Can gene modulation help treat liver fibrosis and MASH?

Liver fibrosis and MASH (metabolic dysfunction-associated steatohepatitis) are serious liver conditions that can lead to cirrhosis. Gene modulation, which involves changing how specific genes work, is being studied as a potential treatment. Early research in cells and animals shows it can reduce scarring and inflammation, but no gene-based therapy is approved for humans yet. This answer explains what the science says so far.

What the research says

A narrative review highlights that gene modulation is one of several strategies to reprogram macrophages, key immune cells in the liver, from a pro-fibrotic to a restorative state ¹. This approach targets signaling pathways like NF-κB and STAT proteins that control macrophage behavior ¹. Another study found that deleting the ISG15 gene in hepatic stellate cells (cells that produce scar tissue) worsened fibrosis in mice, suggesting that boosting ISG15 could be protective ⁵. Conversely, a drug called GTX-11, which modulates the TGFβ pathway, reduced portal pressure and fibrosis in a rat model of MASH ⁶. Additionally, small extracellular vesicles from stem cells, which carry proteins like USP9X that modify gene expression, inhibited abnormal blood vessel growth in MASH mice ⁷. These findings show that gene modulation can influence multiple cell types and pathways involved in fibrosis and MASH.

What to ask your doctor

• Are there any clinical trials testing gene therapies for liver fibrosis or MASH that I might be eligible for?
• How do current treatments for MASH, like GLP-1 agonists or THRβ activators, compare to experimental gene modulation approaches?
• What are the main risks and unknowns about gene modulation for liver disease?
• Should I consider genetic testing to understand my risk for liver fibrosis progression?
• Can lifestyle changes or existing medications help slow fibrosis while gene therapies are being developed?