Alternative splicing: hallmark and therapeutic opportunity in metabolic liver disease DOI Creative Commons

Mingqian Jiang,

Saleh A. Alqahtani,

Wai‐Kay Seto

et al.

Gastroenterology report, Journal Year: 2025, Volume and Issue: 13

Published: Jan. 1, 2025

Abstract Metabolic dysfunction-associated fatty liver disease (MAFLD) has become the leading cause of chronic worldwide, with fibrosis recognized as main prognostic factor and therapeutic target. While early-stage is reversible, advanced poses a significant clinical challenge due to limited treatment options, highlighting need for innovative management strategies. Recent studies have shown that alternative pre-mRNA splicing, critical mechanism regulating gene expression protein diversity, plays fundamental role in pathogenesis MAFLD associated fibrosis. Understanding complex relationship between splicing progression could pave way novel approaches improve outcomes. In this review, we describe intricate mechanisms MAFLD. Specifically, explored pivotal factors, RNA-binding proteins, their interactions metabolic epigenetic regulators. Furthermore, provide an overview latest advancements splicing-based strategies biomarker development. Particular emphasis placed on potential application antisense oligonucleotides rectifying anomalies, thereby laying foundation precision medicine MAFLD-associated

Language: Английский

High inherited risk predicts age-associated increases in fibrosis in patients with MASLD DOI
Luis Antonio Díaz, William Alazawi, Saaket Agrawal

et al.

Journal of Hepatology, Journal Year: 2025, Volume and Issue: unknown

Published: May 1, 2025

Language: Английский

Citations

1
Subtypes of MASLD confer distinct clinical trajectories DOI
Panu K. Luukkonen

Journal of Hepatology, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Language: Английский

Citations

0
Identification of Novel Therapeutic Targets for MAFLD Based on Bioinformatics Analysis Combined with Mendelian Randomization DOI Open Access

Jia-Lin Ren,

Min Wu

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(7), P. 3166 - 3166

Published: March 29, 2025

Metabolic-associated fatty liver disease (MAFLD) is a chronic condition with limited therapeutic options. To identify novel drug targets, we integrated bioinformatics, Mendelian randomization (MR), and colocalization analyses. Using the Gene Expression Omnibus (GEO) database, identified differentially expressed genes constructed protein–protein interaction (PPI) networks, pinpointing 10 hub genes. MR analyses revealed that Ubiquitin-like PHD ring finger domains 1 (UHRF1) causally associated MAFLD driven by same causal variant locus, suggesting its potential as target. Molecular docking disogenin candidate small-molecule targeting UHRF1. Drug affinity responsive target stability (DARTS) assays confirmed direct binding between UHRF1 disogenin. In vitro, significantly reduced mRNA protein levels induced free acids (FFA) in AML12 HepG2 cells, accompanied decreased cellular total cholesterol (TC) triglyceride (TG) levels. vivo, administration alleviated hepatic lipid accumulation, inflammation, fibrosis methionine/choline-deficient (MCD)-diet-fed mice. This study identifies promising for validates agent, providing foundation further investigation.

Language: Английский

Citations

0
MRI Provides New Insights Into the Pharmacologic Mechanism of Bisacodyl: A Blueprint for Understanding Intestinal Drug Mechanisms DOI
Kathleen M. Giacomini

Clinical Pharmacology & Therapeutics, Journal Year: 2025, Volume and Issue: 117(5), P. 1159 - 1161

Published: April 12, 2025

Language: Английский

Citations

0
Experimental Models to Investigate PNPLA3 in Liver Steatosis DOI
Alireza Ramandi,

Anna‐Mae Diehl,

Danny Issa

et al.

Liver International, Journal Year: 2025, Volume and Issue: 45(5)

Published: April 15, 2025

ABSTRACT Patatin‐like phospholipase domain‐containing 3 (PNPLA3) was the first gene identified through genome‐wide association studies to be linked hepatic fat accumulation. A missense variant, encoding PNPLA3‐148M allele, has since been shown increase risk for full spectrum of steatotic liver disease (SLD), from simple steatosis steatohepatitis, cirrhosis, and hepatocellular carcinoma. Despite extensive validation this ongoing research into its pathogenic role, precise mechanisms by which contributes progression SLD remain poorly understood. In review, we evaluate preclinical in vitro vivo models used investigate PNPLA3 involvement SLD, with particular emphasis on metabolic dysfunction‐associated disease. We assess strengths limitations these models, as well challenges arising species differences expression function between human murine systems.

Language: Английский

Citations

0
Gene-based therapies for steatotic liver disease DOI Creative Commons
Viktoriia Iakovleva, Ype P. de Jong

Molecular Therapy, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Language: Английский

Citations

0
Polygenic Risk Score for Metabolic Dysfunction-Associated Steatotic Liver Disease and Steatohepatitis: A Narrative Review DOI Open Access
Tatsuo Kanda, Reina Sasaki, Hiroyuki Abé

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(11), P. 5164 - 5164

Published: May 28, 2025

Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic steatohepatitis (MASH) are spreading worldwide as the most critical causes of cirrhosis hepatocellular carcinoma (HCC). Thus, improving screening managing strategies for patients with MASLD or MASH is necessary. A traditional non-systemic review provided this narrative. Genetic variations associated development MASH, such PNPLA3, TM6SF2, GCKR, MBOAT7, MERTK, HSD17B13, were initially reviewed. PNPLA3 genetic variants appeared to be strongly increased pathogenesis MASLD, cirrhosis, HCC. We also reviewed useful polygenic risk score (PRS) their related occurrence PRSs better predictors HCC in than any single-nucleotide polymorphisms. RNA interference antisense nucleotides against HSD17B13 being developed. Multidisciplinary collaboration cooperation involving hepatologists, geneticists, pharmacologists, pathologists should resolve complicated problems MASH. This narrative highlights importance susceptibility PRS predictive markers personalized medicine future.

Language: Английский

Citations

0
Alternative splicing: hallmark and therapeutic opportunity in metabolic liver disease DOI Creative Commons

Mingqian Jiang,

Saleh A. Alqahtani,

Wai‐Kay Seto

et al.

Gastroenterology report, Journal Year: 2025, Volume and Issue: 13

Published: Jan. 1, 2025

Abstract Metabolic dysfunction-associated fatty liver disease (MAFLD) has become the leading cause of chronic worldwide, with fibrosis recognized as main prognostic factor and therapeutic target. While early-stage is reversible, advanced poses a significant clinical challenge due to limited treatment options, highlighting need for innovative management strategies. Recent studies have shown that alternative pre-mRNA splicing, critical mechanism regulating gene expression protein diversity, plays fundamental role in pathogenesis MAFLD associated fibrosis. Understanding complex relationship between splicing progression could pave way novel approaches improve outcomes. In this review, we describe intricate mechanisms MAFLD. Specifically, explored pivotal factors, RNA-binding proteins, their interactions metabolic epigenetic regulators. Furthermore, provide an overview latest advancements splicing-based strategies biomarker development. Particular emphasis placed on potential application antisense oligonucleotides rectifying anomalies, thereby laying foundation precision medicine MAFLD-associated

Language: Английский

Citations

0