Chronic liver inflammation is one of the most serious complications associated with liver cirrhosis. Researchers from Miguel Hernández University of Elche (UMH) in Spain have identified a molecular mechanism that acts as an immune “switch” and could potentially be harnessed to slow disease progression. The findings show that the liver protein LSECtin, which is progressively lost as cirrhosis advances, plays a key protective role by restraining pro-inflammatory immune responses.
The study, published in JHEP Reports and conducted in mice and human liver tissue samples, demonstrates that LSECtin—expressed by specialized liver cells—blocks the expansion of pro-inflammatory Th17 immune cells and, as a result, attenuates liver damage. This discovery opens new therapeutic possibilities for controlling the inflammation associated with cirrhosis.
The work is co-led by UMH researchers Rubén Francés and Esther Caparrós, from the Department of Clinical Medicine, the Institute for Health Biotechnology Research, Development and Innovation of Elche (IDiBE UMH), the Alicante Institute for Health and Biomedical Research (ISABIAL), and the Spanish Biomedical Research Network in Hepatic and Digestive Diseases (CIBERehd).
An immune ‘switch’ to control inflammation in liver cirrhosis
Cirrhosis is a severe condition in which healthy liver tissue is progressively replaced by scar tissue. At the same time, persistent inflammation accelerates organ damage. UMH researchers observed that the protective protein LSECtin steadily declines as the disease progresses. “When LSECtin levels drop, Th17 cells—an especially inflammatory type of lymphocyte—expand and worsen liver injury,” explains Sebastián Martínez, UMH researcher and first author of the study. These Th17 cells are known to drive intense inflammatory responses that contribute directly to disease progression.
To investigate this process, the researchers used a murine model of cirrhosis in which mice were genetically modified to overexpress LSECtin. “This allowed us to show that restoring LSECtin levels in the liver has a clear protective effect,” says UMH professor Rubén Francés. The team also analyzed human liver samples with and without cirrhosis, confirming that LSECtin loss is a hallmark of the disease in patients, not just in animal models.
The central finding of the study is that LSECtin acts through the LAG-3 receptor, an immune regulatory molecule of growing pharmacological interest. “We identified LAG-3 as the molecular mechanism through which LSECtin ‘switches off’ the Th17 response,” explains UMH professor Esther Caparrós. This LSECtin–LAG-3 interaction blocks Th17 cell expansion and promotes the emergence of regulatory immune cells that foster immune tolerance and reduce inflammation. “It is a dual mechanism: it suppresses what causes harm and enhances what provides protection,” Caparrós summarizes.
Although the study does not yet have direct clinical application, the results pave the way for the development of pharmacological strategies aimed at restoring or mimicking the action of LSECtin in the liver. Since recovering this protein reduces inflammation in experimental models, “the LSECtin–LAG-3 interaction could become a highly promising therapeutic target for cirrhosis,” Caparrós emphasizes. Such an approach could allow clinicians to modulate immune responses at early or advanced stages of the disease, with the potential to slow its progression.
More information
Sebastián Martínez-López et al, LSECtin attenuates hepatic Th17 expansion in a murine model of cirrhosis and signals through the LAG-3 receptor, JHEP Reports (2025). DOI: 10.1016/j.jhepr.2025.101482
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