Proteomic biomarkers in rotator cuff disease: Current evidence and translational implications from a systematic review and network analysis

Rotator cuff disorders are among the most common causes of shoulder pain and dysfunction, primarily driven by chronic inflammation and degenerative changes in tendon tissue. These alterations lead to progressive structural damage and compromised function. In recent years, proteomic profiling has emerged as a promising strategy for identifying molecular signatures associated with disease mechanisms and potential translational applications. A systematic review was conducted using PubMed and Scopus databases, targeting studies published between 2015 and 2024. Included studies focused on proteomic biomarker analysis in synovial fluid, and blood from patients affected by rotator cuff disorders. Methodological quality and risk of bias were evaluated using the Newcastle-Ottawa Scale for observational studies and the RoB 2.0 tool for randomized controlled trials. Seven studies were found to meet the inclusion criteria. Among the most consistently reported proteins were matrix metalloproteinase-1, matrix metalloproteinase-13, interleukin-1β, interleukin-6, and transforming growth factor-β1, with a predominant presence in synovial fluid samples. Enrichment analyses pointed to their involvement in inflammatory cascades, extracellular matrix turnover, and neovascularization. Network analysis of protein-protein interactions highlighted interleukin-6 and matrix metalloproteinase-13 as central nodes, indicating a pivotal role in modulating disease progression. The most reported biomarkers, such as matrix metalloproteinase-1, matrix metalloproteinase-13, interleukin-1 β , interleukin-6, and transforming growth factor- β 1, are associated primarily with inflammatory signaling and extracellular matrix remodeling, highlighting their involvement in molecular pathways related to rotator cuff disease progression and tissue degeneration. Gene Ontology enrichment and KEGG pathway analyses further revealed that these proteins are significantly involved in biological processes relevant to tendon degeneration, including cytokine-mediated signaling, the wound response, and ECM organization. The identified biomarkers, particularly interleukin-6, matrix metalloproteinase-1, matrix metalloproteinase-13, and transforming growth factor-β1, may represent candidates for inclusion in future multi-analyte diagnostic panels, pending rigorous clinical validation. However, at present these applications remain hypothetical. Further large-scale, standardized, and longitudinal studies are required to validate their incremental value beyond imaging and clinical evaluation before any clinical translation can be considered. This systematic review synthesizes current evidence on proteomic biomarkers detectable in the synovial fluid and blood of patients with rotator cuff disorders, highlighting candidate molecules (e.g., IL-6, MMP-1, MMP-13, TGF-β1) that are mechanistically linked to inflammation and extracellular matrix remodeling. While these markers are not disease-specific, they may have translational utility as components of multi-analyte panels for (1) stratifying disease severity, (2) monitoring biological response to conservative or surgical treatments, and (3) potentially informing future strategies for disease stratification and personalized therapeutic approaches. Real-world clinical translation will require standardized sample collection and assay protocols, analytical validation (targeted MS or clinical immunoassays), and prospective studies to define diagnostic thresholds and incremental value over imaging and clinical assessment. Graphical abstract created with BioRender.com