Kruppel-like factor 1 acts upstream of the SKN-1/Nrf transcription factors to modulate oxidative stress, lipid homeostasis and longevity

Castillo-Quan, J. I.; McCarty, A.; Kurdeikaite, U.; Gilmore, K.; Cabral, A.; Mejia, J.; Barrett, J.; La Terza, M.; Johnson, E.; Carroll, A.; Schaffer, J.; Moroz, N.

doi:10.1101/2025.11.22.689963

bioRxiv · 10.1101/2025.11.22.689963

Kruppel-like factor 1 acts upstream of the SKN-1/Nrf transcription factors to modulate oxidative stress, lipid homeostasis and longevity

Castillo-Quan, J. I.·McCarty, A.·Kurdeikaite, U.·Gilmore, K.·Cabral, A.·Mejia, J.·Barrett, J.·La Terza, M.·Johnson, E.·Carroll, A.·Schaffer, J.·Moroz, N.

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Abstract

Maintenance of lipid and redox homeostasis are essential for stress resistance and longevity, but the transcriptional networks coordinating these processes remain incompletely understood. In Caenorhabditis elegans, the transcription factors SKN-1A/Nrf1 and SKN-1C/Nrf2 mediate distinct stress responses that promote proteostasis, lipid homeostasis, and oxidative stress. Here we identify the Kruppel-like factor KLF-1 as a critical upstream regulator of both SKN-1A and SKN-1C. We show that KLF-1 is required for the oxidative stress resistance and longevity of germline-deficient animals. Genetic interaction studies showed that KLF-1 acts in parallel to the lipogenic regulator Sterol regulatory element-Binding Protein 1 (SBP-1/SREBP1), whereas the related KLF-2 exerts opposing effects on lipid accumulation through SBP-1. Together, these findings place KLF-1 and KLF-2 within a transcriptional network that integrates lipid metabolism, oxidative stress responses, and aging. This work uncovers a conserved regulatory network linking KLFs and SKN-1/Nrf transcription factors in the maintenance of lipid homeostasis and longevity assurance.

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Castillo-Quan, J. I., McCarty, A., Kurdeikaite, U., Gilmore, K., Cabral, A., Mejia, J., Barrett, J., La Terza, M., Johnson, E., Carroll, A., Schaffer, J., Moroz, N.. 2025-11-25. Kruppel-like factor 1 acts upstream of the SKN-1/Nrf transcription factors to modulate oxidative stress, lipid homeostasis and longevity. https://doi.org/10.1101/2025.11.22.689963

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