Nature Communications: “Zombie” Cells Amplify Inflammation in Severe Fatty Liver Disease

Scientists at the Mayo Clinic have uncovered how so-called “zombie” cells contribute to inflammation and accelerate the progression of a severe form of fatty liver disease—metabolically associated steatohepatitis (MASH).

The study’s findings were published in the journal Nature Communications.

This disease is becoming increasingly common amid the global rise in obesity and is already one of the leading causes of liver transplantation.

“The key features of MASH are liver scarring and inflammation. If left untreated, the disease can progress to liver cancer. That is why it is so important to understand the mechanisms that trigger it,” said Stella Victorelli, the study’s lead author.

“Zombie” cells are senescent cells that have stopped dividing but remain alive and begin releasing substances that damage tissues and trigger inflammation. When we are young, the immune system efficiently clears these cells, but with age they accumulate and become a source of chronic inflammation.

The researchers found that in these cells, mitochondrial RNA—which normally remains inside the cell’s energy-producing structures—leaks into the main cellular compartment, where it is mistakenly recognized as viral RNA. This activates the immune sensors RIG-I and MDA5, triggering a strong inflammatory response that damages surrounding healthy tissue. When the scientists blocked these sensors, inflammation was sharply reduced.

The study also showed that the proteins BAX and BAK, which help form pores in the mitochondrial membrane, facilitate the release of mitochondrial RNA into the cytoplasm. In a preclinical model system, inhibiting BAX and BAK prevented RNA leakage, reduced inflammation, and improved liver tissue health.

These findings help explain why the accumulation of “zombie” cells is linked to age-related diseases and point to potential new therapeutic targets for treating MASH and other conditions associated with chronic inflammation. The researchers believe that dampening the harmful signals produced by senescent cells could help prevent or slow the progression of inflammatory liver diseases and other age-related pathologies.

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