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Deciphering cytochrome P450 reductase role in MASLD: molecular mechanisms and pathophysiological implications
Catarina Baptista1, Francisco Esteves1,2, Jonathan A Fallowfield3
1Comprehensive Health Research Centre (CHRC) NOVA Medical School, Faculty of Medical Sciences, NOVA University Lisbon, Lisbon, Portugal.
Nature Reviews. Gastroenterology & Hepatology
|April 20, 2026
Summary
NADPH:cytochrome P450 oxidoreductase (CPR) plays a key role in metabolic dysfunction-associated steatotic liver disease (MASLD). Restoring CPR function may offer a new therapeutic strategy for MASLD and MASH.
Area of Science:
- Hepatology and Metabolic Disorders
Background:
- Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health issue.
- MASLD can progress to severe liver conditions like MASH, fibrosis, and cirrhosis.
- NADPH:cytochrome P450 oxidoreductase (CPR) is crucial for liver functions disrupted in MASLD.
Purpose of the Study:
- To examine the role of CPR in MASLD pathophysiology.
- To explore how CPR dysfunction contributes to MASLD progression and heterogeneity.
- To highlight CPR as a potential therapeutic target for MASLD.
Main Methods:
- Review of genetic, biochemical, transcriptomic, and clinical studies.
- Analysis of CPR's involvement in lipid accumulation, oxidative stress, and inflammation.
- Examination of CPR's role in mitochondrial dysfunction and iron homeostasis.
Main Results:
- CPR dysfunction, due to genetic factors or metabolic stress, impacts MASLD.
- CPR is implicated in lipid accumulation, oxidative stress, ferroptosis, and inflammation in MASLD.
- Evidence suggests CPR influences disease heterogeneity and progression.
Conclusions:
- CPR is a significant regulator of hepatic metabolism in MASLD.
- Restoring CPR-dependent pathways, as shown by resmetirom's effect on POR, can improve MASH with fibrosis.
- Understanding CPR's multifaceted role can guide precision medicine for MASLD.
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