Molecular architecture of language‐related cortical areas revealed by integrative proteomic and connectome analyses

Abstract Background Protein expression asymmetry between brain hemispheres is hypothesized to influence functional connectivity, yet its role in language‐related networks remains poorly understood. Additionally, how such molecular differences relate to brain reorganization in glioma requires further exploration. Methods We performed label‐free tandem mass spectrometry on 13 left‐hemispheric language‐related Brodmann areas (BAs) and their right‐hemispheric counterparts from 10 donor brains, identifying protein signatures across 6 language‐related functional modules. We then compared these proteomic profiles with resting‐state structural and functional connectivity data from 26 BAs across 90 subjects from the Human Connectome Project (HCP). Finally, we examined functional compensation in 13 glioma patients with tumors in Wernicke's area, correlating gray matter volume in contralateral homologs with linguistic performance. Results Protein expression heterogeneity was greater within hemispheres than between homologous contralateral BAs. Hierarchical clustering revealed interactions between core language areas (Broca's, Wernicke's, Geschwind's) and auditory/motor regions. Functional connectivity strength correlated with protein expression similarity, particularly in symmetric BA4 (primary motor cortex). Excitatory/inhibitory (E/I) neuronal markers (GRIA1/GRIA4) showed a left‐positive, right‐negative correlation with connectivity, suggesting hemispheric differences in synaptic regulation. Glioma patients exhibited right‐hemispheric compensation, with gray matter volume in Wernicke's homolog correlating with linguistic function. Conclusion Our findings support the hypothesis of a homophilic mixing effect between protein expression similarity and connectome architecture, and help explain brain rearrangement in glioma patients. Key points Protein expression differs more within hemispheres than across homologous regions, with distinct signatures in language‐related brain areas. Functional connectivity strength correlates with protein expression similarity, showing left‐right asymmetry in excitatory/inhibitory synaptic regulation (GRIA1/GRIA4). Right‐hemispheric homologs compensate for left‐hemispheric language‐area damage in glioma patients, linking molecular profiles to functional reorganization.