PFOS at human-relevant concentrations activates a KLF-1–P450 mitochondrial protective axis in Caenorhabditis elegans

Background: Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants that accumulate in humans and wildlife, yet the cellular mechanisms that protect against PFAS toxicity remain poorly understood.

Results: Using a stress-reporter screen, we identified activation of a p38 MAPK-dependent mitochondrial surveillance pathway in response to PFOS exposure. In parallel, unbiased transcriptomic analysis following chronic exposure to 1.5 ppm PFOS, a concentration comparable to the highest PFOS concentrations reported in human blood, and acute exposure to 12.5 ppm PFOS revealed a detoxification program dominated by cytochrome P450 genes, particularly members of the cyp-13A family. We further discovered that the transcription factor KLF-1 is a key regulator of this response. Silencing klf-1 reduced PFOS-induced P450 expression and increased PFOS sensitivity, demonstrating that the KLF-1–P450 axis is protective. Antioxidant treatments suppressed both MAPK signaling and P450 activation, indicating that mitochondrial ROS act upstream of both pathways. Multi-omics analyses integrating the transcriptomic and metabolomic datasets revealed altered branched-chain amino acid metabolism as an additional major signature of PFOS exposure. We also found that PFOS is more toxic than PFOA in C. elegans, whereas the opposite pattern was observed in the related nematode Pristionchus pacificus. These findings demonstrate that PFAS toxicity is both compound-specific and species-dependent. Finally, PFOS activated the KLF-1–P450 axis at concentrations as low as 12.5 ppb, highlighting the potential toxicity of PFOS at environmentally and human-relevant concentrations.

Conclusions: Our findings identify a mitochondrial ROS–KLF-1–P450 protective mechanism that mitigates PFOS toxicity and reveal mitochondrial metabolic dysfunction as a central component of PFAS exposure. The conservation of KLF transcription factors and cytochrome P450 pathways raises the possibility that analogous protective responses may be activated in humans exposed to PFOS.