The role of Nrf2 in anoikis resistance and metastasis in anaplastic thyroid carcinoma

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive endocrine malignancies, characterized by rapid progression, extensive metastasis, and extremely poor prognosis. Despite advances in molecular oncology, the mechanisms driving ATC metastasis and therapeutic resistance remain largely unclear. Cancer cells that detach from the extracellular matrix must evade a specific form of apoptosis known as anoikis, and the ability to survive under these anchorage-independent conditions is a critical prerequisite for metastatic dissemination. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) has emerged as a master regulator of oxidative-stress responses and tumor adaptation, yet its function in governing anoikis resistance in ATC is not well understood. Here we demonstrate that Nrf2 expression is markedly upregulated in ATC tissues and cell lines, where its nuclear translocation drives transcriptional activation of anti-apoptotic and redox-protective genes including BCL-2 and SLC7A11. Under detachment stress, Nrf2 activation enhances cell viability, inhibits apoptosis, and facilitates multicellular aggregate formation, thereby promoting survival. Conversely, genetic silencing or pharmacological inhibition of Nrf2 with Brusatol markedly suppresses proliferation, invasion, and in vivo liver metastasis. Collectively, these findings identify Nrf2 as a pivotal driver of ATC anoikis resistance and metastatic competence through regulation of the BCL-2/SLC7A11 axis. Targeting the Nrf2-dependent survival pathway may thus offer a promising therapeutic strategy for this otherwise refractory malignancy.