Diabetic corneal neuropathy (DCN) is a clinically important yet frequently overlooked complication of diabetes mellitus, characterized by progressive corneal nerve loss, impaired epithelial wound healing, and ocular surface instability. Its pathogenesis is multifactorial, driven by chronic hyperglycemia, dyslipidemia, advanced glycation end‐products (AGEs), mitochondrial dysfunction, oxidative stress, and persistent low‐grade inflammation. These processes synergistically disrupt neurotrophic signaling and promote axonal degeneration. Current therapies—including lubricants, autologous serum eye drops, and topical nerve growth factor—provide symptomatic relief and can promote corneal nerve regeneration. However, their effects are often variable, incomplete, or transient, and they do not fully address the underlying metabolic, inflammatory, and mitochondrial drivers of DCN, underscoring the unmet need for disease‐modifying treatments. Peroxisome proliferator‐activated receptors (PPARs) have recently emerged as compelling therapeutic targets. These nuclear transcription factors regulate key metabolic and inflammatory pathways, including lipid homeostasis, mitochondrial function, and oxidative stress. Among them, PPAR α appears particularly relevant for corneal integrity. PPAR α ‐deficient mice exhibit mitochondrial dysregulation, delayed epithelial repair, abnormal angiogenesis, and significant corneal nerve loss. Conversely, pharmacological activation with fenofibrate or selective PPAR modulators restores mitochondrial integrity, enhances neurotrophin expression, and promotes functional axon regeneration. Human studies corroborate these findings; systemic fenofibrate increases corneal nerve fiber density and improves tear proteomic signatures in patients with Type 2 diabetes, while topical formulations may provide faster and more pronounced neurotrophic effects. Collectively, current evidence positions PPARs—particularly PPAR α —as promising next‐generation therapeutic targets for reprogramming corneal neurodegeneration. Future progress will require innovative ocular delivery systems, biomarker‐guided patient stratification, and rigorously designed clinical trials to fully realize the translational potential of PPAR modulation in DCN.
Camero-Reyes et al. (Thu,) studied this question.