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

Review article grading evidence from human genetics, cell-based studies, and preclinical in vivo models

“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.”

Human cohorts (biobanks), primary human hepatocytes, hepatoma cell lines, and mice in various dietary disease models

“The strongest human evidence implicating the pathway comes from mARC1: large biobank analyses show that partial loss of mARC1 function (MTARC1 p.A165T) protects against liver disease across ancestries and etiologies.”

Human genetics analysis included 12,361 cases and 790,095 controls; mouse studies typically used 6 to 14 subjects per group

“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)”

Mouse dietary models ranged from 2 weeks to 32 weeks; human genetic data represents lifelong exposure

“GAN diet 32 wk, n = 13–14. High-fat diet with 30% fructose water 20 wk, n = 10–13.”

The MTARC1 p.A165T variant is associated with protection against all-cause cirrhosis and lower hepatic fat and liver enzyme levels

“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.”

Complete germline mARC1 deletion reduces fibrosis area in mice, whereas partial protein reduction confers no protection

“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.”

Therapeutic hepatocyte-directed knockdown of mARC1 loses anti-fibrotic effect when initiated at higher disease burden

“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.”

No clinical trials of the axis have been reported; efficacy is model-dependent and not demonstrated in established cirrhosis or for regression of fibrosis

“CYB5R3 activation, and its combination with mARC1 inhibition, remain unproven, and no clinical trial of this axis has been reported.”