Epigenetic antifibrotic effect of expression of long non-coding RNAs GAS5, MEG8, FLRL2 on the development of fibrosis in metabolic dysfunction-associated steatotic liver disease: systematic review

Abstract

Background. Metabolic dysfunction-associated steatotic liver disease (MASLD) — and its progressive inflammatory stage, metabolic dysfunction-associated steatohepatitis (MASH) — has emerged as one of the most frequent causes of liver fibrosis. In the context of MASLD, fibrogenesis is governed by a highly complex interplay of intracellular signaling pathways that are epigenetically modulated by long non-coding RNAs (lncRNAs). The purpose was to systematically evaluate the epigenetic impact of reduced expression of antifibrotic lncRNAs (GAS5, MEG8, FLRL2) on the development and progression of liver fibrosis in MASLD/MASH, with emphasis on key profibrotic signalling pathways ((PI3K/Akt, Wnt/β-catenin, Notch, Arntl/Sirt1) and therapeutic perspectives. Materials and methods. This systematic review was conducted and reported in accordance with the PRISMA 2020 statement (PROSPERO registration CRD420250652980). A comprehensive search of PubMed, Cochrane Library, Scopus, Embase, and Web of Science (2010–2026) was performed using predefined Boolean strings. Original clinical, animal, and in vitro studies that demonstrated reduced expression of the target antifibrotic lncRNAs and their association with increased fibrosis or hepatic stellate cell activation in established MASLD/MASH models or human cohorts were included. Two independent reviewers performed study selection, data extraction, and risk-of-bias assessment (SYRCLE for animal studies, ROBINS-I for observational clinical studies, modified OHAT for in vitro studies). Results. Of 106 identified reports, 42 addressed lncRNAs (GAS5, MEG8, FLRL2) expression as potential biomarkers; ultimately, 8 studies met strict inclusion criteria. Reduced expression of GAS5, MEG8, FLRL2 was consistently associated with hepatic stellate cell activation, epithelial-mesenchymal transition, and activation of the main profibrotic pathways, leading to increased α-SMA and COL1A1 expression. Conclusions. GAS5, MEG8, FLRL2 play a significant epigenetic role in the development of advanced liver fibrosis in MASLD/MASH. A decrease in their expression leads to derepression of profibrotic signaling in key profibrotic signaling pathways (PI3K/Akt, Wnt/β-catenin, Notch, Arntl/Sirt1).