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<p> Objective Poor tendon-bone healing after anterior cruciate ligament reconstruction (ACLR) is often accompanied by impaired osteogenesis and apoptosis, while iron overload and mitochondrial dysfunction may exacerbate this process through ferroptosis. Although total flavonoids of <i>Rhizoma Drynariae</i> (TFRD) are known to have osteogenesis-promoting effects, whether they improve tendon-bone healing by regulating ferroptosis remains unclear. Methods The impact of TFRD on bone formation, ferroptosis, and mitochondrial function was evaluated using an ACLR rat model and a Dexamethasone (Dex)-induced osteoblast injury model. Hematoxylin and Eosin (H&amp;E), Masson, and Alizarin Red staining were used to examine pathological changes at the tendon‑bone interface and osteogenic mineralization. Western blot and immunohistochemistry were performed to assess the protein expression levels of runt-related transcription factor 2 (RUNX2), osteocalcin (OCN), and collagen I (Col I). Quantification of iron levels, malondialdehyde, glutathione, superoxide dismutase, adenosine triphosphate, and CoQ10 were quantified with specific assay kits. Mitochondrial membrane potential and respiratory function were analyzed by JC-1 staining and oxygen consumption rate (OCR) measurements, respectively. The underlying mechanisms were further investigated using a ferroptosis-suppressing protein 1 (FSP1) inhibitor iFSP1 and the ferroptosis inhibitor Fer-1. Results TFRD markedly increased bone mineral density and upregulated the expression of RUNX2, OCN, and Col I in ACLR rats, while also improving fibrin arrangement and calcification. Moreover, TFRD reduced iron accumulation, lipid peroxidation, and mitochondrial damage, and activated the FSP1/CoQ<sub>10</sub> pathway. In vitro experiments demonstrated that TFRD reversed Dex-induced osteoblast apoptosis and differentiation suppression, restoring OCR and ATP levels, and these effects were counteracted by the FSP1 inhibitor iFSP1. Conclusion TFRD alleviates ferroptosis and mitochondrial dysfunction by activating the FSP1/CoQ<sub>10</sub> pathway, thereby promoting osteogenic differentiation and tendon-bone healing. This mechanism offers a promising therapeutic strategy for tendon-bone healing after ACLR.</p>

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Total Flavonoids of Rhizoma Drynariae Ameliorate Tendon-Bone Healing Following Anterior Cruciate Ligament Reconstruction in Rats by Activating the FSP1/CoQ10 Pathway To Inhibit Osteoblast Mitochondrial Dysfunction and Ferroptosis

  • 期刊论文

  • 发表日期：

    2026年5月9日

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  • ZiXun Wang,
  • LiXin Cao,
  • XueFeng Wang

摘要

Objective Poor tendon-bone healing after anterior cruciate ligament reconstruction (ACLR) is often accompanied by impaired osteogenesis and apoptosis, while iron overload and mitochondrial dysfunction may exacerbate this process through ferroptosis. Although total flavonoids of Rhizoma Drynariae (TFRD) are known to have osteogenesis-promoting effects, whether they improve tendon-bone healing by regulating ferroptosis remains unclear. Methods The impact of TFRD on bone formation, ferroptosis, and mitochondrial function was evaluated using an ACLR rat model and a Dexamethasone (Dex)-induced osteoblast injury model. Hematoxylin and Eosin (H&E), Masson, and Alizarin Red staining were used to examine pathological changes at the tendon‑bone interface and osteogenic mineralization. Western blot and immunohistochemistry were performed to assess the protein expression levels of runt-related transcription factor 2 (RUNX2), osteocalcin (OCN), and collagen I (Col I). Quantification of iron levels, malondialdehyde, glutathione, superoxide dismutase, adenosine triphosphate, and CoQ10 were quantified with specific assay kits. Mitochondrial membrane potential and respiratory function were analyzed by JC-1 staining and oxygen consumption rate (OCR) measurements, respectively. The underlying mechanisms were further investigated using a ferroptosis-suppressing protein 1 (FSP1) inhibitor iFSP1 and the ferroptosis inhibitor Fer-1. Results TFRD markedly increased bone mineral density and upregulated the expression of RUNX2, OCN, and Col I in ACLR rats, while also improving fibrin arrangement and calcification. Moreover, TFRD reduced iron accumulation, lipid peroxidation, and mitochondrial damage, and activated the FSP1/CoQ10 pathway. In vitro experiments demonstrated that TFRD reversed Dex-induced osteoblast apoptosis and differentiation suppression, restoring OCR and ATP levels, and these effects were counteracted by the FSP1 inhibitor iFSP1. Conclusion TFRD alleviates ferroptosis and mitochondrial dysfunction by activating the FSP1/CoQ10 pathway, thereby promoting osteogenic differentiation and tendon-bone healing. This mechanism offers a promising therapeutic strategy for tendon-bone healing after ACLR.