Single‐Cell RNA Sequencing and Network Pharmacology Reveal the Potential Role of Oxidative Phosphorylation Inactivation in Diagnosing and Treating Chronic Tendon Injuries

The crucial role of OXPHOS in maintaining tendon homeostasis underscores its potential as a therapeutic target, reflecting that strategies aimed at modulating the OXPHOS pathway may provide promising treatment options. Chronic tendon injuries present a major clinical challenge with limited treatments. This study investigated the molecular mechanisms underlying these injuries using bulk and single-cell RNA sequencing. We identified significant downregulation of oxidative phosphorylation (OXPHOS)-related genes in lesional tendons across multiple cell types, contributing to increased necroptosis. In vitro experiments and molecular docking revealed that valproic acid activates OXPHOS and inhibits necroptosis. These findings highlight the critical role of mitochondrial function in tendon homeostasis and suggest valproic acid as a promising therapeutic candidate for treating chronic tendon injuries by restoring OXPHOS activity.