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Although the World Health Organization has clearly defined silent pituitary adenomas (SPAs) and functional adenomas (non-SPAs), the detailed biological mechanisms remain unclear. This study conducted a comprehensive analysis of clinical, genomic, transcriptomic, and proteomic differences between SPA and non-SPA. The results revealed significant differences in mutational profiles, with a notably higher mutation rate of the TCHH gene in non-SPA samples. Transcriptomic and proteomic analyses identified distinct expression patterns, highlighting the enrichment of the oxidative phosphorylation pathway and other related Gene Ontology terms in SPA samples. To validate these findings, 11 additional pituitary adenoma samples were analyzed, confirming the critical role of oxidative phosphorylation in SPA. Activation of oxidative phosphorylation altered the hormone secretion, and the electron transfer chain inhibitor restored this in both human and rat pituitary adenoma cell lines. Furthermore, a protein-protein interaction network was constructed, revealing key regulatory differences between SPA and non-SPA, and identifying MAPK1, MAPK3, IDH1, and PKM as key hubs in the network. MAPK1 and PKM knockdown significantly reduced the hormone secretion and apoptosis of both cell lines. These findings suggest that the oxidative phosphorylation pathway plays a pivotal role in the secretory functions of pituitary adenomas. This study offers new insights into the biological mechanisms underlying pituitary adenomas and provides valuable directions for future research, emphasizing the importance of oxidative phosphorylation in tumor behavior and potential therapeutic targets.