Deficiency in Inactive Rhomboid Protein2 (iRhom2) Alleviates Alcoholic Liver Fibrosis by Suppressing Inflammation and Oxidative Stress.

ABSTRACT: Chronic alcohol exposure can lead to liver pathology relating to inflammation and oxidative stress, which are two of the major factors in the incidence of liver fibrosis and even liver cancer. The underlying molecular mechanisms regarding hepatic lesions associated with alcohol are not fully understood. Considering that the recently identified iRhom2 is a key pathogenic mediator of inflammation, we performed in vitro and in vivo experiments to explore its regulatory role in alcohol-induced liver fibrosis. We found that iRhom2 knockout significantly inhibited alcohol-induced inflammatory responses in vitro, including elevated expressions of inflammatory cytokines (IL-1β, IL-6, IL-18, and TNF-α) and genes associated with inflammatory signaling pathways, such as TACE (tumor necrosis factor-alpha converting enzyme), TNFR1 (tumor necrosis factor receptor 1), and TNFR2, as well as the activation of NF-κB. The in vivo results confirmed that long-term alcohol exposure leads to hepatocyte damage and fibrous accumulation. In this pathological process, the expression of iRhom2 is promoted to activate the TACE/NF-κB signaling pathway, leading to inflammatory responses. Furthermore, the deletion of iRhom2 blocks the TACE/NF-κB signaling pathway and reduces liver damage and fibrosis caused by alcohol. Additionally, the activation of the JNK/Nrf2/HO-1 signaling pathway caused by alcohol exposure was also noted in vitro and in vivo. In the same way, knockout or deleting iRhom2 blocked the JNK/Nrf2/HO-1 signaling pathway to regulate the oxidative stress. Therefore, we contend that iRhom2 is a key regulator that promotes inflammatory responses and regulates oxidative stress in alcoholic liver fibrosis lesions. We posit that iRhom2 is potentially a new therapeutic target for alcoholic liver fibrosis.

SUBMITTER: Liu Y 

PROVIDER: S-EPMC9317380 | biostudies-literature |

REPOSITORIES: biostudies-literature