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Updated: Jun 23, 2026

A Drosophila In Vivo Injury Model for Studying Neuroregeneration in the Peripheral and Central Nervous System
Published on: May 5, 2018
Targeting OTUD7A-HINT1 deubiquitination activates mTOR signaling for CNS regeneration
Zhen-Gang Liu1,2, Yong-Quan Sun2,3,4, Lai-Yang Zhou2,3,4
1Department of Orthopaedics, China-Japan Union Hospital of Jilin University, Changchun, 130033, China.
None:
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.
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