<p>Challenges in the precise diagnosis and treatment of nasopharyngeal carcinoma (NPC) remain, mainly due to the absence of a multi-omics-based molecular classification and effective targeted therapies. In this study, we performed proteomic and phosphoproteomic analyses of NPC and non-cancerous nasopharyngeal tissues to identify key dysregulated proteins and phosphorylation networks. Based on these profiles, we classified NPC into two distinct molecular subtypes: S1 and S2, which exhibit significant clinical heterogeneity. Notably, the S2 subtype displayed stronger immune suppressive characteristics. By leveraging proteomic data from both cancerous and non-cancerous tissues, as well as from the two molecular subtypes, we developed robust diagnostic and prognostic models. Through computational drug repurposing and experimental validation, we identified Panobinostat, a pan-histone deacetylase inhibitor, as a potent anti-tumor agent for NPC, demonstrating efficacy in both in vitro and in vivo models. Mechanistically, Panobinostat inhibits MYC expression, thereby suppressing the transcriptional activation of key components in the homologous recombination (HR) DNA repair pathway. This reduction in transcriptional activation impairs HR repair efficiency and leads to the accumulation of DNA double-strand breaks (DSBs). Furthermore, combination therapy with Panobinostat and radiotherapy produced a synergistic effect, significantly enhancing NPC suppression. Additionally, we predicted and validated potential drugs for targeting the S2 subtype of NPC. In conclusion, we identified molecular subtypes of NPC, constructed preliminary diagnostic and prognostic marker panels, and observed the therapeutic potential of Panobinostat, as a monotherapy and in combination with radiotherapy. These findings provide a solid foundation for precision diagnosis, prognostic stratification, and personalized treatment strategies for NPC.</p>