METTL14 modulates the nasopharyngeal carcinoma microenvironment via m⁶A-modified YWHAH identified through single-cell...

Nasopharyngeal carcinoma (NPC) is an aggressive malignancy with endemic prevalence in southern China. Emerging evidence highlights the critical function of the N6-methyladenosine (m⁶A) methylation in NPC progression, where sustained cytokine activity contributes to immunosuppression and immune evasion.

Single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing datasets were obtained from the GEO database. High-dimensional downstream analyses, including hdWGCNA, cell-cell communication, and pseudotime analysis was performed to characterize cellular interactions and transcriptional programs. Machine learning algorithms and immune infiltration profiling were integrated with MeRIP-seq to identify the key m⁶A-regulated gene. The post-transcriptional regulatory role was further validated in NPC cells with overexpression or knockdown of METTL14, or in cells with YWHAH silenced.

B cells were identified as the primary senders to the TNF pathway, with epithelial and myeloid cells acting as influencers and receivers. YWHAH emerged as a key TNF-associated, m⁶A-regulated gene, with elevated expression in naive/GC B cells, interleukin (IL)-1β+ tumor-associated macrophages, and differentiated epithelial cells. METTL14-deficient increased YWHAH transcript abundance and RNA stability, whereas TNF-α stimulation further enhanced YWHAH expression. Conversely, YWHAH knockdown impaired NPC cell migration and upregulated IL-6/IL-8 expression, effects that were partially rescued by TNF-α treatment.

Integration of multi-omics data facilitated the identification of YWHAH as a METTL14-regulated gene, which plays a pivotal role in the NPC immune microenvironment. The elevated expression of YWHAH indicates its role in regulating immune balance. Together these findings suggest a potential regulatory link between TNF-α, YWHAH and METTL14 in the context of NPC.