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<p><i>Staphylococcus aureus</i> (SA)-caused osteomyelitis (OM) is inflammation-related refractory disease that seriously degrades the life quality of human beings. Unfortunately, up until now, the molecular mechanisms of OM progression have not been fully delineated, which hampered the development of treatment strategies for this disease. The present study aimed to resolve this issue and a novel DAPK3/AMPK/mTOR-GPX4 signal pathway was significantly linked to the development of OM. Specifically, the rat bone marrow mesenchymal stem cells (rBMSCs) were treated with SA to establish the OM models. SA treatment triggered cell autophagy and ferroptosis and suppressed osteogenic differentiation of rBMSCs. Mechanistically, as it was revealed by our RNA sequencing analysis and cellular experiments, SA significantly increased the expression levels of DAPK3 in a dose-dependent manner, and silencing DAPK3 reversed SA-induced detrimental effects in rBMSCs. Of note, our subsequent experiments confirmed that DAPK3-ablation reduced the phosphorylation of AMPK and ULK1, while increasing the phosphorylation of mTOR and the expression of GPX4. The improvement effects of DAPK3 deficiency on cell autophagy, ferroptosis, and osteogenic differentiation in SA-treated rBMSCs were abrogated by co-treating cells with AMPK activator. In summary, this research verified that silencing of DAPK3 regulated the AMPK/mTOR-GPX4 signal pathway to modulate cell autophagy, ferroptosis and osteogenic differentiation, ameliorating OM progression.</p>

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DAPK3-Ablation Regulates the AMPK/mTOR-GPX4 Signaling Pathway to Affect Biological Functions of Staphylococcus aureus-Treated Bone Marrow Mesenchymal Stem Cells and Potentially Ameliorate Osteomyelitis

  • 期刊论文

  • 发表日期：

    2025年7月2日

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  • Nannan Kou,
  • Runyao Zhang,
  • Feifei Liu,
  • Hongliang Zhou,
  • Zhihua Wang,
  • Lirong Ren

摘要

Staphylococcus aureus (SA)-caused osteomyelitis (OM) is inflammation-related refractory disease that seriously degrades the life quality of human beings. Unfortunately, up until now, the molecular mechanisms of OM progression have not been fully delineated, which hampered the development of treatment strategies for this disease. The present study aimed to resolve this issue and a novel DAPK3/AMPK/mTOR-GPX4 signal pathway was significantly linked to the development of OM. Specifically, the rat bone marrow mesenchymal stem cells (rBMSCs) were treated with SA to establish the OM models. SA treatment triggered cell autophagy and ferroptosis and suppressed osteogenic differentiation of rBMSCs. Mechanistically, as it was revealed by our RNA sequencing analysis and cellular experiments, SA significantly increased the expression levels of DAPK3 in a dose-dependent manner, and silencing DAPK3 reversed SA-induced detrimental effects in rBMSCs. Of note, our subsequent experiments confirmed that DAPK3-ablation reduced the phosphorylation of AMPK and ULK1, while increasing the phosphorylation of mTOR and the expression of GPX4. The improvement effects of DAPK3 deficiency on cell autophagy, ferroptosis, and osteogenic differentiation in SA-treated rBMSCs were abrogated by co-treating cells with AMPK activator. In summary, this research verified that silencing of DAPK3 regulated the AMPK/mTOR-GPX4 signal pathway to modulate cell autophagy, ferroptosis and osteogenic differentiation, ameliorating OM progression.