Abstract: Recent studies have found that the suppression of phosphatase and tensin homolog is one of the most effective single-gene approaches for promoting optic nerve regeneration. This effect is primarily mediated through the activation of the protein kinase B/phosphoinositide 3-kinase/mammalian target of rapamycin signaling pathway. The purpose of this article is to elucidate how the downregulation of phosphatase and tensin homolog is involved in each key phase of optic nerve regeneration and to summarize the potential targets for therapeutic interventions in this process. Optic nerve regeneration progresses through five phases: stress response, growth navigation, nerve regeneration, synaptic reconstruction, and remyelination. During the stress response phase, the suppression of phosphatase and tensin homolog enhances the survival of retinal ganglion cells and promotes the proliferation of microglia. In the nerve regeneration phase, reduced levels of phosphatase and tensin homolog facilitate mitochondrial transport, while inhibition of the phosphatase and tensin homolog-L isoform specifically promotes mitophagy. During the synaptic reconstruction phase, the deletion of phosphatase and tensin homolog modulates the synthesis of axon extension-related proteins and stabilizes microglial microtubules, thereby accelerating the clearance of damaged synapses and the formation of new ones. During the remyelination phase, the knockout of phosphatase and tensin homolog promotes the proliferation of oligodendrocyte progenitor cells and the differentiation of oligodendrocytes, relieving myelination obstruction. This paper also discusses current strategies and translational challenges for neuron-specific inhibition of phosphatase and tensin homolog, including off-target effects, delivery precision, and long-term safety. By integrating molecular insights with emerging bioengineering approaches, this paper provides a framework for developing targeted therapies for optic nerve regeneration and broader applications in the field of central nervous system regeneration.

Key words: growth cone, mammalian target of rapamycin, microglia, mitochondria, neural regeneration, oligodendrocyte, optic nerve regeneration, phosphatase and tensin homolog, phosphoinositide 3-kinase, synaptogenesis