Hyperlipidemia-induced metabolic dysregulation impairs tendon homeostasis: the role of TGF-β/Smad2 signaling pathway in lipid-mediated extracellular matrix remodeling

Background: signaling pathway serves as a central regulator of tendon ECM metabolic homeostasis, among which the TGF-β/Smad2 axis can directly mediate the balanced regulation of collagen synthesis and degradation in tendons, yet its specific role and underlying molecular mechanism in hyperlipidemia-induced tendon ECM dysfunction remain poorly defined. Methods: /Smad2 signaling axis in tendon tissue. Specifically, we assessed TβRII localization within lipid rafts, TGF-β activation, downstream transcription of Col1a1 and lysyl oxidase (LOX), and matrix metalloproteinase-1 (MMP-1) activity. Results: RII localization in lipid rafts, leading to impaired TGF-β activation. This suppressed Smad2 signaling, decreased Col1a1 transcription and LOX expression, and increased MMP-1 activity. Consequently, tendon collagen synthesis declined while degradation rose, undermining structural integrity and intrinsic repair capacity. Conclusion: /Smad2 axis is the critical mechanism linking metabolic dysregulation to tendon matrix failure. Restoring TGF-β/Smad2 signaling represents a promising therapeutic strategy to mitigate hyperlipidemia-induced tendon damage and poor healing.