Integrated multi-omics atlas reveals PTM-driven signaling and immunologic remodeling in a mouse model of age-related subclinical hypothyroidism.

OBJECTIVE: Age-related subclinical hypothyroidism (AR-SCH) profoundly impairs thyroid structural and functional integrity in the elderly, yet the systemic molecular architecture driving AR-SCH pathogenesis remains poorly understood. This study aimed to construct a comprehensive multi-omic atlas of the AR-SCH mouse thyroid. METHODS: Global proteomics, site-specific N-glycoproteomics, and phosphoproteomics were integrated to profile thyroid tissues from AR-SCH and control mice. RESULTS: In total, 6,666 proteins, 2,476 site-specific N-glycans, and 11,929 phosphorylation sites were identified. Global proteomics revealed a widespread reduction of functional proteins (81.7% downregulated), primarily associated with cytoskeletal structural remodeling and tissue degeneration under AR-SCH conditions. N-glycoproteomics identified altered fucosylation and reduced N-glycosylation associated with extracellular-matrix organization and local immune-related processes. Furthermore, an extensive hypophosphorylation trend (91.53% downregulated sites) was associated with suppression of intracellular signaling cascades, possibly involving autophagic clearance and perturbed apoptotic homeostasis. CONCLUSION: Multi-omics integration suggests an interconnected network as a convergent hallmark of AR-SCH progression, characterized by cytoskeletal reconfiguration, immune regulation shifts, and signaling attenuation that synergistically contribute to systemic thyroid decline, offering a therapeutic window for preserving endocrine homeostasis.