Metallothionein Safeguards Hepatic Zn-Fe Homeostasis and Restrains Yap-Driven Hepatic Fe Overload to Protect Against Chronic Liver Fibrosis.

BACKGROUND

Redox-active iron (Fe) overload and antioxidant zinc (Zn) deficiency are hallmarks of chronic liver fibrosis, yet their upstream regulatory mechanisms remain elusive.

OBJECTIVE

Here, we identify the redox-sensitive metallothionein (MT) as a critical regulator in the injured liver that integrates trace-metal homeostasis with Hippo-Yap signalling.

METHODS &

RESULTS

MT expression was transiently induced in early-stage murine and human liver fibrosis but declined sharply in advanced disease. Genetic deletion of MT in mice exacerbated CCl4-induced liver injury, characterized by severe Zn depletion, pathological Fe accumulation, and aggravated fibrosis. Mechanistically, MT loss impaired the activity of Zn-dependent matrix metalloproteinases and unleashed pathological Fe deposition, which amplified lipid peroxidation and oxidative damage. We revealed that MT deficiency suppressed the upstream Hippo kinase Mst1, promoting the nuclear translocation and activation of the transcriptional coactivator Yap. Crucially, pharmacological inhibition of Yap with verteporfin rescued the Fe overload and attenuated fibrosis in MT-deficient livers but did not correct the Zn depletion, establishing Yap as a key downstream driver of Fe dysregulation. The analysis of human fibrotic and cirrhotic livers confirmed a conserved inverse correlation between MT levels and nuclear Yap accumulation, accompanied by severe Fe deposition.

CONCLUSIONS

These findings reveal MT as a key hepatocyte integrator of trace-metal homeostasis and Yap signalling and suggest that therapeutic strategies enhancing MT activity or combining Zn supplementation with Yap inhibition may offer new avenues to prevent or reverse chronic liver fibrosis.