Integrated multi-omics profiling of thymoma identifies subtype-specific remodeling and myasthenia gravis–associated targets

Thymoma is a rare thymic epithelial tumor strongly associated with myasthenia gravis (MG), yet the tumor-intrinsic molecular basis of this link remains unclear. Here, we integrated untargeted metabolomics, lipidomics, and label-free quantitative proteomics of paired thymoma and adjacent thymic tissues with MG status, clinicopathologic data, immunohistochemistry, and TCGA transcriptomic validation. Thymoma displayed coordinated alterations in amino acid and nucleotide metabolism alongside structured lipid subclass changes consistent with membrane remodeling. Proteomic analysis resolved three molecular subtypes with distinct pathway programs tightly coupled to lipid metabolism, identifying HMGCS1 and SCP2 as subtype-enriched, lipid-linked hubs. An MG-associated module comprising creatine, MePC(37:4), ACP5, AP1S1, NECTIN4, and fatty acid pathways was uncovered, with AP1S1 serving as an independent prognostic marker. A 13-lipid panel accurately distinguished thymoma from adjacent thymus as a proof-of-concept classifier. This multi-omics study highlights HMGCS1, SCP2, and AP1S1 as prioritized candidates for further mechanistic and translational investigation.