The p16 isoform of CDKN2A inhibits ferroptosis to promote the progression of papillary thyroid carcinoma by influencing the p53/SLC7A11/GPX4 pathway

BACKGROUND: Although papillary thyroid carcinoma (PTC) has a relatively good prognosis, it is also prone to recurrence and metastasis. Cyclin-dependent kinase inhibitor 2 A (CDKN2A) can affect tumor progression by regulating ferroptosis, but its role in PTC remains unclear. MATERIALS AND METHODS: ⁺, ROS, GSH, C11-BODIPY lipid peroxidation, and transmission electron microscopy. Cell proliferation and migration were assessed by CCK-8, colony formation, wound-healing, and Transwell assays. The p53/SLC7A11/GPX4 pathway was examined, and rescue experiments were conducted using p53 agonist and inhibitor. In vivo tumorigenicity was evaluated using a nude mouse xenograft model. RESULTS: CDKN2A was upregulated in PTC and associated with advanced clinicopathological features and lipid metabolism, but was not an independent prognostic factor. Silencing CDKN2A (p14, p16) induced ferroptosis, inhibiting tumor progression; in contrast, overexpression of p14 and p16 inhibited ferroptosis and promoted malignant phenotypes, with p16 playing a predominant role. Moreover, overexpression of p16 could partially resist the induction of ferroptosis by RSL3. Mechanistically, p53 agonist/inhibitor rescue experiments suggested p16 affected p53/SLC7A11/GPX4 pathway. In vivo, p16 overexpression increased tumor growth by inhibiting ferroptosis. CONCLUSION: CDKN2A promotes PTC progression by suppressing ferroptosis via indirect regulation of p53/SLC7A11/GPX4 pathway, primarily through the p16 isoform. Targeted inhibition of p16 isoform is a potential therapeutic strategy for PTC.