Retinoic acid protects against lipopolysaccharide-induced ferroptotic liver injury and iron disorders by regulating Nrf2/HO-1 and RARβ signaling.

Acute liver injury (ALI) can progress to severe liver diseases, making its prevention and treatment a focus of research. Retinoic acid (RA) has been shown to have anti-oxidative and iron-regulatory effects on organs. In this study, we investigated the effect of RA on lipopolysaccharide (LPS)-induced ALI in both in vivo and in vitro experiments. We found that RA significantly reduced LPS-induced serum iron and red blood cell-associated disorders, as well as decreased serum ALT and AST levels. RA also reversed the accumulation of non-heme iron and labile iron in LPS-induced mice and hepatocytes by increasing the expression of FTL/H and Fpn. Furthermore, RA inhibited tissue reactive oxygen species (ROS) and malondialdehyde (MDA) production and improved the expression of Nrf2/HO-1/GPX4 in mice and Nrf2 signaling in hepatocytes. In vitro experiments employing RAR agonists and antagonists have revealed that retinoic acid (RA) can effectively inhibit cell ferroptosis induced by lipopolysaccharide (LPS), erastin, and RSL3. The mechanism underlying this inhibition may involve the activation of retinoic acid receptors beta (RARβ) and gamma (RARγ). Knocking down the RARβ gene in Hepatocytes cells significantly diminished the RA's protective effect, indicating that the anti-ferroptotic role of RA was partially mediated by RARβ signaling. Overall, our study demonstrated that RA inhibited ferroptosis-induced liver damage by regulating Nrf2/HO-1/GPX4 and RARβ signaling.