The CYB5R3–mARC1 Redox Axis in Metabolic Dysfunction-associated Steatotic Liver Disease: Mechanistic Basis and Therapeutic Prospects across the Steatosis–Cirrhosis–Hepatocellular Carcinoma Spectrum

Abstract

Metabolic dysfunction-associated steatotic liver disease affects roughly 38% of adults, yet approved agents do not correct the upstream redox-metabolic perturbations—a depressed nicotinamide adenine dinucleotide (NAD+/NADH) ratio, saturated lipid excess, and endoplasmic reticulum (ER) stress—that drive hepatocyte injury. Cytochrome b5 reductase 3 (CYB5R3) couples NADH oxidation to fatty acid desaturation, nuclear factor erythroid 2-related factor 2 (NRF2)-linked antioxidant and cholesterol-handling pathways, NAD+/sirtuin signaling, and ER-phagy, and is the sole electron input to mitochondrial amidoxime-reducing component 1 (mARC1). This review grades every link in the axis across the steatosis–cirrhosis–hepatocellular carcinoma spectrum, reporting effect estimates with sample sizes and test statistics alongside a study-level appraisal of clinical relevance. The common MTARC1 p.A165T variant protects against all-cause cirrhosis (odds ratio, 0.91; 95% CI, 0.89–0.94; P = 2.3 × 10−11; 12,361 cases, 790,095 controls), with lower hepatic fat, liver enzyme levels, and low-density lipoprotein cholesterol levels. Germline mARC1 deletion reduces picrosirius red fibrosis area by 24–50% depending on diet, without altering histological disease activity, whereas partial protein reduction confers no protection. Critically, therapeutic hepatocyte-directed knockdown loses its anti-fibrotic effect when started at higher disease burden and in the choline-deficient model: efficacy depends on the depth, compartment, and timing of inhibition. Deep, hepatocyte-restricted mARC1 inhibition by GalNAc-conjugated oligonucleotides—which also avoids a male-predominant cardiac liability—is therefore the most credible near-term strategy, only in pre-cirrhotic F2–F3 disease. CYB5R3 activation, and its combination with mARC1 inhibition, remain unproven, and no clinical trial of this axis has been reported. Falsifiable in vivo and pharmacodynamic biomarker roadmaps are proposed, together with the efficacy, delivery, and safety uncertainties specific to advanced cirrhosis and a non-invasive pharmacodynamic framework.