Insulin Modulates NK Cell Activity in Liver Fibrosis MASH Patients via the STING Pathway

Area of Science:

• Immunology
• Hepatology
• Metabolic Diseases

Background:

• The Stimulator of Interferon Genes (STING) pathway is crucial for innate immunity but its role in natural killer (NK) cells during liver fibrosis is understudied.
• Metabolic dysfunction-associated steatohepatitis (MASH) is linked to immune dysregulation in the liver.

Purpose of the Study:

• To investigate the relationship between STING expression, NK cell activity, and insulin receptor (IR) signaling in MASH patients with varying liver fibrosis stages.
• To explore the therapeutic potential of targeting STING and insulin signaling for restoring NK cell function in liver fibrosis.

Main Methods:

• Peripheral NK cells were isolated from healthy controls and MASH patients (early: F1/F2; advanced: F3/F4).
• Flow cytometry assessed STING, IR, and NK cell activation/inhibitory markers. Cytotoxicity assays evaluated NK cell function against hepatic stellate cells.
• STING agonists and insulin were used to examine their effects on NK cell activity and signaling.

Main Results:

• STING expression in NK cells correlated with liver fibrosis severity; advanced fibrosis showed inhibited STING and impaired NK cell cytotoxicity and IFN-γ production.
• STING agonist treatment restored STING expression and enhanced NK cell activity across all fibrosis stages.
• Insulin and STING agonist combination synergistically upregulated IR and STING, improving NK cell function and cytotoxicity, especially in advanced fibrosis.

Conclusions:

• NK cell dysfunction in liver fibrosis is associated with altered STING and insulin signaling.
• Targeting the STING and insulin signaling pathways presents a promising therapeutic strategy to restore NK cell function and immune surveillance in MASH-related liver fibrosis.