Quercetin attenuates tendon stem/progenitor cell senescence and promotes aged tendon repair via AKT/NF-κB/NLRP3-mediated mitophagy activation

Hao Wang; Yu-Cheng Gao; Ming-Zhang; Guang-Chun Dai; Pan-Pan Lu; Ying-Juan Li; Mu-Min Cao; Xiao-Yu Liu; Ren-Wang Sheng; Liu Shi; Cheng Zhang; Wen-Guo Cui; Yun-Feng Rui

doi:10.1016/j.jare.2025.08.013

Quercetin attenuates tendon stem/progenitor cell senescence and promotes aged tendon repair via AKT/NF-κB/NLRP3-mediated mitophagy activation

J Adv Res. 2025 Aug 11:S2090-1232(25)00604-6. doi: 10.1016/j.jare.2025.08.013. Online ahead of print.

Authors

Affiliations

¹ Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, PR China; Orthopaedic Trauma Institute, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, PR China; Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, PR China.
² Department of Geriatrics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, PR China.
³ Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China. Electronic address: wgcui80@hotmail.com.
⁴ Department of Orthopaedics, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, PR China; Orthopaedic Trauma Institute, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, PR China; Trauma Center, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Ding Jia Qiao, Nanjing, Jiangsu 210009, PR China. Electronic address: ruiyunfeng@126.com.

PMID: 40803494
DOI: 10.1016/j.jare.2025.08.013

Abstract

Introduction: Aged tendon exhibits impaired regenerative capacity due to the accumulation of senescent tendon stem/progenitor cells (TSPCs), which secrete senescence-associated secretory phenotype (SASP) factors and display compromised differentiation. Despite its clinical significance in recurrent tendon injury, no targeted therapies exist to counteract TSPCs senescence.

Objectives: This study aimed to investigate the anti-senescent effects of quercetin on TSPCs through a mechanistic exploration of the AKT/mitochondrial/SASP axis and to develop a dipeptide-hydrogel delivery system (DPH@QUE) for the localized treatment of age-related tendon injury.

Methods: Senescent TSPCs were treated with quercetin in vitro to assess SASP reduction and tenogenic differentiation via molecular profiling. Mechanistically, AKT phosphorylation and mitochondrial function were analyzed. In vivo, DPH@QUE was administered to aged rat Achilles tendon injury models, with histopathological and functional evaluations conducted at 8 weeks post-intervention.

Results: Quercetin significantly alleviated senescence in TSPCs, as evidenced by decreased secretion of SASP and enhanced tenogenic differentiation. Mechanistically, the inhibition of AKT phosphorylation ameliorated mitochondrial dysfunction and suppressed SASP secretion by modulating the NF-κB/NLRP3 signaling axis, thereby attenuating TSPCs senescence. Furthermore, the sustained release of quercetin using a dipeptide hydrogel into the site of Achilles tendon injury in elderly rats produced exceptional anti-inflammatory and reparative effects, effectively restoring endogenous tendon regeneration.

Conclusion: Our findings suggest quercetin could alleviate senescent phenotypes in TSPCs through AKT-mediated mitochondrial stabilization and SASP suppression. The DPH@QUE delivery system enables effective translation of these anti-aging effects into functional tendon regeneration, providing a novel therapeutic strategy for aging tendon injury.

Keywords: Cellular senescence; Inflammation; SASP; Tendon aging; Tendon stem/progenitor cells.