Alterperylenol as a Novel Thioredoxin Reductase Inhibitor Induces Liver Cancer Cell Apoptosis and Ferroptosis.

Natural products are a rich resource for discovering innovational drugs. Herein, we isolated and characterized two compounds dihydroalterperylenol (DAP) and alterperylenol (AP) from Alternaria sp. MG1, an endophytic fungus isolated from Vitis quinquangularis, and investigated the underlying antitumor mechanism of AP. Mechanistically, AP inhibits the growth of HepG2 cells by targeting the selenoprotein thioredoxin reductase (TrxR) and ultimately induces cell apoptosis and ferroptosis. Compared to DAP, the α,ß-unsaturated carbonyl structure of AP is an indispensable moiety for its antitumor activity and TrxR inhibition. Specifically, inhibition of TrxR causes the extensive reactive oxygen species and consequently results in DNA damage, G2/M cell cycle arrest, and mitochondrial fission. Furthermore, ferroptosis is driven via excess toxic lipid peroxidation and elevation of intracellular iron levels via regulating iron-related proteins. In vivo validation also shows that AP owns anticancer activity in xenograft mice. Collectively, our results disclose a novel natural TrxR inhibitor AP exerting the antitumor effect via inducing cell apoptosis and ferroptosis and evidence that AP is a promising candidate agent for liver carcinoma therapy. The link of TrxR inhibition to ferroptosis further highlights the physiological importance of TrxR in regulating ferroptosis.