METTL3-mediated m6A modification of lncRNA MALAT1 promotes colorectal cancer progression by activating the NF-κB signaling pathway

Colorectal cancer (CRC), a prevalent malignancy of the digestive system, is often characterized by poor patient prognosis due to high rates of recurrence and metastasis. N6-methyladenosine (m 6 A) modification represents a crucial epigenetic mechanism regulating RNA (including lncRNAs) function and is increasingly implicated in tumor progression. However, the underlying regulatory mechanism of m 6 A modification in CRC pathogenesis remain incompletely understood. We first integrated bioinformatic analysis data, which revealed a significant positive correlation and co-enrichment of methyltransferase-Like 3 (METTL3) and the lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in a high-risk prognostic signature. Functional validation included in vitro assessments of cellular proliferation, migration, invasion, apoptosis, and m 6 A methylation levels following METTL3 or MALAT1 suppression, alongside in vivo xenograft tumor models to evaluate the effects of a METTL3 inhibitor on tumor growth dynamics and m 6 A modification levels. Finally, mechanistic profiling was conducted to dissect NF-κB pathway activity. METTL3 and MALAT1 were markedly upregulated in CRC tissues and cell lines. Molecular docking identified trihydroxy methylcyclohexane aminoglycoside (TMA) as a high-affinity METTL3-binding compound. Inhibition of METTL3 or MALAT1 significantly impaired cellular proliferation, migration, and invasion, while promoting apoptosis. RNA immunoprecipitation quantitative PCR (RIP-qPCR) and RNA stability assays established that METTL3 maintains MALAT1 stability via m 6 A modification. In vivo, suppression of METTL3 potently inhibited xenograft tumor growth without observable toxicity. Western blot and immunohistochemistry (IHC) analyses further verified that this METTL3-MALAT1 axis activates the NF-κB pathway by modulating IκBα degradation and p65 nuclear translocation. Collectively, our work elucidates the METTL3-m 6 A-MALAT1-NF-κB regulatory axis in CRC, advancing the understanding of epigenetic mechanisms in cancer progression and providing a theoretical foundation for developing METTL3-targeted therapeutic strategies.