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<p>Axon regeneration in the central nervous system (CNS) remains limited, imposing severe constraints on functional recovery after injury. Here, we reveal that the deubiquitinase OTU deubiquitinase 7 A (OTUD7A) critically regulates CNS regeneration by modulating histidine triad nucleotide-binding protein 1 (HINT1) stability. OTUD7A stabilizes HINT1 protein through specific removal of K63-linked ubiquitin chains at lysine 7. Screening of the small-molecule deubiquitinase inhibitor PR-619 identified HINT1 as a key ubiquitination-regulated target. Notably, genetic knockdown of <i>Hint1</i> alone was sufficient to improve RGC survival and promote optic nerve regeneration, thereby activating mTOR signaling, while PR-619 administration enhanced tissue preservation and axon repair after spinal cord injury. A multi-gene therapeutic strategy further enhanced optic nerve regeneration in the optic nerve crush (ONC) model. These findings identify the OTUD7A–HINT1–mTOR axis as a potential therapeutic target in CNS regeneration.</p><p></p>

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Targeting OTUD7A-HINT1 deubiquitination activates mTOR signaling for CNS regeneration

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月20日

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  • Zhen-Gang Liu,
  • Yong-Quan Sun,
  • Lai-Yang Zhou,
  • Ze-Yu Liu,
  • Ling-Wei Zhao,
  • Feng-Quan Zhou,
  • Bo-Yin Zhang,
  • Chang-Mei Liu

摘要

Axon regeneration in the central nervous system (CNS) remains limited, imposing severe constraints on functional recovery after injury. Here, we reveal that the deubiquitinase OTU deubiquitinase 7 A (OTUD7A) critically regulates CNS regeneration by modulating histidine triad nucleotide-binding protein 1 (HINT1) stability. OTUD7A stabilizes HINT1 protein through specific removal of K63-linked ubiquitin chains at lysine 7. Screening of the small-molecule deubiquitinase inhibitor PR-619 identified HINT1 as a key ubiquitination-regulated target. Notably, genetic knockdown of Hint1 alone was sufficient to improve RGC survival and promote optic nerve regeneration, thereby activating mTOR signaling, while PR-619 administration enhanced tissue preservation and axon repair after spinal cord injury. A multi-gene therapeutic strategy further enhanced optic nerve regeneration in the optic nerve crush (ONC) model. These findings identify the OTUD7A–HINT1–mTOR axis as a potential therapeutic target in CNS regeneration.