Formononetin Inhibits Hepatic I/R-Induced Injury through Regulating PHB2/PINK1/Parkin Pathway

Abstract

Formononetin (FN), an isoflavone compound mainly isolated from soy and red clover, had showed its anti-inflammation, antioxidative effects in some degenerative diseases and cholestasis. However, the role of FN in protecting ischemia/reperfusion- (I/R-) induced liver injury and the possible mechanism were unclear. In this study, effects of FN on liver injury were investigated in a rat hepatic I/R model; further, mitophagy-related proteins were measured by immunoblotting or immunofluorescence. The possible roles of PHB2 and PINK1 in regulating mitophagy by FN were verified using adeno-associated virus knockdown. The results showed that FN had protective effects against hepatic I/R injury through regulating PINK1/Parkin-regulated mitophagy. Further, we found that FN inhibited PARL expression and prevented PGAM5 cropped by increasing the expression of PHB2. The knockdown of PINK1 or PHB2 both abolished the protective effects of FN. Taken together, our findings indicated that the isoflavone compound FN promoted PHB2/PINK1/Parkin-mediated mitophagy pathway to protect liver from I/R-induced injury. These results provided novel insights into the potential prevention strategies of FN and its underlying mechanisms.

Potential mechanisms of formononetin against inflammation and oxidative stress: a review

“…FMNT may reduce oxidative stress in liver disease, showing hepatoprotective potential. Mitochondrial dysfunction produces excess ROS, while FMNT promoted PHB2/PINK1/Parkin-mediated mitophagy pathway, reduced the production of ROS and then alleviated ischemia/reperfusion-induced liver injury (Ma et al, 2022). The H 2 O 2 molecule is a precursor of free radicals that can cause cell death (Halliwell, 1989).…”

“…Another study revealed that FMNT was able to elevate levels of SOD, CAT and GSH-Px in db/db mice, alleviating diabetic nephropathy (Lv et al, 2020). Studies of ischemia reperfusion showed apparent roles of FMNT in improving the activities of CAT, SOD and GSH-Px, and relieved damage of the cell membrane and increase in permeability evoked by superfluous oxygen-free radicals (Zhao et al, 2021;Ma et al, 2022). Except for ischemia-reperfusion, oxidative stress caused by overproduction of ROS and depletion of antioxidants in the defense system has also been implicated in the pathogenesis of acute myocardial infarction (AMI).…”

Molecular Factors and Pathways of Hepatotoxicity Associated with HIV/SARS-CoV-2 Protease Inhibitors

“…Alcoholic extracts of lotus leaves, rich in flavonoids, have the potential to treat dyslipidemia in rats treated with LPV and RTV [155]. Third, the red clover isoflavones, formononetin, and biochanin A were shown to modulate NFκB/pAkt signaling molecules and protect against RTV-induced hepatotoxicity in in vivo animals [73,156,157]. Some flavonoids, such as quercetin, not only protect against drug-induced hepatotoxicity but are also effective as antiparasitic and anti-HIV/SARS-CoV-2 agents [158].…”