Dual targeting of AMRC12 and <i>Malassezia globosa</i> disrupts MYC liquid condensates-driven nuclear pore complex biogenesis in neuroblastoma

<b>Rationale:</b> Neuroblastoma (NB) is a predominant extra-cranial malignancy in childhood, while molecular drivers of its progression and effective treatment strategies have yet to be clarified. <b>Methods:</b> RNA sequencing was performed to identify transcriptional regulators and corresponding target genes. To explore the biological effects and underlying mechanisms of these regulators, a comprehensive methodology was utilized, encompassing chromatin immunoprecipitation, dual-luciferase reporter assay, qRT-PCR, western blot, alongside gene over-expression and silencing techniques, co-immunoprecipitation, and mass spectrometry. The MTT assay, soft agar colony formation, Matrigel invasion, and nude mouse xenograft models were applied to assess oncogenic properties. Patient survival was analyzed using the log-rank test. <b>Results:</b> Armadillo repeat containing 12 (ARMC12) was identified as a MYC-interacting modulator within liquid condensates to up-regulate critical nucleoporin-encoding targets (<i>NUP62</i>/<i>NUP93</i>/<i>NUP98</i>), which promoted nuclear pore complex (NPC) biogenesis to facilitate nuclear trafficking of oncogenic effectors, thereby enhancing invasion and metastasis of NB. As a protein within extracellular vesicles of <i>Malassezia globosa</i> colonizing NB tissues, MGL_0381 also facilitated MYC transactivation via physical interaction to accelerate NPC biogenesis and NB progression. Tioconazole (TCZ) and UU-T02 were identified as efficient inhibitors blocking ARMC12-MYC and MGL_0381-MYC interaction, and synergistically reduced NPC number and aggressive features of NB. High <i>ARMC12</i>, <i>MYC</i>, <i>NUP62</i>, <i>NUP93</i>, or <i>NUP98</i> levels served as markers of unfavorable patient outcomes in clinical cohorts. <b>Conclusions:</b> These findings collectively demonstrate that dual targeting of AMRC12 and <i>Malassezia globosa</i> disrupts MYC liquid condensates-driven NPC biogenesis during NB progression.