How Fructose Fuels Liver Damage When Insulin Resistance Strikes
A new study has uncovered how fructose worsens liver disease when insulin resistance is already present. Published in Nature Communications in 2025, the research highlights the role of follistatin—a glycoprotein—in accelerating fat buildup and inflammation in the liver. The findings suggest both dietary adjustments and potential drug treatments could help manage the condition.
The study, led by researchers Tao, Stoehr, Tok, and colleagues, focused on Metabolic Associated Steatotic Liver Disease (MASLD). They discovered that fructose metabolism triggers a chain reaction, activating genes linked to fat production through transcription factors like SREBP-1c and ChREBP. These factors become far more active when follistatin levels rise.
Fructose also disrupts the liver’s energy balance by interfering with the insulin receptor substrate (IRS) pathway. This impairment locks the liver into a state that favours fat storage and inflammation. In mice, higher follistatin levels matched increased signs of liver damage, including inflammation and scarring, pointing to its potential as a marker for disease severity.
When researchers genetically suppressed follistatin, fructose-induced liver fat decreased—even in cases of full insulin resistance. This suggests combining follistatin inhibitors with other treatments might offer stronger protection against MASLD. The study further showed that fructose fuels harmful processes by pushing the liver toward new fat creation and oxidative stress.
The research underscores the need for controlled fructose intake as a preventive step against worsening liver disease. It also opens doors for targeted therapies that disrupt the follistatin-fructose interaction. Such approaches could help reduce liver fat and inflammation, particularly in patients with severe insulin resistance.
