FTO deficiency mediates ferroptosis to exacerbate cobalt-induced neurotoxicity

Cobalt, a toxic environmental contaminant, has been implicated in human neurological damage. However, the detailed molecular basis of cobalt-triggered neurotoxicity remains poorly uncovered. In the present study, we elucidated the N6-methyladenosine (m6A) demethylase fat mass and obesity-associated protein (FTO) downregulation mediates the activation of ferroptosis to drive cobalt-triggered neurodegeneration. We established an in vitro model using H4 cells and an in vivo model using C57BL/6 mice. Animal experiments provided initial evidence underscoring the critical involvement of ferroptosis in cobalt-associated neurotoxicity. Furthermore, in vitro assays revealed that ferroptosis is triggered subsequent to oxidative stress induced by cobalt exposure. Notably, MeRIP-seq profiling of H4 cells and mouse cortex revealed that ferroptosis-associated genes exhibited differential m6A modification, suggesting m6A modification might be involved in modulating ferroptosis. Concurrently, Gene Ontology and KEGG enrichment analyses revealed that genes bearing differential m6A modifications were significantly clustered within pathways linked to ferroptosis as well as neurodegenerative diseases. Moreover, we found that FTO depletion effectively enhanced ferroptosis following cobalt-induced oxidative stress. Mechanistically, FTO depletion enhanced m6A modification of GPX4 and transferrin receptor protein 1 (TFRC) mRNAs, leading to reduced GPX4 and elevated TFRC expression, which aggravated cobalt-induced ferroptosis. More importantly, we observed that central nervous system specific knockout of Fto exacerbated cobalt-induced neurobehavioral deficits and neuropathological damage through ferroptosis activation. Collectively, these results provide important insights into cobalt-induced neurotoxicity by targeting FTO deficiency-mediated ferroptosis and offer an innovative strategy for investigating neurodegenerative processes driven by environmental toxicants.