MMRN1 suppresses thyroid cancer progression via activation of the Hippo signaling pathway

INTRODUCTION: Thyroid cancer (TC) represents the most frequently diagnosed malignancy of the endocrine system, with its incidence continuing to increase worldwide. Multimerin 1 (MMRN1), a glycoprotein implicated in various cancers, exhibits context-dependent roles, but its function in TC remains unexplored. The Hippo pathway, a key regulator of cell proliferation and apoptosis, is frequently dysregulated in TC. We hypothesized that MMRN1 inhibits TC progression by activating the Hippo signaling pathway. METHODS: Bioinformatics analysis of GSE33630 identified differentially expressed genes (DEGs) in TC. MMRN1 expression was validated in TC cell lines (BCPAP, TPC-1, IHH-4, HTH83) and normal thyroid cells (NTHY-ORI3.1) via RT-qPCR and Western blot. Functional assays assessed proliferation, migration, and invasion. Hippo pathway activity was evaluated after MMRN1 modulation. Oxidative stress and ferroptosis markers (ROS, SOD, CAT, GSH, MDA, GPX4, TF, TFR1) were analyzed. RESULTS: MMRN1 was downregulated in TC tissues and cell lines. Overexpression of MMRN1 suppressed TC cell proliferation, migration, and invasion while promoting apoptosis. Mechanistically, MMRN1 activated Hippo signaling, increasing p-MST1/2, p-LATS1/2, and p-YAP levels. Verteporfin reversed these effects. Additionally, MMRN1 modulated oxidative stress markers (including ROS and the indirect lipid peroxidation marker MDA) and altered GPX4 activity and iron metabolism, suggesting enhanced ferroptosis sensitivity. CONCLUSION: MMRN1 acts as a tumor suppressor in TC by activating the Hippo pathway and modulating oxidative stress and ferroptosis. These findings highlight MMRN1 as a potential therapeutic target for TC treatment.