Molecular Gatekeepers of Aqueous Outflow: From Mechanotransduction to Gene Therapy in Trabecular Meshwork Health and Disease.

The trabecular meshwork (TM) plays a pivotal role in regulating aqueous humor outflow and maintaining stable intraocular pressure (IOP). When its function becomes impaired, it is a key factor in the development of primary open-angle glaucoma and other outflow disorders. Current therapies, such as topical medications, laser procedures, and surgery, can effectively lower IOP, but they rarely target the underlying cellular and molecular damage within the TM. Emerging approaches are shifting focus from bypassing to restoring TM function. These include Rho-associated protein kinase (ROCK) inhibitors, which help relax the TM; gene-based strategies such as clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 and small interfering ribonucleic acid (siRNA), which aim to correct or silence disease-driving genes; and stem or progenitor cell transplantation to replenish damaged tissue. Combining these modalities with minimally invasive glaucoma surgeries (MIGS) may further improve long-term outcomes by reducing scarring and supporting TM health. As these innovations rapidly evolve, there is a strong need for a comprehensive review to bring together existing evidence, assess their translational potential, and provide direction for future clinical applications. Collectively, such advances signal a paradigm shift in glaucoma management, from simply reducing pressure to actively restoring the TM's intrinsic ability to self-regulate, ultimately offering hope for the sustained preservation of vision.