Abstract / Summary
Abstract Background Downregulation of the main L-tyrosine (L-TYR) degradation pathway ( LTYM ) is a recurrent feature of liver disease and hepatocellular carcinoma (HCC) and correlates with poor prognosis, yet the underlying regulatory mechanisms remain unclear. Methods Here, we investigate this process using a novel murine model of hereditary tyrosinemia type I (FAH-G337S ⁺/⁺ ), which recapitulates subacute disease progression toward HCC. Results We show that L-TYR accumulation and the buildup of toxic intermediates, including fumarylacetoacetate and succinylacetone, are associated with robust downregulation of LTYM enzymes at both the protein and transcriptional levels. Mechanistically, we demonstrate that the transcription factor NRF2 directly binds to Maf recognition elements in the promoter regions of LTYM genes, leading to their repression. This regulation is likely mediated through competition with the transcriptional repressor BACH1, establishing a dynamic regulatory axis that reflects intracellular oxidative stress. Pharmacological perturbation of the NRF2 pathway with brusatol restores LTYM expression, supporting the functional relevance of this regulatory axis. Conclusions Our findings identify the LTYM pathway as a sensor of oxidative stress and reveal NRF2-mediated repression as a key driver of its dysregulation, providing a mechanistic link between altered tyrosine metabolism and poor clinical outcomes in HCC and other liver disorders.