Loss of CSE couples with BRAF V600E to fuel thyroid cancer metastatic progression through zinc-dependent activation of the EMT machinery.

BACKGROUND

BRAF V600E, the principal oncogenic driver in papillary thyroid carcinoma (PTC), strongly correlated with lymph node metastasis, yet the underlying molecular mechanisms remain elusive.

METHODS

This study screened effector related to the BRAF V600E mutation and PTC progression through bioinformatics analysis. The precise functional roles and regulatory networks of cystathionine γ-lyase (CSE), a primary hydrogen sulfide (H₂S)-producing enzyme, in thyroid cancer metastasis were then investigated in cell and mice models. Finally, these findings were further validated in a cohort of clinical pathological samples.

RESULTS

We identified that CSE is aberrantly silenced in advanced thyroid cancer. Mechanistically, BRAF V600E-driven MAPK activation upregulates miR-31-5p, which directly targets the CSE 3'UTR to inhibit its translation. The consequent H₂S deficiency disrupts intracellular metallo-homeostasis, triggering intracellular zinc accumulation that stabilizes Zeb1, MMP-2, thereby orchestrating the epithelial-mesenchymal transition (EMT). Critically, the metastatic potential of thyroid cancer cells relies strictly on CSE enzymatic activity. Pharmacological reconstitution of the H₂S pool using exogenous donors effectively bypasses CSE enzymatic deficiency, eliminates excess zinc, and reactivates metastasis-suppressive signaling.

CONCLUSIONS

These findings uncover a novel miR-31-5p/CSE/H₂S/Zinc axis that fuels BRAF-driven progression. These findings provide a compelling mechanistic rationale for utilizing H₂S-based interventions as a potential therapeutic strategy against BRAF-driven thyroid cancer metastasis.