Hesperidin mitigates lead-induced neurotoxicity via TFEB-dependent restoration of mitochondrial function, oxidative balance, and neuroinflammation in rats

Lead (Pb) neurotoxicity remains a global concern, causing irreversible cognitive and motor impairments through mechanisms like mitochondrial dysfunction, oxidative stress and inflammation. Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy that also coordinates mitochondrial function, has emerged as a novel target in neuroprotection. This study evaluated the neuroprotective potential of hesperidin (natural flavonoid) against Pb-induced neurotoxicity, with a focus on the role of TFEB. Rats were orally administered lead acetate (100 mg/kg) once daily for 30 days to induce neurotoxicity, followed by hesperidin (50 and 100 mg/kg, p.o.) treatment. Cognitive and motor functions were assessed through Morris Water Maze and rotarod tests, while biochemical analyses measured oxidative stress markers (TBARS, GSH), inflammatory cytokines (TNF-α, IL-6, NF-κB), and mitochondrial complex I–III activities. Pb exposure significantly impaired learning, memory, and motor coordination, increased oxidative and inflammatory markers, and reduced mitochondrial function. Hesperidin treatment improved behavioral outcomes and restored redox balance, inflammatory markers and mitochondrial enzyme activity. However, co-treatment with eltrombopag, a TFEB inhibitor, abolished these protective effects, confirming TFEB’s involvement. These findings highlight hesperidin’s ability to mitigate Pb neurotoxicity through TFEB-mediated restoration of mitochondrial function and suppression of oxidative stress and inflammation. Targeting TFEB may offer a novel therapeutic strategy for heavy metal-induced neurodegeneration.