Role of HNF4A-AS1/HNRNPC-mediated HNF4A Ubiquitination Protection against Ritonavir-induced Hepatotoxicity

Molecular Pharmacology, Journal Year: 2025, Volume and Issue: 107(3), P. 100021 - 100021

Published: Feb. 7, 2025

Ritonavir (RTV) is an important drug for anti-human immunodeficiency virus treatment and mainly metabolized by cytochrome P450 (CYP) 3A4. Clinically, the most common side effect of RTV hepatoxicity. We previously showed that long noncoding RNA hepatocyte nuclear factor 4 alpha (HNF4A) antisense 1 (HNF4A-AS1) negatively regulated CYP3A4 expression participated in RTV-induced hepatotoxicity vitro, but mechanism has not been well understood. In this study, similar results were observed mouse, where liver-specific knockdown Hnf4aos (homolog human HNF4A-AS1) led to increased serum aspartate (∼1.8-fold) alanine transaminase (∼2.4-fold) levels enlarged degenerated hepatocytes 24 hours after administration. Meanwhile, endoplasmic reticulum stress markers GRP78, PDI, XBP-1 about 2.4-fold, 2.1-fold, 2.7-fold, respectively. The aggravated liver injury correlated with knockdown, attributable heightened Cyp3a11 CYP3A4) (mRNA protein 1.8-fold 2.5-fold, respectively). Importantly, vitro studies revealed underlying HNF4A-AS1 mediated interaction between heterogeneous ribonucleoprotein C HNF4A, whereas promoted HNF4A degradation through ubiquitination pathway, thereby decreasing alleviating injury. Overall, our findings unveil a novel which regulates influence SIGNIFICANCE STATEMENT: CYP3A4, whose overexpression highly ritonavir (RTV)-induced role was confirmed mice. found HNRNPC form complex facilitate protein, hepatotoxicity.

Language: Английский

m6A-modified LINC02418 induces transcriptional and post-transcriptional modification of CTNNB1 via interacting with YBX1 and IGF2BP1 in colorectal cancer

Cell Death Discovery, Journal Year: 2025, Volume and Issue: 11(1)

Published: March 13, 2025

Abstract Colorectal cancer (CRC) represents a significant menace to human health, but its molecular pathogenesis remains unclear. Herein, we explored the functional role of LINC02418 in CRC progression. The function was determined through vitro and vivo experiments. mechanism by quantitative real-time PCR (qPCR) analyses, western blot, luciferase reporter assay, methylated RNA immunoprecipitation (MeRIP) pull-down, (RIP) assay chromatin (ChIP) assay. results revealed that expression upregulated tissues high related unfavorable survival patients. Besides, knockdown resulted inhibition proliferation metastasis cells vivo. Mechanistically, found METTL3-mediated m6A modification induced aberrant CRC. could interact with YBX1 enhance DNA-binding ability CTNNB1 promoter, resulting transcriptional activation CTNNB1. In post-transcriptional stage, also stability promoting interaction between IGF2BP1 protein mRNA. What is more, be transcriptionally enhanced protein. Collectively, this study unveils novel oncogenic for might therapeutic target treatment.

Language: Английский