Lipoic Acid Modulates Nrf2/HO-1 Pathway to Suppress Inflammation in Fungal Keratitis Through Host-Directed...

Lipoic acid (LA), a dithiol antioxidant with an exemplary ocular safety profile, was investigated for its capacity to temper the oxidative-inflammatory milieu that drives fungal keratitis. Human corneal epithelial cells tolerated LA up to 60 µM without viability loss and, upon Aspergillus fumigatus challenge, LA induced a three-fold escalation of nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation and a five-fold surge in its downstream effector heme oxygenase-1 (HO-1). Pharmacological silencing of Nrf2 with ML385 or catalytic blockade of HO-1 with tin protoporphyrin IX abrogated these molecular events and reinstated interleukin-1β and tumor necrosis factor-α expression, affirming strict Nrf2/HO-1 dependence. Parallel experiments in a murine keratitis model corroborated the in vitro observations: topical LA diminished corneal opacity and inflammatory scores by 47%, concurrently amplifying corneal Nrf2 and HO-1 expression while halving cytokine transcripts; co-administration of SnPPIX nullified these benefits. Collectively, the data delineate a coherent mechanistic hierarchy in which LA, at clinically attainable concentrations, increases Nrf2 protein levels and enhances nuclear translocation, potentiates HO-1 activity, and thereby quells pathogen-induced cytokinic turbulence. These findings position LA as a readily translatable, host-directed adjunct capable of complementing antifungal chemotherapy and suggest broader therapeutic vistas for Nrf2-centric modulation of sight-threatening corneal inflammation.