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<p>Neuropathic pain (NP) is a common chronic pain that lacks durable, mechanism-based therapies, making it a global health concern. Mitochondrial protection is essential to alleviate oxidative stress and maintain normal energy metabolism, playing a critical role in the treatment of NP. Mammalian ste20-like kinase 2 (Mst2) is a key protein in the Hippo pathway and plays a pivotal role in regulating mitochondrial function. Sirt1 mediates autophagy and BNIP3-related mitophagy,&#xa0;and is modulated by the phosphorylation of the Hippo pathway. Utilizing a sciatic nerve constriction injury (CCI) model on male rats to simulate traumatic NP, we further administered Mst2-siRNA to the injured sciatic nerve. Behavioral tests revealed that Mst2 knockdown significantly alleviated CCI-induced NP. Morphological analysis and western blot showed that the observed effects of Mst2 knockdown were attributed to the promotion of autophagy and the activation of BNIP3-mediated mitophagy. These processes contributed to the protection of mitochondria, myelin and axons within the sciatic nerve. In&#xa0;vitro studies in Schwann cell line and SH‑SY5Y‑derived neuroblastoma cells confirmed that Mst2 knockdown promotes autophagic flux and induces BNIP3‑mediated mitophagy, safeguarding mitochondrial function. Mechanistically, our study further showed that Mst2 downregulation reduces Sirt1 phosphorylation and elevates FOXO3‑driven BNIP3 transcription, establishing the significant role of Mst2 in Sirt1/FOXO3/BNIP3 regulation. These findings position Mst2 as a critical modulator in nerve injury-induced NP, highlighting autophagy and mitophagy regulation as potential targets for novel NP therapies.</p>

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Mammalian Sterile 20-Like Kinase 2 Knockdown Alleviates Neuropathic Pain in Rats by Mitochondrial Protection

  • 期刊论文

  • 发表日期：

    2025年7月22日

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  • Qing Zeng,
  • Bei-Xu Huang,
  • Chang Liu,
  • Nen Liang,
  • Jian Yu,
  • Song-Jie Liao

摘要

Neuropathic pain (NP) is a common chronic pain that lacks durable, mechanism-based therapies, making it a global health concern. Mitochondrial protection is essential to alleviate oxidative stress and maintain normal energy metabolism, playing a critical role in the treatment of NP. Mammalian ste20-like kinase 2 (Mst2) is a key protein in the Hippo pathway and plays a pivotal role in regulating mitochondrial function. Sirt1 mediates autophagy and BNIP3-related mitophagy, and is modulated by the phosphorylation of the Hippo pathway. Utilizing a sciatic nerve constriction injury (CCI) model on male rats to simulate traumatic NP, we further administered Mst2-siRNA to the injured sciatic nerve. Behavioral tests revealed that Mst2 knockdown significantly alleviated CCI-induced NP. Morphological analysis and western blot showed that the observed effects of Mst2 knockdown were attributed to the promotion of autophagy and the activation of BNIP3-mediated mitophagy. These processes contributed to the protection of mitochondria, myelin and axons within the sciatic nerve. In vitro studies in Schwann cell line and SH‑SY5Y‑derived neuroblastoma cells confirmed that Mst2 knockdown promotes autophagic flux and induces BNIP3‑mediated mitophagy, safeguarding mitochondrial function. Mechanistically, our study further showed that Mst2 downregulation reduces Sirt1 phosphorylation and elevates FOXO3‑driven BNIP3 transcription, establishing the significant role of Mst2 in Sirt1/FOXO3/BNIP3 regulation. These findings position Mst2 as a critical modulator in nerve injury-induced NP, highlighting autophagy and mitophagy regulation as potential targets for novel NP therapies.