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Scientific

An international study led by CiMUS-USC identifies loss of a key metabolic enzyme as a driver of liver fibrosis

  • Descubren que la pérdida de la enzima fosfoenolpiruvato carboxiquinasa 1 (PCK1) activa las células responsables de esta enfermedad
  • El hallazgo, publicado en Cell Metabolism, abre nuevas vías terapéuticas para frenar su progresión 
     

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately 30–38% of the adult population and has become one of the leading causes of chronic liver disease worldwide. This condition can progress to fibrosis, cirrhosis and even liver cancer. Despite its high prevalence and severity, therapeutic options remain very limited. To date, only one approved drug, resmetirom, is available, improving the condition in only about 25% of patients, particularly with regard to halting or reversing fibrosis — the main mortality factor associated with the disease. In this context, a research team at CiMUS-USC has identified a crucial role for the enzyme phosphoenolpyruvate carboxykinase 1 (PCK1) in the activation of hepatic stellate cells, the main drivers of fibrosis development.
From a clinical perspective, the study opens the door to innovative strategies specifically targeting hepatic stellate cells, including the use of nanoparticles or other selective delivery systems aimed at modulating PCK1 activity and slowing liver fibrosis progression. The research group has recently been awarded a Proof-of-Concept grant from the Spanish State Research Agency to further develop these strategies.

 

When PCK1 fails, fibrosis is triggered

The study demonstrates that PCK1 expression is significantly reduced in hepatic stellate cells from patients with MASLD and fibrosis, as well as in several animal models of the disease. This reduction is associated with increased severity of liver damage.

Through experiments in human cells and animal models, researchers showed that the absence of PCK1 in hepatic stellate cells leads to their activation, promoting fibrosis. Notably, mice lacking PCK1 specifically in these cells developed liver fibrosis even without exposure to harmful external factors such as unhealthy diets.

Conversely, increasing PCK1 levels reduced cell activation and slowed fibrosis progression, positioning this enzyme as a potential new therapeutic target. “Our results indicate that maintaining PCK1 activity in hepatic stellate cells is essential to preserve liver metabolic balance and prevent fibrosis development,” explain the study’s lead authors, Eva Nóvoa and Tamara Parracho.

The researchers nevertheless urge caution: “We observe that this mechanism is relevant in both animal models and human cells, but much work remains before determining whether it could become an effective and safe therapeutic strategy for patients with MASLD.”

The study highlights the urgent need to explore new therapeutic options, as MASLD incidence continues to increase worldwide while current treatments remain limited.

International collaboration

The work was led by the Molecular Metabolism group at CiMUS under the coordination of Dr. Rubén Nogueiras, with participation from CiMUS researchers Dr. Miguel López, Dr. Marta Varela-Rey and Dr. Carlos Diéguez, as well as collaborators from several national and international institutions, including Clínica Universidad de Navarra, Hospital Clínic de Barcelona, CIC bioGUNE, Universidad Autónoma de Madrid, the University of Lille (France), the University of Lübeck (Germany), and Columbia University (USA).

Lack of PCK1 in hepatic stellate cells causes liver fibrosis by fueling tricarboxylic acid cycle and increasing glycolysis. Novoa, Eva et al. Cell Metabolism.

About CiMUS-USC

The Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS) at the University of Santiago de Compostela conducts cutting-edge research focused on chronic diseases. Its mission is to generate high-impact knowledge connected to society and aimed at improving patient outcomes.

Its activity is structured around two major programmes: Molecular Mechanisms of Disease and Integrative Translational Research, linking fundamental discoveries with clinical translation and fostering technology transfer and therapeutic innovation.

CiMUS is an open and collaborative research centre that promotes synergies with universities, healthcare institutions, industry partners and innovation stakeholders at regional, national and international levels. The centre holds the CIGUS recognition from the Xunta de Galicia (ED431G/2023/02) and is funded by the Regional Ministry of Education, Science, Universities and Vocational Training and co-funded by the European Union through the Galicia ERDF 2021–2027 Programme. It has also recently been accredited nationally as a María de Maeztu Unit of Excellence by the Spanish Ministry of Science, Innovation and Universities (grant CEX2024-001463-M).