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Background: METTL3 is an RNA methyltransferase that mediates m6A modification and is implicated in mRNA biogenesis, decay, and translation. However, the biomechanism through which METTL3 regulates MALAT1-miR-1914-3p-YAP axis activity to induce NSCLC drug resistance and metastasis is not very clear. Methods: The expression of mRNA was analyzed by qPCR assays. Protein levels were analyzed by western blotting and immunofluorescent staining. Cellular proliferation was detected by CCK8 assays. Cell migration and invasion were analyzed by wound healing and transwell assays, respectively. Promoter activities and gene transcription were analyzed by luciferase reporter assays. Finally, m6A modification was analyzed by MeRIP. Results: METTL3 increased the m6A modification of YAP. METTL3, YTHDF3, YTHDF1, and eIF3b directly promoted YAP translation through an interaction with the translation initiation machinery. Moreover, the RNA level of MALAT1 was increased due to a higher level of m6A modification mediated by METTL3. Meanwhile, the stability of MALAT1 was increased by METTL3/YTHDF3 complex. Additionally, MALAT1 functions as a competing endogenous RNA that sponges miR-1914-3p to promote the invasion and metastasis of NSCLC via YAP. Furthermore, the reduction of YAP m6A modification by METTL3 knockdown inhibits tumor growth and enhances sensitivity to DDP in vivo. Conclusion: Results indicated that the m6A mRNA methylation initiated by METTL3 promotes YAP mRNA translation via recruiting YTHDF1/3 and eIF3b to the translation initiation complex and increases YAP mRNA stability through regulating the MALAT1-miR-1914-3p-YAP axis. The increased YAP expression and activity induce NSCLC drug resistance and metastasis. [ABSTRACT FROM AUTHOR]

African swine fever (ASF), caused by the African swine fever virus (ASFV), is one of the most important infectious diseases that cause high morbidity and mortality in pigs and substantial economic losses to the pork industry of affected countries due to the lack of effective vaccines. The need to develop alternative robust antiviral countermeasures, especially anti-ASFV agents, is of the utmost urgency. This study shows that fangchinoline (FAN), a bisbenzylisoquinoline alkaloid found in the roots of Stephania tetrandra of the family Menispermaceae, significantly inhibits ASFV replication in porcine alveolar macrophages (PAMs) at micromolar concentrations (IC 50 = 1.66 µM). Mechanistically, the infection of ASFV triggers the AKT/mTOR/NF-κB signaling pathway. FAN significantly inhibits ASFV-induced activation of such pathways, thereby suppressing viral replication. Such a mechanism was confirmed using an AKT inhibitor MK2206 as it inhibited AKT phosphorylation and ASFV replication in PAMs. Altogether, the results suggest that the AKT/mTOR pathway could potentially serve as a treatment strategy for combating ASFV infection and that FAN could potentially emerge as an effective novel antiviral agent against ASFV infections and deserves further in vivo antiviral evaluations.