**Background:** Diabetic corneal neuropathy (DCN) is a common complication of diabetes, affecting 47–64% of patients, yet treatment options are limited to symptomatic therapies like lubricants. Fenofibrate, a PPAR-α agonist used for dyslipidemia, has shown neuroprotective effects in animal models of peripheral neuropathy and corneal neuropathy. This study aimed to evaluate the effects of oral fenofibrate on corneal nerve regeneration and ocular surface health in patients with type 2 diabetes.
**Methods:** This single-arm, open-label interventional study enrolled 30 patients with type 2 diabetes (mean age 60.8 ± 9.3 years, 80.8% male) and 20 age-matched healthy controls. Patients had mild to moderate diabetic nephropathy (creatinine clearance 30–60 mL/min and/or albuminuria) and HbA1c <9%. They received oral fenofibrate for 30 days: 100 mg/day if creatinine clearance was 30–59 mL/min (n=21) or 300 mg/day if >60 mL/min (n=9). Assessments were performed before and after treatment, including in vivo confocal microscopy (IVCM) for corneal nerve parameters (CNFD, CNFW, etc.) and epithelial cell morphology, clinical ocular surface tests (corneal sensitivity, TBUT, Schirmer I, Oxford and NEI staining scores), tear neuromediator analysis (SP, CGRP, NPY, NGF by ELISA), and tear proteomic analysis with pathway enrichment (GSEA). Linear mixed models were used for statistical analysis.
**Key Results:** After 30 days of fenofibrate, CNFD significantly increased from 9.5 ± 6.2 to 12.6 ± 4.4 fibers/mm² (P=0.01), restoring it to a level comparable to controls (12.3 ± 6.0 fibers/mm²). CNFW significantly decreased from 0.024 ± 0.001 to 0.022 ± 0.001 mm/mm² (P=0.01), indicating reduced nerve edema. Corneal epithelial cell circularity improved from 0.73 ± 0.016 to 0.72 ± 0.021 (P=0.04). Clinically, TBUT improved from 5.7 ± 1.5 to 6.2 ± 1.8 seconds (P=0.006), Oxford score decreased from 0.8 ± 0.8 to 0.6 ± 0.6 (P=0.01), and NEI score decreased from 1.2 ± 1.1 to 0.7 ± 0.6 (P=0.008). Tear SP levels significantly increased from 1,239.4 ± 719.2 to 1,669.0 ± 948.4 pg/mL (P=0.03), and this change was significantly associated with CNFD improvement (β=0.003, P=0.013). Proteomic analysis revealed upregulation of neurotrophin signaling (ES 0.59, P=0.01), MAPK signaling (ES 0.53, P=0.009), and linoleic acid metabolism (ES 1.00, P=0.01), along with downregulation of complement cascades (ES -0.78, P=0.001), neutrophil extracellular trap formation (ES -0.69, P=0.001), and platelet activation (ES -0.66, P=0.01). Serum triglycerides decreased from 1.8 ± 1.1 to 1.4 ± 0.8 mmol/L (P=0.002).
**Clinical Implications:** This study provides the first clinical evidence that oral fenofibrate promotes corneal nerve regeneration and improves ocular surface health in patients with type 2 diabetes. The improvements in CNFD, CNFW, TBUT, and corneal staining suggest fenofibrate addresses the underlying neuropathy rather than just symptoms. The increase in tear SP and modulation of neurotrophin and anti-inflammatory pathways support a neuroprotective mechanism. Given fenofibrate is already approved for dyslipidemia and is affordable, it could be a promising novel treatment for DCN. Limitations include the single-arm design, short duration (30 days), and lack of assessment in healthy controls over time. Further randomized controlled trials with longer follow-up are needed to confirm these findings.