SIRT6-COX6A1 axis mediates prenatal 6:2 FTOH-induced neuronal damage via mitochondrial dysfunction.

Prenatal exposure to 6:2 fluorotelomer alcohol (6:2 FTOH), an emerging environmental contaminant, raises concerns regarding developmental neurotoxicity, but the underlying mechanisms remain unclear. Combining network toxicology and transcriptomics in a prenatal mouse exposure model, we discovered that 6:2 FTOH suppressed silent information regulator 6 (SIRT6) expression in the developing brain, leading to hyperacetylation and autophagic degradation of cytochrome c oxidase subunit 6A1 (COX6A1), an essential element of the mitochondrial electron transport chain. This cascade reduced COX6A1 mitochondrial content, triggered mitochondrial dysfunction, and ultimately reduced neurotransmitter content. Molecular docking predicted favorable binding affinities between 6:2 FTOH and both SIRT6 and COX6A1. Importantly, restoring SIRT6 or COX6A1 expression in vitro reversed 6:2 FTOH-induced neurotoxicity. These findings reveal a novel mechanism where SIRT6-mediated deacetylation preserves COX6A1 stability and mitochondrial function, and demonstrate that an environmental contaminant can hijack this pathway to inflict neuronal damage. The SIRT6-COX6A1 axis represents a potential therapeutic target for neuronal damage induced by environmental contaminant.