Deciphering cytochrome P450 reductase role in MASLD: molecular mechanisms and pathophysiological implications.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent and rapidly growing global health concern characterized by hepatic steatosis, oxidative stress and inflammation that can progress to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis and cirrhosis. NADPH:cytochrome P450 oxidoreductase (CPR, encoded by POR), the essential electron donor for microsomal cytochrome P450 enzymes and other redox partners, orchestrates xenobiotic detoxification, lipid metabolism, steroid and bile acid biosynthesis, and redox balance - processes disrupted in MASLD. This Perspective examines emerging evidence from genetic, biochemical, transcriptomic and clinical studies that implicate CPR in the pathophysiology of MASLD, including its roles in lipid accumulation, oxidative stress, mitochondrial dysfunction, iron homeostasis, ferroptosis and inflammatory signalling. We discuss how CPR dysfunction, driven by genetic polymorphisms or metabolic stress, contributes to disease heterogeneity and progression. These insights highlight CPR as a relevant and potentially actionable regulator of hepatic metabolism. The current FDA approval of resmetirom, a thyroid hormone receptor-β agonist, which increases POR transcription levels, provides translational proof that restoring CPR-dependent pathways can ameliorate MASH with fibrosis. A deeper understanding of the multifaceted role of CPR could inform precision medicine strategies for this complex and widespread liver disease.