Unlocking the Role of lncRNAs in MASLD and Liver Fibrosis

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is a growing global health concern, affecting approximately 30% of the adult population worldwide.

A significant subset of individuals with MASLD progress to metabolic dysfunction-associated steatohepatitis (MASH), which increases the risk of liver fibrosis and hepatocellular carcinoma (HCC).

Currently, resmetirom is the only approved treatment for MASLD. However, with the rising prevalence of obesity and diabetes fueling MASLD cases, there is an urgent need for new therapeutic approaches.

A recent study published in eGastroenterology explores the role of long non-coding RNAs (lncRNAs) in the progression of MASLD and liver fibrosis. LncRNAs are non-protein-coding RNA molecules that regulate gene expression and play a critical role in metabolic and fibrotic processes.

Researchers Dr. Henry Wade, Kaichao Pan, Bingrui Zhang, Dr. Wenhua Zheng, and Dr. Qiaozhu Su conducted an in-depth analysis of how lncRNAs interact with microRNAs and other key factors in liver disease progression.

LncRNAs influence metabolic functions in hepatocytes, hepatic stellate cells (HSCs), and Kupffer cells, impacting lipid metabolism, inflammation, apoptosis, and fibrosis development.

For instance, H19, one of the most well-studied lncRNAs, promotes hepatic lipid accumulation and fibrosis by interacting with sterol regulatory element-binding proteins (SREBPs) and peroxisome proliferator-activated receptors (PPARs). Similarly, MALAT1 has been linked to worsening liver fibrosis by modulating inflammatory pathways through nuclear factor-kappa B (NF-κB) and toll-like receptors (TLRs).

A key finding of the study is the dual role of lncRNAs in liver health. Some, such as Gas5 and MEG3, exhibit protective effects by reducing lipid buildup in hepatocytes and inhibiting HSC activation. In contrast, lncRNAs like HOTAIR and NEAT1 contribute to liver disease by triggering fibrotic and inflammatory responses.

These contrasting functions suggest that lncRNA-targeted therapies could offer a twofold strategy for treating MASLD: suppressing harmful lncRNAs while enhancing protective ones.

The study also highlights how lncRNAs interact with microRNAs and transcription factors to regulate liver cell function. For example, H19 promotes steatosis through its interactions with miR-130a and heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), while HOTAIR influences DNA methylation via miR-148b and DNMT1. These complex molecular networks underscore the potential of lncRNA-based therapies.

Dr. Qiaozhu Su emphasizes the promise of lncRNAs as both diagnostic markers and therapeutic targets:

"Understanding how lncRNAs contribute to MASLD and fibrosis opens new avenues for treatment. Given their regulatory roles in metabolism and inflammation, lncRNA-based therapies could significantly impact the future of liver disease management."

Despite their potential, lncRNA-targeted therapies face notable challenges. The species-specific nature of lncRNAs complicates translational research, making it difficult to apply findings from animal models to human treatments.

The study recommends prioritizing the identification of lncRNAs that are conserved across species to enhance clinical applicability. Additionally, developing effective delivery methods, such as nanoparticle-mediated RNA delivery, will be crucial for advancing lncRNA-based therapies.

This research underscores the need for continued exploration of lncRNAs as key regulators of liver disease. With MASLD cases on the rise, harnessing the therapeutic potential of lncRNAs could mark a major step forward in improving liver disease treatment and patient outcomes.