Tailoring UPS-to-autophagy transition to restore RGC prosperity and functionality in a rodent traumatic optic neuropathy model

Ching-Yun Wang; Lawrence Chen; Jia-Ying Chien; Hsin-Yu Ho; Ting-Yi Lin; Shun-Ping Huang

doi:10.1016/j.exer.2025.110489

Tailoring UPS-to-autophagy transition to restore RGC prosperity and functionality in a rodent traumatic optic neuropathy model

Exp Eye Res. 2025 Jun 13:110489. doi: 10.1016/j.exer.2025.110489. Online ahead of print.

Authors

Ching-Yun Wang¹, Lawrence Chen², Jia-Ying Chien³, Hsin-Yu Ho⁴, Ting-Yi Lin⁵, Shun-Ping Huang⁶

Affiliations

¹ Department of Medical Education, Taichung Veterans General Hospital, Taichung, Taiwan; Department of Ophthalmology, Chang Gung Memorial Hospital, Chiayi, Taiwan.
² Biological Sciences Collegiate Division, University of Chicago, Chicago, IL.
³ Department of Biochemical Science and Technology, National Chia-Yi University, Chia-Yi City, Taiwan.
⁴ School of Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
⁵ Doctoral Degree Program of Translational Medicine, Academia Sinica, Taipei, Taiwan.
⁶ Department of Biochemical Science and Technology, National Chia-Yi University, Chia-Yi City, Taiwan; Department of Ophthalmology, Taichung Tzu Chi Hospital, Taichung, Taiwan. Electronic address: sphuang0728@mail.ncyu.edu.tw.

PMID: 40517885
DOI: 10.1016/j.exer.2025.110489

Abstract

Direct or indirect injury to the optic nerve can lead to traumatic optic neuropathy (TON), a pathological process eventually resulting in long-term vision loss. Experimentally, optic nerve crush (ONC) simulates TON by inducing retinal ganglion cell (RGC) apoptosis and vision loss. This study investigates the neuroprotective effect of a HECT domain-E3 ubiquitin ligase inhibitor, Compound 056, on retinal ganglion cells after traumatic injury. Experimental traumatic optic neuropathy (TON) was induced by mechanical compression of the rodent optic nerve. Compound 056 was administered (60 mg/kg) subcutaneously once on the same day after TON induction. Compound 056 treatment (60 mg/kg) significantly increased RGC survival and preserved visual function after TON induction. The number of TUNEL-positive cells was significantly decreased, and optic disc edema was reduced. Bulk RNA sequencing revealed that HUWE1, an E3 ubiquitin ligase, was potentially linked to the suspended autophagy and NLRP3-mediated neuroinflammation after TON induction. We demonstrated that compound 056 effectively alleviated neuroinflammation and enhanced autophagic flux at transcriptomic and protein levels. These findings suggest compound 056 may have therapeutic potential in treating TON by modulating NLRP3 inflammasome pathways and the autophagic flux within the retina and optic nerve.