The Emerging Functional Landscape of piRNAs in Ocular Health and Disease

P-element-induced wimpy testis (PIWI)-interacting RNAs (piRNAs) are a distinct class of small non-coding RNAs increasingly recognized as regulators of gene expression beyond their canonical function in PIWI-dependent transposon silencing. First characterized in the germline, recent evidence demonstrates that PIWI-piRNA pathways are active in somatic tissues and contribute to cellular homeostasis and adaptive stress responses through epigenetic, transcriptional, post-transcriptional, and translational mechanisms. Although piRNAs regulate several diseases, their roles in ocular physiology and pathology remain poorly understood. In the eye, piRNA pathways may govern retinal homeostasis and responses to oxidative stress, inflammation, angiogenesis, and fibrosis. This review synthesizes current knowledge on piRNA biogenesis, molecular mechanisms, and emerging functions in ocular tissues and examines evidence linking PIWI-piRNA dysregulation to major ocular diseases, including age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, and subretinal fibrosis. We evaluate the current evidence and highlight that, although disease-associated piRNA signatures and emerging mechanistic links to angiogenesis, oxidative stress, fibrosis, and cellular stress responses have been reported, most findings remain correlative and lack physiological validation. We discuss key challenges, including incomplete piRNA annotation, cell-type-specific activity, and variability in PIWI-piRNA regulatory mechanisms. We also outline future perspectives for defining the roles of PIWI-piRNA networks in ocular physiology and evaluating their potential as biomarkers and therapeutic targets for vision-threatening diseases.