miR-144 is the epigenetic target for emodin to ameliorate oxidative stress induced by dietary oxidized fish oil via Nrf2 signaling in Wuchang bream, Megalobrama amblycephala

Oxidative stress caused by external stressors could induce severe cellular and tissue injury, even induce immune impairment or unexpected death. This study was aimed to uncover the underlying epigenetic mechanism of miRNAs in response to oxidative stress under emodin stimulation in Megalobrama amblycephala intestine. RNA sequencing reveals 60 differentially expressed genes (DEGs) under oxidative stress were mainly function in metabolic, intestinal inflammation, and virus defense signaling. mRNA-miRNA co-expression networks reveal dynamically regulated miRNAs by oxidative stress to be largely embedded in energy metabolism, oxidative homeostasis, cell apoptosis and cancerization signaling. Specifically, PI3K-Akt, focal adhesion, MAPK, and Nrf2Keap1 signaling were dysregulated by miR-144, miR-155, and miR-200a. Binding site prediction shown miR-144 inhibits Nrf2, miR-155 inhibits PI3K and Bach1, and miR-200a inhibits MAPK1 and Keap1 by targeting to their 3'-UTR. Mechanistically, miR-144 was solidly confirmed as the negative regulator of Nrf2 by dual luciferase reporter assay. With qRT-PCR analysis, we found emodin alleviates oxidative stress through activating miR-144, miR-155, and miR-200a expression and subsequently downregulating the PI3K-Akt, MAPKs, and Nrf2-Keap1 pathway at the post-translational level. Herein, the epigenetic schematic indicates miR-144, miR-155, and miR-200a are target miRs for emodin to resist oxidative stress along with MAPKs, PI3K-Akt, and Nrf2-Keap1 signaling. Taken together, our findings suggest that miR-144/Nrf2 could serve as genetic modifiers of nutrient-related injury stress and could provide novel insights into the therapeutic effects of emodin on oxidized lipid induced oxidative stress in M. amblycephala.

Automated summary

In response to oxidative stress, miR-144, miR-155, and miR-200a play key roles in regulating metabolic, inflammatory, and immune response signaling pathways in the intestine of Megalobrama amblycephala. They alleviate oxidative stress-induced damage by targeting Nrf2, PI3K, MAPK, and Keap1, providing potential therapeutic targets for oxidative stress-related injuries and offering insights into the effects of emodin in combating oxidized lipid-induced oxidative stress.