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 Krüppel-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.