Selective NRF2 target induction despite falling NFE2L2 transcription across the MASLD spectrum: implications for marginal donor grafts and KEAP1-targeted therapy.

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) affects one-third of adults, and one in five progresses to metabolic dysfunction-associated steatohepatitis (MASH), which can cause liver failure, burdening hepatology clinics and transplant waiting lists. NRF2-KEAP1 axis is the principal regulator of hepatic antioxidant defence, yet its status across the disease spectrum is unclear. We mapped NRF2-KEAP1 transcriptional signatures across control, steatosis and MASH livers.

METHODS: Eight GEO datasets (590 biopsies: 154 control, 134 steatosis, 302 MASH) were harmonised by log2 transformation, within-dataset Z-scoring and ComBat correction. The pre-specified panel comprised NFE2L2, KEAP1 and six NRF2 targets (GCLC, GCLM, HMOX1, NQO1, SRXN1, TXNRD1). Groups were compared by ANOVA with Tukey post-hoc tests.

RESULTS: NFE2L2 was highest in control and reduced in steatotic and MASH livers (both p < 0.001), with KEAP1 reciprocally elevated. Targets were induced selectively where NQO1 and TXNRD1 peaked in MASH while HMOX1 was highest in control. NFE2L2-to-target co-expression was preserved across stages. Across fibrosis stages, NFE2L2 and KEAP1 were unchanged while NQO1 and TXNRD1 rose. Thus NQO1 and TXNRD1 rise in MASH even as NFE2L2 transcription falls.

CONCLUSIONS: NFE2L2 transcription decreases once MASLD is established, yet its targets are induced selectively and co-expression is preserved, so the pathway stays coherent while its output shifts. These are mRNA findings. We propose control of NRF2 at the protein level as a hypothesis consistent with our data and the pattern supports assessing NRF2 protein status in marginal donor livers and therapies targeting KEAP1.