Objective: Myopic traction maculopathy (MTM) is a common cause of visual impairment in patients with high myopia, although its precise pathogenesis remains unclear. This study aimed to identify significantly altered factors in the vitreous humor (VH) associated with clinical manifestations, and to explore potential biomarkers and therapeutic targets for MTM.

Methods: VH samples were collected from patients with MTM and control patients with vitreomacular interface disorders. Proteomic profiling via ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was performed to identify dysregulated proteins and enriched signaling pathways Key differentially expressed proteins (DEPs) were validated using protein microarray and ELISA, and their correlations with axial length (AL), and disease severity were evaluated.

Results: A total of 310 DEPs were identified in the VH, mainly associated with the extracellular matrix (ECM). Fibrosis‑related proteins (TGF‑β2, MMP‑2, TIMP‑2, and PRG4) and oxidative stress‑related proteins (PRDX2, ANG, and CAT) were significantly upregulated in the MTM group and showed positive correlation with AL. Among these, only PRG4 and PRDX2 levels correlated with the severity of retinal traction.

Conclusions: Alterations in the VH microenvironment, particularly those involving oxidative stress and ECM hydration regulation, likely contribute to the development and progression of MTM, PRG4 demonstrates a strong association with traction severity and warrants further investigation as a potential biomarker.