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

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Long noncoding RNA USP30-AS1 promotes Influenza A Virus replication by enhancing PHB1 function

Veterinary Microbiology, Journal Year: 2025, Volume and Issue: 303, P. 110444 - 110444

Published: Feb. 26, 2025

Language: Английский

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Long noncoding RNAs as potential targets for overcoming chemoresistance in upper gastrointestinal cancers

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 179, P. 117368 - 117368

Published: Aug. 30, 2024

In the last decade, researchers have paid much attention to role of noncoding RNA molecules in human diseases. Among most important these are LncRNAs, which with a length more than 200 nucleotides. LncRNAs can regulate gene expression through various mechanisms, such as binding DNA sequences and interacting miRNAs. Studies shown that may be valuable therapeutic targets treating cancers, including upper-gastrointestinal cancers. Upper gastrointestinal mainly referring esophageal gastric among deadliest Despite notable advances, traditional chemotherapy remains common strategy for However, chemoresistance poses significant obstacle effective treatment upper resulting low survival rate. Chemoresistance arises from events, enhancement efflux detoxification agents, reduction drug uptake, alteration targeting, prodrug activation, strengthening EMT stemness, attenuation apoptosis cancerous cells. Tumor microenvironment also plays an chemoresistance. Interestingly, series studies revealed influence mechanisms associated some aforementioned events serve promising mitigating this review paper, following concise overview we will intriguing findings investigations detail.

Language: Английский

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Identification and Functional Characterization of Alternative Transcripts of LncRNA HNF1A-AS1 and Their Impacts on Cell Growth, Differentiation, Liver Diseases, and in Response to Drug Induction

Non-Coding RNA, Journal Year: 2024, Volume and Issue: 10(2), P. 28 - 28

Published: April 21, 2024

The long non-coding RNA (lncRNA) hepatocyte nuclear factor-1 alpha (HNF1A) antisense 1 (HNF1A-AS1) is an important lncRNA for liver growth, development, cell differentiation, and drug metabolism. Like many lncRNAs, HNF1A-AS1 has multiple annotated alternative transcripts in the human genome. Several fundamental biological questions are still not solved: (1) How really exist samples, such as samples lines? (2) What expression patterns of different at conditions, including during growth after exposure to xenobiotics (such drugs), disease metabolic dysfunction-associated steatotic (MASLD), alcohol-associated (ALD) cirrhosis, obesity? (3) Does siRNA used previous studies knock down one or transcripts? (4) Do have same functions gene regulation? presented data confirm existence several lines, but also identify some new transcripts, which Ensembl genome database. Expression identified highly correlated with differentiation matured hepatocyte-like cells from embryonic stem (hESC), HepaRG cells, response rifampicin induction, various conditions. levels cytochrome P450 enzymes, CYP3A4, induction.

Language: Английский

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METTL3-mediated lncRNA HNF1A-AS1/HNF4A-AS1 m6A modification regulates CYP expression

Drug Metabolism and Disposition, Journal Year: 2024, Volume and Issue: 52(10), P. 1104 - 1114

Published: Aug. 21, 2024

Interindividual variations in the expression and activity of cytochrome P450 enzymes (CYPs) led to lower therapeutic efficacy or adverse drug events. We previously demonstrated that CYPs are regulated by long non-coding RNAs (lncRNAs) HNF1A-AS1 HNF4A-AS1 via transcription factors (TFs) including hepatocyte nuclear factor 1a (HNF1A), 4a (HNF4A), pregnane X receptor (PXR). However, upstream mechanisms regulating poorly understood. N6-methyladenosine (m6A) is a prevalent epi transcriptomic modification mammalian RNA. Therefore, aim this study was investigate whether m6A regulates affects CYP HepG2 Huh7 cells. The methyltransferase-like 3 (METTL3) inhibitor, STM2457, significantly suppressed induced expression. Consistent with this, loss-of-function assay METTL3 cell lines resulted down-regulation its downstream HNF1A, PXR, at RNA level, as well some proteins, up-regulation HNF4A-AS1. results gain-of-function experiments showed opposite trend. Mechanistically, subsequent stability confirmed affected both lncRNAs, but ways; is, reduced increased stability. Rescue regulation on TFs may require involvement these two lncRNAs. Altogether, our demonstrates involved TFs-mediated affecting HNF1A-AS1/HNF4A-AS1 Significance Statement While impact lncRNAs (HNF1A-AS1 HNF4A-AS1) TF studied, remains unexplored. This systematically investigated their (HNF1A, HNF4A, PXR) cells, revealing lncRNA-TF-CYP

Language: Английский

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