biostudies-literatureUnknown22(4)Radom MRadioiodine (RAI) therapy, used for treating differentiated thyroid cancers (DTCs), hinges on the functional expression of the sodium-iodide symporter (NIS). However, up to 60% of papillary thyroid carcinomas, the most common DTC subtype, harbor BRAF^V600E mutations, which are strongly associated with reduced NIS expression, impaired RAI uptake, and poor differentiation scores. For patients with RAI-refractory, a promising therapeutic strategy is to restore RAI sensitivity by inducing tumor redifferentiation. Here, we demonstrate that NOX4-derived reactive oxygen species (ROS) contribute to NIS repression in BRAF^V600E-mutated thyroid cancer cells. Particularly, NOX4-generated oxidative DNA damage recruits DNA repair proteins, including OGG1 and MSH2/MSH6 proteins, whicInternational journal of biological sciences1674-1692https://www.ebi.ac.uk/biostudies/studies/S-EPMC12905579biostudies-literatureNOX4-derived oxidative DNA damage impairs thyroid differentiation through an epigenetic mechanism in BRAF-mutated radioactive iodine refractory papillary thyroid cancer cells.PMC12905579Harinquet MBuffet CBani MADroin NDayris TCazarin JGhuzlan AABraye FAglave MLeboulleux SMesloub YGodefroy KDupuy Cde Faria CCRadom MLamartina LNobre CfalseNOX4-derived oxidative DNA damage impairs thyroid differentiation through an epigenetic mechanism in BRAF-mutated radioactive iodine refractory papillary thyroid cancer cells.Radioiodine (RAI) therapy, used for treating differentiated thyroid cancers (DTCs), hinges on the functional expression of the sodium-iodide symporter (NIS). However, up to 60% of papillary thyroid carcinomas, the most common DTC subtype, harbor BRAF^V600E mutations, which are strongly associated with reduced NIS expression, impaired RAI uptake, and poor differentiation scores. For patients with RAI-refractory, a promising therapeutic strategy is to restore RAI sensitivity by inducing tumor redifferentiation. Here, we demonstrate that NOX4-derived reactive oxygen species (ROS) contribute to NIS repression in BRAF^V600E-mutated thyroid cancer cells. Particularly, NOX4-generated oxidative DNA damage recruits DNA repair proteins, including OGG1 and MSH2/MSH6 proteins, whic2026-01-01T00:00:00Z20262026-07-15T16:32:03.852Z2026-07-07T03:08:37.172ZS-EPMC129055794169458010.7150/ijbs.123980