Gliosis is a biological process that occurs during injury repair in the central nervous system and is characterized by the overexpression of the intermediate filaments (IFs) glial fibrillary acidic protein (GFAP) and vimentin. A common thread in manyThe overexpression of glial fibrillary acidic protein (GFAP) 2 with vimentin is a hallmark of reactive gliosis in the central nervous system (CNS) (1, 2). These intermediate filaments (IFs) are expressed by reactive astrocytes and macro-and microglia during traumatic and inflammatory injury and in a range of CNS degenerative diseases (2). In fact, an enigma of major retinal diseases, including age-related macular degeneration, glaucoma, diabetic retinopathy, and retinopathy of prematurity, is retinal gliosis, for which there is no available clinical treatment (3-5).Important fundamental insights on the structural and mechanical functions of IFs (6, 7) have now been validated in mouse lines deficient in type III IFs (2). These studies have illuminated that, whereas overexpression of vimentin and GFAP during CNS stress response and injury repair contributes to scar formation (8), their deficiency can be protective of tissue functions in certain contexts. For instance, pathogenic angiogenesis is impaired in vimentin-deficient (Vim KO) mice due to the decreased ability of newly formed blood vessels to cross the retinal inner limiting membrane in the model of hypoxia-induced retinal neovascularization (9). Interestingly, that study also identified in vimentin and GFAP double deficient (Vim GFAP dKO) mice, and to a lesser extent in Vim KO mice, that the retinal ganglion layer is highly sensitive to mechanical stress, which was not observed in GFAP KO mice. Pathological neovascularization was also reduced in Vim KO mice in the corneal alkali injury model (10) and delayed vascularization in skin injury model (11), which is attributed to defective vascular endothelial cell integrity (12), because vimentin is the sole type III IF expressed in endothelial cells (13). On the other hand, Vim GFAP dKO mice subjected to spinal cord or brain injury recover favorably with improvement of glial scars (14). In fact, the complete absence of type III IFs in Vim GFAP dKO mice helps promote axonal regeneration and regain ambulatory function after spinal cord injury (15). These Vim GFAP dKO

Background: Withaferin A (WFA) is a vimentin-targeting inhibitor that has potent anti-proliferative activity. Results: WFA protects against corneal fibrosis by down-regulating injury-induced vimentin to exert epithelial cell cycle arrest and inhibit myofibroblast expression, which is a mechanism closely mimicked in vimentin-deficient mice during injury healing. Conclusion: Vimentin is a novel fibrosis target. Significance: Ocular fibrotic conditions that overexpress vimentin could be treatable with WFA.