Metabolic dysfunction-associated steatotic liver disease (MASLD), a multifactorial disease that encompasses a spectrum of pathological conditions, ranging from simple steatosis, metabolic dysfunction-associated steatohepatitis (MASH), and fibrosis/cirrhosis, is associated with increased mortality. However, there are currently no standard diagnostic markers or effective treatments. Hence, there is an urgent need to elucidate the pathogenesis of MASLD to identify viable therapeutic targets.

This research, published in the Genes & Diseases journal by a team from Queen's University Belfast, Jinan University, Guangxi Medical University, University of Chicago, and University of Nebraska-Lincoln, delineate the mechanism of microRNA-34a-5p (miR-34a) in the progressive liver injury of MASLD and liver fibrosis.

Using a mouse hepatocyte cell line (AML12), researchers simulated MASLD conditions by exposing cells to free saturated fatty acids, palmitic acid, and/or inflammatory cytokine tumor necrosis factor-alpha (TNFα). Both treatments significantly increased miR-34a levels in hepatocytes. The elevated miR-34a dysregulated hepatic lipid and VLDL metabolism, leading to lipotoxicity and metabolic inflammation that contribute to the development of steatosis in hepatocytes.

The team further demonstrated that miR-34a overexpression induced hepatocyte ballooning degeneration—a hallmark of MASH—and a profibrogenic status in hepatocytes. Additionally, it was shown that the injured hepatocytes were found to release miR-34a into their environment, acting as a paracrine signal to activate hepatic stellate cells (HSCs). This interaction promoted endoplasmic reticulum (ER) stress and the expression of fibrogenic mediators, i.e., α-SMA, TGFβ2, and COL1A1, sustaining the development of liver fibrosis.

Additionally, liver tissues from obese patients diagnosed with steatosis, MASH, and fibrosis were subjected to analysis by hematoxylin-eosin and Masson's trichrome staining. A consistent pattern of increased miR-34a expression was observed, rising from early steatosis, peaking at MASH, and remaining elevated in fibrosis. Interestingly, these phenotypes were recapitulated in a human MASLD-like STAM mouse model, in which MASLD and liver fibrosis were induced via streptozotocin treatment and high-fat feeding. Notably, elevated expression of miR-34a was found in mouse liver tissues, reflecting the progression of liver injury from steatosis to MASH to liver fibrosis.

In summary, this study presents three novel mechanisms of miR-34a: (i) Lipotoxicity-induced miR-34a overexpression triggers ER stress and hepatocyte ballooning degeneration; (ii) Secreted miR-34a from injured hepatocytes facilitates pathological communication with HSCs, activating fibrogenic pathways and enhancing liver fibrosis; (iii) Elevated miR-34a expression correlates with disease progression in both human MASLD patients and a MASLD mouse model. In conclusion, this study offers a novel perspective for the developing pharmaceutical strategies that can manipulate the expression of miR-34a in MASLD and halt disease progression toward liver fibrosis.

Reference

Title of Original Paper: Elevated miR-34a induced by lipotoxicity and inflammation mediates pathophysiological communication between hepatocytes and hepatic stellate cells in liver fibrosis

Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101648

Funding Information:

• The British Heart Foundation (UK) (No. PG/19/86/34788)
• Northern Ireland Chest Heart & Stroke (UK) (2019_08)
• NIH grant R01 GM147913
• Nebraska Research Initiative grant

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

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