2. Academic Validation
  3. Paeoniflorin mitigates iron overload-induced osteoarthritis by suppressing chondrocyte ferroptosis via the p53/SLC7A11/GPX4 pathway

Paeoniflorin mitigates iron overload-induced osteoarthritis by suppressing chondrocyte ferroptosis via the p53/SLC7A11/GPX4 pathway

  • Int Immunopharmacol. 2025 Jun 19:162:115111. doi: 10.1016/j.intimp.2025.115111.
Boyu Wu 1,  Zhiqiang Luo 2,  Zehua Chen 3,  Yifan Lu 2,  Jianhui Duan 4,  Zhuo Yang 5,  Guoliang Lu 6
Affiliations

Affiliations

  • 1 Department of Orthopaedics, Dongguan Hospital of Guangzhou University of Chinese Medicine (Dongguan Hospital of Traditional Chinese Medicine), Dongguan 523000, China.
  • 2 Hunan University of Chinese Medicine, Changsha 410000, China.
  • 3 Hunan University of Chinese Medicine, Changsha 410000, China; Knee Joint Department, Orthopedics Hospital of Traditional Chinese Medicine Zhuzhou City, Zhuzhou 412000, China.
  • 4 Department of Orthopaedics, Changde First Hospital of Traditional Chinese Medicine, 415000, China. Electronic address: ZYYdjianhui@163.com.
  • 5 Department of Orthopaedics, Changde First Hospital of Traditional Chinese Medicine, 415000, China. Electronic address: yangzhuo780199@outlook.com.
  • 6 Department of Orthopaedics, Dongguan Hospital of Guangzhou University of Chinese Medicine (Dongguan Hospital of Traditional Chinese Medicine), Dongguan 523000, China. Electronic address: dglugl@163.com.
PMID: 40540898 DOI: 10.1016/j.intimp.2025.115111
Abstract

Background: Ferroptosis in chondrocytes is increasingly recognized as a key driver of osteoarthritis (OA) progression. Although paeoniflorin (PAE) has demonstrated potent anti-inflammatory and antioxidant properties in multiple disease models, its role in modulating OA through Ferroptosis remains unclear.

Purpose: This study aimed to investigate the protective role of PAE against iron overload-induced OA (IOOA) via the p53/solute carrier family 7 member 11 (SLC7A11)/Glutathione Peroxidase 4 (GPX4) signaling pathway.

Methods: An iron overload model was established in chondrocytes using ferric ammonium citrate for in vitro experiments, while an in vivo IOOA model was induced in mice via destabilization of the medial meniscus combined with iron dextran injection. Subsequent evaluations included cell viability, cartilage matrix metabolism, iron accumulation, oxidative stress markers, and mitochondrial function. To investigate the underlying mechanism, Western blot, immunofluorescence (IF), and Nutlin-3 (a p53 activator) intervention were employed to assess the involvement of the p53/SLC7A11/GPX4 pathway. In vivo assessments included micro-computed tomography imaging, histological analysis, and IF.

Results: PAE significantly improved chondrocyte viability, restored matrix metabolism, reduced iron accumulation and oxidative stress, and protected mitochondrial function under iron overload conditions. Mechanistically, PAE downregulated p53 and upregulated SLC7A11 and GPX4 expression, thereby suppressing Ferroptosis. Nutlin-3 partially reversed these protective effects. In vivo, PAE mitigated subchondral bone loss and cartilage destruction, reduced iron deposition, and restored GPX4 and type II Collagen (COL2) expression while lowering matrix metalloproteinase 13 (MMP13) levels.

Conclusion: PAE alleviates iron overload-induced OA progression by inhibiting Ferroptosis through regulation of the p53/SLC7A11/GPX4 pathway, offering new insights into ferroptosis-targeted OA therapy.

Keywords

Ferroptosis; Osteoarthritis; Paeoniflorin; p53/SLC7A11/GPX4 pathway.

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