Divergence of the CYB5R3–mARC1 Redox Axis Across the Human MASLD-to-Hepatocellular-Carcinoma Continuum: An Exploratory Analysis of Liver-Biopsy and Tumor Cohorts

Vollständiger Abstract

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CYB5R3 (NADH–cytochrome b5 reductase 3) and mARC1, the product of MTARC1, draw on the same cytochrome-b5 electron relay, so they are usually treated as two ends of one redox axis. Whether they behave as a unit across the continuum from metabolic dysfunction–associated steatotic liver disease (MASLD) to hepatocellular carcinoma (HCC) has not been established. In TCGA-LIHC, higher CYB5R3 expression was associated with shorter overall survival in a continuous multivariable Cox model adjusted for age, sex, and stage (n = 339, 114 deaths; HR 1.23 per SD, 95% CI 1.01–1.48, p = 0.035), although it added essentially nothing to a clinical model containing age, sex, and stage (change in Harrell C-index 0.005, 95% CI −0.015 to +0.037). The direction was reproduced in the only independent cohort examined, GSE14520 (n = 242, 96 deaths; unadjusted HR 1.42 per SD, 95% CI 1.14–1.76, p = 0.0015), in which higher MTARC1 was associated with longer survival (unadjusted HR 0.73 per SD, 95% CI 0.60–0.89, p = 0.0017); both single-gene estimates fall below conventional significance after adjustment for age, sex, and TNM stage (HR 1.24, 95% CI 0.99–1.56, p = 0.058 and HR 0.89, 95% CI 0.72–1.10, p = 0.29; n = 225, 86 deaths), although CYB5R3 remains nominally significant in an adjusted model containing both genes (HR 1.27, 95% CI 1.01–1.59, p = 0.039), so that cohort replicates direction rather than independent prognostic value. Across the primary tumors of the analysis set, no correlation between the two transcripts was detectable (Spearman rs = −0.03, 95% CI −0.13 to +0.08, p = 0.62; n = 339), so the axis is not demonstrably a unit at the expression level. In three human liver-biopsy cohorts spanning the MASLD histological spectrum (393 biopsies with fibrosis staging), CYB5R3 gave estimates that differed in sign between cohorts and were uninformative when pooled (fibrosis stage, random-effects rs = +0.01, 95% CI −0.24 to +0.26, q = 0.95, I2 = 83%). MTARC1 behaved differently, falling with fibrosis stage in all three cohorts (pooled rs = −0.22, 95% CI −0.32 to −0.13, q = 3 × 10−5, I2 = 0%), as did PARP16 (−0.17, I2 = 0%), while SCD rose in all three (+0.13, I2 = 0%). This is consistent with the inconsistency being specific to CYB5R3 rather than a property of the cohorts, although the fibrogenic positive controls were themselves heterogeneous (I2 = 53–62%), I2 is estimated from only three cohorts, and the difference between the CYB5R3 and MTARC1 coefficients was not formally tested. These observations are associative and hypothesis-generating. They provide no support for the widely assumed corollary that hepatic CYB5R3 becomes deficient as steatotic liver disease advances, so a therapeutic strategy predicated on that corollary currently rests on mouse gain-of-function data alone, without corroboration from human tissue. What they do support is narrower: within a single physically coupled electron-transfer axis, the two members behave differently before malignancy—MTARC1 tracks fibrosis stage reproducibly while CYB5R3 shows no reproducible relationship—and carry opposite prognostic directions after malignancy, significant for MTARC1 only before covariate adjustment.