IGF2BP3 promotes non‑small cell lung cancer progression by stabilizing TROAP and inhibiting ferroptosis

N6-methyladenosine (m6A) modification, the most abundant internal modification in eukaryotic mRNA, exerts critical roles in tumorigenesis and cancer progression. Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), a key m6A reader protein, is aberrantly expressed in multiple human cancers and associated with poor prognosis. However, the precise mechanism by which IGF2BP3-mediated m6A modification regulates non-small cell lung cancer (NSCLC) progression, particularly via the modulation of ferroptosis, remains largely unclear. This study aimed to investigate the underlying molecular mechanisms of the IGF2BP3/m6A/trophinin-associated protein (TROAP) axis in NSCLC progression. In our study, bioinformatics analysis using the GEPIA database revealed that IGF2BP3 and TROAP were upregulated in lung adenocarcinoma and lung squamous cell carcinoma tissues compared to normal tissues, with their expression positively correlated. Functionally, IGF2BP3 knockdown inhibited cell proliferation and induced ferroptosis both in vitro and in vivo, characterized by increased lipid peroxidation and Fe 2+ accumulation, alongside the downregulation of the core ferroptosis inhibitors SLC7A11 and GPX4. Mechanistically, as verified by RIP-qPCR, IGF2BP3 directly binds to TROAP mRNA and enhances its stability and expression, putatively through its m6A-reading function. Rescue experiments demonstrated that TROAP overexpression reversed the anti-tumor effects and ferroptosis induction caused by IGF2BP3 knockdown. Collectively, these findings suggest a novel IGF2BP3/TROAP/SLC7A11/GPX4 regulatory axis that may drive the malignant progression of NSCLC by suppressing ferroptosis, identifying potential therapeutic targets for NSCLC treatment. Nevertheless, definitive evidence for m6A-dependent regulation awaits direct m6A site validation.