Retinal and choroidal neovascularization (RNV and CNV) represent pivotal pathological features of several vision-threatening ocular disorders, including proliferative diabetic retinopathy (DR), retinopathy of prematurity (ROP), retinal vein occlusion (RVO), and wet age-related macular degeneration (wAMD), among others (Gariano and Gardner, 2005). Anti-vascular endothelial growth factor (VEGF) or combined with anti-angiopoietin 2 (Ang2) therapies have been gradually applied in clinic, and become an important means to treat intraocular NV diseases in addition to traditional methods such as vitrectomy, laser photocoagulation and photodynamic therapy. However, the economic burden of long-term therapy and the prevalence of patients with suboptimal responses to anti-VEGF therapy highlight the necessity of investigating additional pro-angiogenic factors and alternative pathological pathways in the mechanisms underpinning intraocular NV (Mettu et al., 2021; Rofagha et al., 2013; Tolentino, 2011). Given these circumstances, it is crucial to explore the etiological and pathological mechanisms involved in intraocular NV and to identify new, safe, and effective therapeutic targets for the timely prevention and treatment of blindness.

Retinoic acid receptor-related orphan receptor γt (RORγt) is a key nuclear transcription factor for the differentiation of T helper 17 (Th17) cells and γδT cells, playing a crucial role in immune responses, inflammation, and angiogenesis by regulating pro-inflammatory factors such as interleukin 17 (IL-17) and IL-22 (Jetten and Cook, 2020; Ruan et al., 2011; Tesmer et al., 2008). Previous studies in ophthalmology have primarily focused on the role of RORγt in ocular diseases such as dry eye disease, Graves' ophthalmopathy, and autoimmune uveitis (Yemanyi et al., 2023). In the context of intraocular NV, clinical research has suggested that IL-17 gene polymorphisms and Th17 cells are associated with AMD and its related low-grade chronic inflammation (Chen et al., 2017; Zhang et al., 2015), indicating a potential role of RORγt in AMD pathogenesis. Talia DM and colleagues demonstrated that the use of small-molecule inhibitors of RORγt, including SR1001 (a RORα/γt inverse agonist) and digoxin (a RORγt inhibitor), in the oxygen-induced retinopathy (OIR) mouse model effectively reduced RNV. This was achieved by suppressing IL-17A and tumor necrosis factor α (TNF-α) expression, thereby inhibiting VEGF secretion by retinal Müller and ganglion cells (Talia et al., 2016). A recent research work further reported that SR1001 significantly reduced retinal inflammation, oxidative stress, and capillary degeneration in a DR mouse model (Zapadka et al., 2020). They also identified RORγt-positive cells in the retinas of DR mice, and in vitro experiments confirmed that RORγt could promote vascular endothelial cell apoptosis. However, the exact role and mechanisms of RORγt in RNV and CNV remain insufficiently explored. GSK805 (C23H18Cl2F3NO4S) was identified in a high-throughput screen for RORγt ligands (Sun et al., 2020; Xiao et al., 2014). Acting as an inverse agonist, it stabilizes the receptor in a transcriptionally inactive state (Sun et al., 2020). Pre-clinical studies have already demonstrated its efficacy in mouse models of demyelination (Zhu et al., 2019) and inflammatory bowel disease (Withers et al., 2016). Here, we extend these observations to ocular NV, evaluating GSK805's ability to suppress both retinal and choroidal NV while identifying the RORγt-expressing cell types and signaling pathways involved.