Application of multi-omics to reveal the protective mechanism of Portulaca oleracea ethanol extract against alcoholic liver disease in mice

Abstract Portulaca oleracea L. (POL) is widely used Chinese traditional edible and medicinal plant, which has been proved having potential benefits to multiple diseases, including liver disease. However, its mechanism of action with alcoholic liver disease (ALD) remains incompletely understood. The aim of this study was to elucidate the regulatory relationship with POL alcohol extract (POE) to ALD in mice. The findings showed that POE could effectively lower the rise in alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), malondialdehyde (MDA), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels brought on by alcohol use. Meanwhile, POE maintained high-density lipoprotein cholesterol (HDL-C), superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) levels, and alleviated the impact of alcohol induced edema, necrosis, and fatty deformation of liver tissue. According to RNA-seq and proteomics data, POE reversed 288 genes and 49 proteins that were up-regulated and 140 genes and 39 proteins that were down-regulated because of alcohol consumption. Among them, 16 targets were co-regulated, and most of them were linked to ferroptosis, endoplasmic reticulum (ER) stress, lipid metabolism and inflammation. Furthermore, the mRNA and protein levels of seven targets associated with ferroptosis and fatty acid oxidation, serine (or cysteine) peptidase inhibitor, clade A, member 3N (Serpin3n), haptoglobin (Hp), leucine-rich α-2-glycoprotein 1 (Lrg1), lipocalin 2 (Lcn2), DnaJ heat shock protein family member B9 (Dnajb9), acyl-CoA synthetase long-chain family member 4 (Acsl4) and cytochrome P450, family 8, subfamily b, polypeptide 1 (Cyp8b1), were validated, and the results consistent with the omics analysis. Overall, this research uncovers the mechanisms that underlie POE’s protective benefits against alcohol-induced liver damage are related with POE’s ability to inhibition of inflammation, ferroptosis and oxidative stress in the liver and to modulate lipid oxidation, identifies POE as a successful ALD treatment as well as discerns the key therapeutic targets.