Rosmarinic Acid Attenuates Isoniazid-Induced Neurotoxicity by Restoring Mitochondrial Dynamics and Suppressing Oxidative Stress, Ferroptosis, Neuroinflammation, and Apoptosis

Despite the continued global burden of tuberculosis and the essential role of isoniazid (INH) in first-line antituberculosis therapy, INH-induced neurotoxicity remains a major clinical challenge that compromises treatment adherence, and effective, well-characterized neuroprotective strategies are still lacking. This study investigated the neuroprotective effects of rosmarinic acid (RA) against INH-induced neurotoxicity, evaluating oxidative stress, inflammation, iron metabolism, energy homeostasis, mitochondrial dynamics, ferroptosis, and apoptosis using biochemical, molecular, and histopathological approaches. INH markedly increased malondialdehyde while reducing superoxide dismutase and glutathione, and increased TNF-α, IL-1β, and IL-6 while decreasing IL-10. INH also disturbed iron homeostasis (increased Fe²⁺), impaired energy metabolism (reduced ATP), and disrupted mitochondrial dynamics (increased Drp-1; decreased Mfn-2 and PGC-1α). NF-κB activation was accompanied by increased ACSL4 and decreased GPX4 and FTH1, reflecting ferroptosis, alongside increased Bax, Caspase-3, and Cytochrome c and reduced Bcl-2, indicating mitochondrial apoptosis. RA treatment suppressed oxidative stress, enhanced antioxidant defense, attenuated inflammation, restored iron and energy homeostasis, improved mitochondrial dynamics, and inhibited NF-κB activation, ferroptosis, and apoptosis. These findings demonstrate that RA exerts potent neuroprotective effects against INH-induced brain injury by simultaneously targeting oxidative stress, mitochondrial dysfunction, iron dyshomeostasis, neuroinflammation, ferroptosis, and apoptosis. To our knowledge, this is among the first studies to comprehensively address these interconnected pathways, including ferroptosis and iron dyshomeostasis, in INH-induced neurotoxicity. RA may thus represent a promising therapeutic candidate for preventing INH-induced neurotoxicity. © 2026 Elsevier Ltd