Krüppel-like factors regulate lipid homeostasis to modulate SKN-1/Nrf activity, oxidative stress resistance and longevity.

Maintenance of lipid and redox homeostasis is 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 resistance. Here, we identify the Krüppel-like factor KLF-1 as a regulator of lipid accumulation that modulates SKN-1 activity. KLF-1 was required for SKN-1A and SKN-1C activation and for the oxidative stress resistance and longevity of germline-deficient animals, without changing skn-1 transcript abundance. KLF-1 selectively modulated the lipid homeostatic response of SKN-1A but was dispensable for its proteasome recovery response. Genetic and supplementation experiments further indicated that KLF-1 influences SKN-1A activation through lipid accumulation, while its regulation of SKN-1C involves both lipid-dependent and lipid-independent mechanisms. KLF-1 and the related KLF-2 exerted opposing effects on lipid accumulation while acting independently of the lipogenic regulator Sterol regulatory element-Binding Protein 1 (SBP-1/SREBP1). Consistent with these opposing effects, KLF-1 and KLF-2 regulated the expression of unc-51/ULK1, atg-9/ATG9A, and lipl-1/LIPJ/K in opposite directions, implicating lipophagy-associated pathways in their regulation of lipid homeostasis. Together, these findings establish KLF-dependent regulation of lipid homeostasis as an upstream physiological determinant of SKN-1 activity, linking lipid metabolism with oxidative stress resistance and longevity.