Annexin A1 triggers autophagy to orchestrate radioiodine resistance in thyroid cancer via upregulating HMGB1

Abstract Purpose This study aims to investigate the mechanisms underlying ANXA1 and HMGB1-regulated autophagy in relation to growth and radioresistance in thyroid cancer cells. This exploration seeks to provide new theoretical insights and potential therapeutic targets for clinical management of 131I-resistant thyroid cancer. Methods The expression levels of ANXA1 in thyroid cancer tissues and cells were assessed through immunohistochemical staining and Western blot analysis. The correlation between ANXA1 expression levels and resistance to 131I was evaluated using cell viability assays (CCK-8), apoptosis analysis and colony formation assays. Additionally, the relationship between ANXA1 and autophagy was investigated by employing mRFP-GFP-LC3 virus transfection in conjunction with confocal microscopy to assess autophagic flux, as well as through Western blotting. Proteomics analysis, co-immunoprecipitation (Co-IP) results, along with various in vitro and in vivo experiments further elucidated the relationship between ANXA1 and HMGB1. Results This study demonstrated for the first time that ANXA1 promotes the development of 131I resistance through the activation of autophagic flux. Proteomic analysis, co-immunoprecipitation (Co-IP) results, as well as various in vitro and in vivo experiments corroborated that ANXA1 activates autophagy by upregulating HMGB1 expression, thereby facilitating 131I drug resistance in thyroid cancer cells. Conclusion This study unveils a novel mechanism by which ANXA1 fosters drug resistance to 131I in thyroid cancer via regulation of the HMGB1-mediated autophagy pathway. This not only provides a new theoretical framework for understanding iodine resistance in thyroid cancer but also identifies a potential molecular target for developing combination therapy strategies aimed at treating iodine-refractory thyroid cancer.