Cytochrome P450 Reductase in MASLD: Nature Reviews Gastroenterology & Hepatology | August 2026

Introduction:

Metabolic dysfunction-associated steatotic liver disease (MASLD) involves complex disturbances in hepatic lipid metabolism, oxidative stress, inflammation, and mitochondrial function. NADPH:cytochrome P450 oxidoreductase (CPR), encoded by POR, is the essential electron donor for microsomal cytochrome P450 enzymes and other redox proteins. This Perspective examines emerging evidence positioning CPR as an important regulator of MASLD pathogenesis and progression.

Why was this study needed?

. The molecular mechanisms responsible for the heterogeneity and progression of MASLD remain incompletely understood.

. CPR regulates several processes relevant to MASLD, including lipid metabolism, xenobiotic processing, bile acid synthesis, and cellular redox balance.

. Genetic variation in POR and metabolic stress can alter CPR activity and potentially influence disease susceptibility.

. Understanding CPR-dependent pathways could reveal new biomarkers and therapeutic targets for precision treatment of MASH.

Results:

Evidence from genetic, biochemical, transcriptomic, and clinical studies indicates that altered CPR activity can influence multiple interconnected mechanisms of MASLD. CPR dysfunction contributes to hepatic lipid accumulation, oxidative stress, mitochondrial dysfunction, disturbed iron homeostasis, ferroptosis, and inflammatory signalling, providing a potential mechanistic link between metabolic dysfunction and progressive liver injury. Genetic polymorphisms affecting POR and acquired alterations induced by metabolic stress might partly explain interindividual differences in MASLD severity and progression. Importantly, the MASH therapy resmetirom, a thyroid hormone receptor-β agonist, increases POR transcription, providing translational support for the therapeutic relevance of restoring CPR-associated metabolic pathways.

Clinical Impact:

CPR represents a potential molecular bridge connecting metabolic abnormalities with hepatocellular injury and fibrosis progression. Characterizing POR variants and CPR activity could eventually contribute to molecular phenotyping of MASLD and help identify patients most likely to benefit from pathway-specific therapies.

Bottom Line:

CPR is emerging as a key regulator of MASLD through its effects on lipid metabolism, oxidative stress, mitochondrial function, ferroptosis, and inflammation, making the POR–CPR pathway a promising target for precision MASH therapy.