Proteomic trajectories in human rotator cuff degeneration: a systematic review of immunohistochemical studies

Abstract Background Rotator cuff (RC) repairs heal unreliably, particularly in chronic disease. The molecular mechanisms underlying failed repair remain poorly understood. While individual studies have examined protein expression in diseased RC tissue, no synthesis has investigated these findings across various disease stages. This systematic review explores the stage-specific protein expression of human RC degeneration using immunohistochemistry. Methods Following PRISMA guidelines, MEDLINE, Embase, and Cochrane Library were systematically searched to September 2025 for human studies that use immunohistochemistry to evaluate protein expression in intraoperative RC tendon or muscle biopsies. Study quality was appraised with Joanna Briggs Institute (JBI) tools. No meta-analysis was performed due to heterogeneity. Results Forty-seven studies were included. Despite methodological heterogeneity, convergent molecular patterns emerged within disease stages. Partial and small tears demonstrated hypoxic-inflammatory-apoptotic signatures (HIF-1α, BNip3, IL-6, IL-1β, MMP-1/3/9) with preserved regenerative markers (Ki67, CD34), suggesting reparative potential. Medium tears exhibited sustained angiogenic activity (VEGF) and emerging adipogenic drift (PPARγ, C/EBPα). Large and massive tears showed depletion of anabolic factors (TGF-β1, BMP-5), M2-macrophage predominance (CD206, CD163), and fibrofatty infiltration. Patient comorbidities (diabetes, vitamin D deficiency, smoking) amplified inflammatory and adipogenic signatures. Conclusions Cross-sectional human immunohistochemical evidence infers a stage-associated molecular trajectory: inflammatory-hypoxic stress with retained reparative capacity at earlier disease stages to fibrotic–adipogenic failure at later stages. This molecular framework may support future approaches to surgical decision-making and precision therapies.