METTL7B ‐Mediated m6A Modification of PLEKHA4 Suppresses Ferroptosis via Reducing AURKA Wei Lin, Kunlin Wu, Jinshu Chen, Zhaomei Yu, Huihao Zhang, Xiangjin Chen

ABSTRACT

The malignant progression of papillary thyroid carcinoma (PTC) is closely associated with the acquisition of ferroptosis resistance by tumor cells; however, the upstream regulatory mechanisms remain poorly understood. This study aims to elucidate the function and molecular mechanisms of the methyltransferase‐like 7B (METTL7B)/pleckstrin homology domain‐containing family A member 4 (PLEKHA4)/aurora kinase A (AURKA) signaling axis in ferroptosis resistance in PTC. Our results showed that PLEKHA4 was highly expressed in PTC. By binding to kelch‐like protein 12 (KLHL12), PLEKHA4 inhibited KLHL12‐mediated ubiquitination and degradation of AURKA, thereby stabilizing the AURKA protein and enhancing ferroptosis resistance in PTC cells. Upstream, METTL7B stabilized PLEKHA4 mRNA and upregulated its expression through N6‐methyladenosine (m6A) modification. Both in vitro and in vivo experiments confirmed that knockdown of METTL7B increased ferroptosis sensitivity and suppressed PTC progression. This study reveals a novel paradigm in which PLEKHA4, as an effector of m6A modification, regulates ferroptosis by interfering with ubiquitin‐mediated degradation, providing a theoretical basis for targeting this pathway in the treatment of PTC.