Mitochondrial translation impairment-triggered neuroinflammation mediates fluoride-induced cognitive deficits.

Fluoride exposure poses multi-organ toxicity, including skeletal fluorosis, dental fluorosis, neuroinflammation, and cognitive deficits. While fluoride-induced neurotoxicity is linked to mitochondrial dysfunction-particularly via disrupted mitochondrial translation-the mechanistic interplay between translational impairment, neuroinflammation, and cognitive decline remains poorly defined. Here, integrated proteomic and functional analyses revealed that fluoride upregulates mitochondrial ribosomal protein L15 (MRPL15) through its upstream transcription factor CCAAT/enhancer-binding protein-α (C/EBPα) in both in vivo and in vitro models. This dysregulation perturbed mitochondrial translation fidelity, culminating in mitochondrial reactive oxygen species (mtROS) overproduction. Elevated mtROS activated the NLRP3 inflammasome, triggering pyroptotic cell death and subsequent hippocampal-dependent cognitive impairment. Importantly, the natural compound curcumin (CUR) attenuated fluoride neurotoxicity by enhancing mitochondrial bioenergetics and suppressing the mtROS/NLRP3-pyroptosis axis. Our findings establish mitochondrial translation disruption as a novel mechanism underlying fluoride-induced neuroinflammation and cognitive deficits, urging a critical re-evaluation of fluoride safety thresholds in environmental health policies.