A team of Korean researchers has discovered that specific genetic mutations found in patients with fatty liver disease can cause inflammation in the liver and worsen liver damage.

The team, led by Professors Lee Jae-jun and Bae Si-hyun of the Department of Gastroenterology at the Catholic University of Korea Eunpyeong St. Mary's Hospital, and Professor Sung Pil-soo of the Department of Gastroenterology at Seoul St. Mary's Hospital, announced Wednesday that the “PNPLA3 I148M” gene mutation in patients with metabolic dysfunction-associated liver disease (MASLD) may influence the progression of immune-mediated liver damage.

The study results were published in the international academic journal, “Journal of Gastroenterology,” under the title “The PNPLA3 I148M variant is associated with immune cell infiltration and advanced fibrosis in MASLD: a prospective genotype–phenotype study.”

MASLD is a condition where fat accumulates in the liver, often accompanied by metabolic disorders, such as obesity, diabetes, and hypertension. In some cases, it can progress to cirrhosis or liver cancer.

While it was already known that the PNPLA3 gene variant (GG genotype) influences MASLD, this study is the first to clarify how the variant is involved in immune cell infiltration and inflammatory responses within liver tissues.

The research team analyzed the PNPLA3 genotype in 70 patients diagnosed with MASLD who received treatment at Eunpyeong St. Mary's Hospital and Seoul St. Mary's Hospital in 2024. They collected oral epithelial cells or liver biopsy tissues and analyzed the PNPLA3 genotype. For liver tissue, they quantitatively evaluated the extent of CD3 (T cells) and CD68 (macrophages) infiltration using immunohistochemistry.

The results showed that patients with the PNPLA3 GG genotype, which has a mutation, had a higher rate of liver fibrosis (F3 or F4) compared to patients with the GC/CC genotype, which has no or few mutations. Additionally, increased infiltration of CD3⁺ and CD68⁺ immune cells in the periportal region, along with inflammatory responses, was observed. In the GG genotype group, the expression of genes that activate immune responses or cause liver fibrosis (CD8A, GZMB, CCL2, TIMP1, etc.) was also elevated.

The research team emphasized that the study results prove that the progression and speed of immune-mediated liver damage may vary depending on the genes in patients with MASLD.

“This study is significant as it is the first in the world to suggest that PNPLA3 variants induce the infiltration and activation of immune cells in the liver, which can lead to fibrosis,” Professor Lee said. “This finding could serve as a basis for predicting patient prognosis or developing treatments targeting immune pathways in the future.”

Professor Bae said, “This study provides meaningful data for predicting differences in fibrosis progression or treatment responses based on PNPLA3 genotypes, which could contribute to the realization of precision medicine.”

Professor Sung said, “This is the first study to highlight immune cell activation as a cause of disease progression in MASLD. It is expected to contribute to refining treatment targets in the future.”