The role of YTHDF1 in the diagnosis and prognosis of lung adenocarcinoma and its inhibitor LY-411575 in the targeted intervention of lung adenocarcinoma growth

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Background: YTHDF1, a regulator of N6-methyladenosine (m6A) modification, participates in regulating the pathological mechanism of cancer, but its role in lung adenocarcinoma (LUAD) remains in need of deeper elucidation. This study aimed to uncover potential molecular characteristics of YTHDF1 in LUAD, establishing a conceptual foundation for disease management. Methods: YTHDF1 expression was analyzed in LUAD using The Cancer Genome Atlas (TCGA) data, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blotting. A competitive endogenous RNA (ceRNA) network was established to explore molecular interactions, and LUAD was categorized based on YTHDF1 expression levels. Survival rates and immune cell infiltration were compared between categories. Genes related to YTHDF1 were identified based on weighted gene co-expression network analysis (WGCNA), and related functional enrichment analysis was performed. Chemotherapy drug sensitivity against YTHDF1 was predicted using the pRRophetic algorithm and the Genomics of Drug Sensitivity in Cancer (GDSC) data. YTHDF1-specific small molecule inhibitors were screened, and their effects on LUAD progression were analyzed in vitro and in vivo. Results: Results showed YTHDF1 was up-regulated in LUAD and may be a new diagnostic biomarker of LUAD. Increased YTHDF1 expression was related to poor prognosis and immune dysregulation in LUAD. The study identified 130 co-expressed genes and 37 chemotherapy drugs associated with YTHDF1 expression. The small molecule inhibitor LY-411575 targeting YTHDF1 could inhibit the growth of LUAD cells. Conclusions: Our study indicates that elevated expression of YTHDF1 is a predictor of poor prognosis in patients with LUAD and may serve as a potential diagnostic biomarker and therapeutic target for this disease. In addition, we identified LY-411575 as a YTHDF1 inhibitor that effectively inhibits the proliferation of LUAD cells in vivo and in vitro, highlighting its potential as a LUAD targeted therapy.

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