DAMP: bridging mechanotransduction and immune responses in tendinopathy

Tendinopathy is increasingly recognized as a chronic degenerative disorder driven by sterile inflammation, where persistent mechanical stress and dysregulated innate immunity converge to disrupt tissue homeostasis. Damage-associated molecular patterns (DAMPs), released from stressed or injured tenocytes and resident immune cells, serve as key mediators translating mechanical overload into sustained inflammatory responses. Their persistent release perpetuates inflammation, extracellular matrix disorganization, and impaired tissue repair, thereby establishing a self-sustaining cycle of degeneration. Recent studies have highlighted DAMPs as central regulators in the initiation and maintenance of tendon inflammation, reflecting an intricate interplay between mechanical cues, metabolic stress, and immune dysfunction. This review summarizes current understanding of DAMP-mediated mechanisms in tendinopathy, emphasizing their roles in inflammation, fibrosis, and tissue remodeling. We also discuss the therapeutic implications of modulating DAMP-driven signaling pathways to restore immune homeostasis and promote regenerative healing. A clearer understanding of these immunomechanical interactions provides a foundational framework for developing mechanism-based treatments that target the underlying causes of tendinopathy.