Glaucoma is a leading cause of irreversible blindness worldwide, with primary open-angle glaucoma (POAG) being the most common subtype. Increased intraocular pressure (IOP) is a major risk factor for blindness in POAG (Faralli et al., 2019), and the only effective clinical treatment involves reducing IOP to slow the progression of vision loss (Feng et al., 2023; Jayaram et al., 2023). In POAG, trabecular meshwork (TM) dysfunction arises from the synthesis and accumulation of extracellular matrix (ECM) proteins (Kasetti et al., 2017), increasing resistance to aqueous humor outflow and leading to elevated IOP (Onakoya et al., 2009; Vranka et al., 2015). The balance of ECM synthesis and turnover is critical for maintaining aqueous humor outflow and is influenced by complex interactions involving growth factors, such as the transforming growth factor-beta (TGF-β) family, and matrix metalloproteinases (MMPs) (Agarwal and Agarwal, 2018; Fujimoto et al., 2023) (see Table 1, Table 2, Table 3).
TGF-β2, a multifunctional cytokine in the TGF-β family (Tan et al., 2024), is produced by the ciliary and lens epithelium and is significantly elevated in the aqueous humor of some POAG patients (Inatani et al., 2001; Picht et al., 2001). Elevated TGF-β2 enhances ECM deposition, obstructing aqueous humor outflow and increasing IOP (Oikawa et al., 2023; Wordinger et al., 2007). It has been extensively studied as a key pathogenic driver in POAG (Braunger et al., 2015; Fleenor et al., 2006; Fuchshofer and Tamm, 2012), with evidence showing that it induces ECM remodeling and high IOP in experimental models (McDowell et al., 2013; Shepard et al., 2010). Therapeutics such as interleukin-6 (IL-6), vitamin E, and bone morphogenetic protein-7 (BMP-7) can mitigate ECM dysregulation by counteracting TGF-β2. Natural compounds like salidroside and osthole have also shown promise in reducing TGF-β2-induced ECM deposition (Fan et al., 2019, 2020b).
Salidroside, a phenylpropionic acid glycoside (Fan et al., 2020a), possesses diverse pharmacological properties, including antioxidant, anti-inflammatory, anti-fatigue, and anti-tumor effects (Amsterdam and Panossian, 2016; Masi et al., 2023; Polumackanycz et al., 2022; Rong et al., 2020; Wang et al., 2023b; Zhu et al., 2022). It has demonstrated efficacy in alleviating oxidative stress in dry eye disease, suppressing renal fibrosis, and regulating ECM homeostasis in TGF-β2-induced high IOP models (Liang et al., 2023; Liu et al., 2023; Rong et al., 2020; Yang et al., 2022). However, the precise mechanisms by which salidroside modulates TGF-β2-driven ECM dysregulation remain unclear.
High-throughput molecular biology techniques, including transcriptomics, proteomics, and metabolomics, provide powerful tools for exploring complex biological processes (Hood, 2003; Su et al., 2011; Zhao et al., 2018). Transcriptomics enables genome-wide analysis (Su et al., 2011), while proteomics reveals protein expression and function within specific contexts (Mallick and Kuster, 2010). Metabolomics complements these approaches by capturing metabolic changes reflective of genetic, epigenetic, and environmental influences (Gold et al., 2022). Combining these multi-omics approaches offers a holistic understanding of biological systems, facilitating the identification of molecular mechanisms and therapeutic targets in diseases such as POAG.
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