Hyperlipidemia exacerbates frozen shoulder fibrosis by activating the TGF-β/Smad2/3 signaling pathway via the TBX5-TNC-Itgα2 axis.

Hyperlipidemia is strongly implicated in frozen shoulder, but the molecular mechanisms linking this systemic metabolic disorder to localized joint fibrosis remain unknown. To elucidate this, we established a hyperlipidemic rat model and employed transcriptomics, along with comprehensive molecular validation assays, in human synovial fibroblasts. We discovered that oxidized low-density lipoprotein initiates the fibrotic cascade by upregulating the transcription factor TBX5. TBX5 then transcriptionally promotes the expression of the extracellular matrix protein tenascin-C (TNC). TNC subsequently binds to integrinα2 (Itgα2) on fibroblasts, thus activating the potent profibrotic TGF-β/Smad2/3 signaling pathway. In vivo targeting of TBX5 significantly mitigated both mobility loss and joint capsule fibrosis in the hyperlipidemic rat model. This work defines the TBX5-TNC-Itgα2 axis as a novel molecular bridge connecting systemic HL to localized pathology, identifying critical targets for developing precision anti-fibrotic therapies.