Abstract
Background and Objective: Glaucoma leads to progressive and irreversible blindness, characterized by damage to the optic nerve, often due to elevated intraocular pressure (IOP). Pigmentary glaucoma (PG) is a secondary glaucoma secondary to the release of melanin granules obstructing aqueous humor outflow, resulting in elevated IOP and optic nerve damage. PG may also involve abnormalities in melanin synthesis and melanocyte activation in the iris pigment epithelium (IPE), a pathologic contributor that remains underrecognized. The objective of this article is to integrate melanin biosynthesis pathways with evidence of aberrant melanogenesis in PG to propose a unifying pathological mechanism. Methods: A search was conducted using PubMed, Google Scholar and Web of Science databases for English-language publications from January 2020 to April 2025. We have resident background for such review from January 1983 to 2020 already available. Search terms included combinations of MeSH terms and free-text keywords, such as "melanosome", "pigment dispersion glaucoma", "melanin synthesis", "melanin signaling", "melanocyte biology", "melanocyte activation", with or without combination with keyword "pathophysiology", and "animal model". The title and abstract screening were followed by full-text review to identify relevant articles. Key Content and Findings: This review integrates melanin synthesis, melanosome development, abnormal IPE pigment release of dysfunctional late-stage melanosomes, and cytotoxic intermediate sequestration from defective premelanosome protein (PMEL), to explore how aberrant melanogenesis may contribute to PG pathophysiology. We found cholesterol to have an active role in melanin biogenesis and activation by facilitating early-stage melanosome maturation, structural integrity, and melanogenic protein transport. Given its involvement in IOP regulation and association with melanogenesis, a thorough exploration of melanogenesis and associated biomolecules is warranted. Conclusions: Understanding melanogenesis, melanocyte activation and the role of cholesterol may bring about more disease-specific interventions.