BRAF-activated ARSI suppressed EREG-mediated ferroptosis to promote BRAFV600E (mutant) papillary thyroid carcinoma progression and sorafenib resistance.

Abstract

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer, and patients with the BRAF^V600E mutation often exhibit aggressive tumor behavior. Here, we identified Arylsulfatase I (ARSI) as a gene whose expression was significantly upregulated in BRAF^V600E PTC and was associated with poor prognosis. High ARSI expression correlated with advanced disease stage, BRAF mutation, and worse overall survival in PTC patients. Functional studies revealed that ARSI promoted the tumor growth, cell migration, and epithelial-mesenchymal transition (EMT) of BRAF^V600E PTC cells in vitro. In vivo studies confirmed that ARSI suppression inhibited tumor growth and metastasis in mouse models of PTC. Mechanistically, ARSI knockdown triggered ferroptosis in BRAF^V600E-mutant PTC cells and sensitized PTC cells to sorafenib-induced ferroptosis. Epiregulin (EREG) was identified as a downstream target of ARSI and is regulated by STAT3 transcriptional activation. EREG overexpression rescued the ferroptosis resistance and malignant phenotypes induced by ARSI knockdown in BRAF^V600E-mutant PTC cells. Finally, we constructed a prognostic signature and diagnostic model based on ARSI and EREG expression data, which demonstrated high predictive value for identifying high-risk PTC patients with the BRAF^V600E mutation. Our study highlights the critical role of ARSI in promoting aggressive phenotypes and therapeutic resistance in BRAF^V600E PTC through ferroptosis regulation. Targeting the ARSI-EREG axis may offer novel therapeutic avenues for improving outcomes in BRAF^V600E PTC patients.