Theaflavin-3,3'-digallate attenuates chondrocyte senescence via modulating FGF7 and KEAP1/NRF2 signaling pathway

  • Free Radic Biol Med. 2026 Sep:253:1-17. doi: 10.1016/j.freeradbiomed.2026.05.303.
Hongwei Kou  1 ,  Feng Lu  2 ,  Maoyuan Li  3 ,  Yimin Liu  4 ,  Shishou Li  5 ,  Guangrong Yin  6 ,  Jie Chen  7 ,  Gongyin Zhao  8 ,  Liangliang Wang  9 ,  Yuji Wang  10 ,  Chao Xu  11
Affiliations
  • 1. Graduate School of Dalian Medical University, 9 West Section, Shunnan Road, Dalian, 116044, China. Electronic address: [email protected].
  • 2. Nanjing Medical University, Nanjing, 210000, China. Electronic address: [email protected].
  • 3. Nanjing Medical University, Nanjing, 210000, China. Electronic address: [email protected].
  • 4. Nanjing Medical University, Nanjing, 210000, China. Electronic address: [email protected].
  • 5. Graduate School of Dalian Medical University, 9 West Section, Shunnan Road, Dalian, 116044, China. Electronic address: [email protected].
  • 6. Department of Orthopedics, The Second People's Hospital of Changzhou, The Third Affiliated Hospital of Nanjing Medical University, Changzhou, 213003, China. Electronic address: [email protected].
  • 7. Trauma Central, The Second People's Hospital of Changzhou, The Third Affiliated Hospital of Nanjing Medical University, Changzhou, 213003, China. Electronic address: [email protected].
  • 8. Department of Orthopedics, The Second People's Hospital of Changzhou, The Third Affiliated Hospital of Nanjing Medical University, Changzhou, 213003, China. Electronic address: [email protected].
  • 9. Department of Orthopedics, The Second People's Hospital of Changzhou, The Third Affiliated Hospital of Nanjing Medical University, Changzhou, 213003, China. Electronic address: [email protected].
  • 10. Department of Orthopedics, The Second People's Hospital of Changzhou, The Third Affiliated Hospital of Nanjing Medical University, Changzhou, 213003, China; Department of Orthopedics, The Third Affiliated Hospital of Gansu University of Chinese Medicine, 222 Silong Road, Baiyin, 730900, China; Center for Bone Disease Rehabilitation, The Second People's Hospital of Changzhou, The Third Affiliated Hospital of Nanjing Medical University, Changzhou, 213003, China. Electronic address: [email protected].
  • 11. Trauma Central, The Second People's Hospital of Changzhou, The Third Affiliated Hospital of Nanjing Medical University, Changzhou, 213003, China. Electronic address: [email protected].
PMID: 42162842 DOI: 10.1016/j.freeradbiomed.2026.05.303
Abstract

Studies have demonstrated that chondrocyte senescence is involved in the pathological progression of osteoarthritis. This study aimed to investigate the effect of TF3 on chondrocyte senescence and its underlying molecular mechanism. Primary chondrocytes were isolated from mice, and senescence-related markers, Mitochondrial Metabolism levels, and the expression of the FGF7/Keap1-NRF2-related pathway were examined using CCK-8 assay, Western blot, β-galactosidase staining, and fluorescence staining. RNA Sequencing and molecular docking were further employed to explore the mechanisms by which TF3 inhibits chondrocyte senescence. A mouse model of destabilization of the medial meniscus (DMM) was established, and the anti-senescence and cartilage protective effects of TF3 were evaluated through H&E staining, immunohistochemistry, micro-CT, and Safranin O/Fast Green staining. The results showed that TF3 suppressed the expression of senescence-associated proteins, including p16Ink4a, p21, IL-6, and MMP13, while promoting the expression of Coll2a1 in IL-1β induced cell senescence model. Additionally, TF3 reduced β-galactosidase activity and alleviated DNA damage. RNA Sequencing and experimental findings revealed that the anti-senescence effect of TF3 might be related to the regulation of oxidative stress and Mitochondrial Metabolism. Furthermore, the FGF7 and Keap1/NRF2 pathway were involved in TF3-mediated inhibition of chondrocyte senescence. NRF2 knockdown and exogenous rFGF7 supplementation abrogated the protective effects of TF3 against chondrocyte senescence. Animal experiments further confirmed that TF3 exerted anti-senescence effects and delayed joint degeneration. This study reveals important molecular mechanisms by which TF3 inhibits chondrocyte senescence and retards OA progression, suggesting that TF3 may serve as a potential novel therapeutic strategy for OA.

Keywords
Cellular senescence; Fibroblast growth factor 7; Nuclear factor erythroid -related factor 2; Osteoarthritis; Theaflavin-3,3′-digallate.
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