Researchers from NOVA Medical School, in collaboration with the University of Edinburgh, are proposing a new perspective on the role of a previously underestimated enzyme in the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD), the leading cause of chronic liver disease worldwide. In a Perspective published in Nature Reviews Gastroenterology & Hepatology, the team brings together and reinterprets existing evidence suggesting that the enzyme CPR (cytochrome P450 oxidoreductase) may play a central role in a condition affecting roughly one third of the global adult population.
MASLD, formerly known as “non-alcoholic fatty liver disease,” is characterized by the accumulation of fat in the liver and is strongly associated with obesity, insulin resistance, and type 2 diabetes. It is estimated to affect between 30% and 38% of adults worldwide, and its prevalence is expected to continue rising in the coming years.
In many individuals, the disease develops silently and remains asymptomatic for years. However, it can gradually progress to more severe stages, including liver inflammation, fibrosis (scarring of liver tissue), cirrhosis, and even hepatocellular carcinoma. Despite its global burden, MASLD still has limited treatment options, and its underlying molecular mechanisms remain incompletely understood.
CPR is an enzyme located in liver cells that acts as a central molecular “activator” of the cytochrome P450 system. By transferring electrons to these enzymes, it enables a wide range of biochemical reactions involved in drug metabolism, lipid processing, steroid hormone synthesis, and detoxification. As Michel Kranendonk, principal investigator at NOVA Medical School, explains, “changes in its expression or activity can have profound metabolic consequences and significantly impact liver health.”
Although CPR plays a fundamental role in hepatic metabolism, it has received relatively little attention in the context of MASLD. This Perspective integrates genetic, biochemical, and clinical evidence suggesting that alterations in CPR function may contribute to oxidative stress, fat accumulation in the liver, inflammation, and disease progression. The authors also highlight the importance of genetic variation in the POR gene, which encodes CPR, as a potential explanation for differences in disease susceptibility and variability in treatment response among individuals.
“Understanding these genetic and functional differences is essential for improving our interpretation of disease mechanisms and patient variability,” says Catarina Baptista, junior researcher at NOVA Medical School and first author of the paper. “Ultimately, this knowledge could help identify which patients are most likely to benefit from specific treatments and support the discovery of new therapeutic targets.”
The paper also discusses a relevant link to resmetirom, the first drug approved by the FDA in 2024 for the treatment of advanced MASLD with fibrosis. The authors note that this therapy increases POR expression in the liver, strengthening the hypothesis that modulating CPR activity could represent a promising avenue for future therapeutic strategies.
The authors conclude that further research is needed to clarify CPR’s role in MASLD progression and to unravel the mechanisms involved, with the ultimate goal of advancing more precise, personalized approaches to treatment.
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The Xenobiotic Metabolism Laboratory at NOVA Medical School, led by Michel Kranendonk, has spent the past two decades studying the molecular mechanisms of CPR and its role in liver metabolism. More recently, the team has expanded its focus to include models of liver disease and metabolic dysfunction, including the development of advanced cell-based systems designed to mimic the human liver environment.
This Perspective article emerged from the researchers’ effort to bring together years of accumulated findings and place them within a broader, clinically relevant framework.
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Baptista, C., Esteves, F., Fallowfield, J. A., Kendall, T. J., Nelson, L. J. & Kranendonk, M. (2026). "Deciphering cytochrome P450 reductase role in MASLD: molecular mechanisms and pathophysiological implications." Nature Reviews Gastroenterology & Hepatology. DOI: 10.1038/s41575-026-01202-y