IGF2BP3 stabilizes TROAP mRNA and suppresses ferroptosis in non-small cell lung cancer

A new study published in Discover Oncology on 28 October 2026 reports that the m6A reader protein IGF2BP3 promotes the progression of non-small cell lung cancer (NSCLC) by stabilizing the mRNA of trophinin-associated protein (TROAP) and thereby suppressing ferroptosis, an iron-dependent form of regulated cell death.

The investigation began with bioinformatics analysis using the GEPIA database, which showed that both IGF2BP3 and TROAP are upregulated in lung adenocarcinoma and lung squamous cell carcinoma tissues compared with normal tissues, and that their expression levels are positively correlated. IGF2BP3 is a key reader protein for N6-methyladenosine (m6A), the most abundant internal modification in eukaryotic mRNA, and it has been found aberrantly expressed in multiple human cancers, where its presence is associated with poor prognosis. The authors set out to clarify how IGF2BP3-mediated m6A modification contributes to NSCLC progression, particularly through modulation of ferroptosis, a question they describe as remaining largely unclear.

Functionally, the team found that knocking down IGF2BP3 inhibited cell proliferation and induced ferroptosis both in vitro and in vivo. The ferroptosis induction was characterized by increased lipid peroxidation and accumulation of Fe2+, alongside downregulation of SLC7A11 and GPX4, which the study identifies as core inhibitors of ferroptosis. These results suggest that IGF2BP3 helps lung cancer cells evade this form of cell death by maintaining the expression of anti-ferroptotic defenses.

Mechanistically, the researchers used RNA immunoprecipitation followed by quantitative PCR (RIP-qPCR) to verify that IGF2BP3 directly binds to TROAP mRNA and enhances both its stability and its expression. The authors state that this enhancement occurs putatively through IGF2BP3’s m6A-reading function, meaning the connection to m6A is proposed rather than directly demonstrated. Rescue experiments strengthened the proposed pathway: when TROAP was overexpressed, the anti-tumor effects and ferroptosis induction caused by IGF2BP3 knockdown were reversed, placing TROAP downstream of IGF2BP3 in the mechanism.

Collectively, the findings suggest that an IGF2BP3/TROAP/SLC7A11/GPX4 axis may drive malignant progression of NSCLC by suppressing ferroptosis, and the authors present the axis as identifying potential therapeutic targets for NSCLC treatment. The study is a preprint-style early-release version shared to provide faster access to peer-reviewed, accepted research; it is citable and carries a permanent DOI, but remains subject to further edits before the final Version of Record.

The authors also note an important limitation: definitive evidence for m6A-dependent regulation of TROAP by IGF2BP3 awaits direct validation of the m6A sites themselves. As such, while the RIP-qPCR data support direct binding of IGF2BP3 to TROAP mRNA and the functional experiments link the axis to ferroptosis suppression, the precise m6A-mediated mechanism remains to be confirmed. If validated, the proposed axis could offer a route toward therapies that sensitize NSCLC cells to ferroptosis by targeting IGF2BP3 or TROAP.

Subject of Research: The role of the m6A reader protein IGF2BP3 and TROAP in suppressing ferroptosis during non-small cell lung cancer progression

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

Article References: Ji, M., Chen, T., Yuan, B., Du, Q., Wang, Y., Xia, G., Zhang, Y., Li, Q., Xiang, C., & Tu, Y. (2026). IGF2BP3 promotes non‑small cell lung cancer progression by stabilizing TROAP and inhibiting ferroptosis. Discover Oncology. https://doi.org/10.1007/s12672-026-06165-9

Image Credits: AI Generated

DOI: 10.1007/s12672-026-06165-9

Keywords: IGF2BP3, TROAP, non-small cell lung cancer, ferroptosis, m6A modification, SLC7A11, GPX4, lung adenocarcinoma, lung squamous cell carcinoma, RIP-qPCR, lipid peroxidation, Discover Oncology