ABSTRACT Background Chronic tendon injuries, characterized by persistent pain, reduced flexibility, and impaired function, pose a significant clinical challenge. Current therapeutic strategies for these injuries are limited. This study highlighted the crucial role of OXPHOS in maintaining tendon homeostasis and suggested potential therapeutic strategies targeting the OXPHOS pathway. Method This study utilized both bulk‐sequencing (bulk‐seq) and single‐cell RNA sequencing (scRNA‐seq) to analyze the heterogeneity in tenocytes, vascular endothelial cells, tendon‐derived stem cells, adipocytes, and neurons from both non‐lesional and lesional tendons. Key oxidative phosphorylation (OXPHOS)‐related genes, such as COX15, COX4I1, COX5B, COX7A1, COX8A, NDUFA12, NDUFA5, NDUFB10, NDUFB3, NDUFC1, NDUFS1, and NDUFS4, were found to be significantly downregulated in lesional tendons compared with non‐lesional ones, indicating impaired energy metabolism. This reduction in OXPHOS activity may contribute to increased necroptosis in chronic tendon injuries. Furthermore, bisphenol A and valproic acid were found to activate OXPHOS‐related genes. Results The findings highlighted the crucial role of OXPHOS in maintaining tendon homeostasis and demonstrated potential therapeutic strategies targeting the OXPHOS pathway, such as bisphenol A and valproic acid, to enhance healing in chronic tendon conditions. Conclusion 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.
Niu et al. (2026) studied this question.