stroke by activating antioxidant signaling pathways99. The above studies suggest that ELA inhibition of the ferroptosis pathway has a certain potential in the treatment of hypertension and cardiovascular and cerebrovascular diseases, which needs further clinical and basic experiments to verify.