Ethambutol-associated ocular toxicity: Pharmacological mechanisms and opportunities for prodrug design

Ethambutol remains an essential component of first-line antitubercular therapy despite being plagued by ocular toxicity, largely dependent on dosage and duration, most commonly ethambutol-induced optic neuropathy (AEON). For the past decade, an increasing number of clinical and experimental findings have associated damage to the retinal ganglion cells with host genetic susceptibility, oxidative stress, chelation of metal ions, and mitochondrial dysfunction. In parallel, prodrug strategies that preserve antimycobacterial potency while reducing off-target toxicity have taken on new interest following advances in the development of drugs for tuberculosis. This narrative review collates the literature related to the clinical range, pharmacological mechanisms, and translational prospects associated with ethambutol-associated ocular toxicity within the period from 2015 to 2025. Particular emphasis is placed on prodrug-based mitigation strategies.