Krüppel-like factors modulate SKN-1 activity and lipid balance to control worm lifespan
KLF-1 drives SKN-1 activation through lipophagy-linked pathways to promote oxidative stress resistance and extend lifespan in germline-deficient Caenorhabditis elegans.
In Caenorhabditis elegans, researchers discovered that the Krüppel-like factor KLF-1 controls lipid accumulation to modulate the transcription factors SKN-1A and SKN-1C. KLF-1 was required for SKN-1 activation and for the oxidative stress resistance and longevity seen in germline-deficient worms, without changing skn-1 transcript levels. KLF-1 selectively governed the lipid homeostatic response of SKN-1A, but was dispensable for its proteasome recovery response. Genetic and supplementation experiments revealed that KLF-1 stimulates SKN-1A through lipid accumulation, whereas it regulates SKN-1C via both lipid-dependent and lipid-independent mechanisms. In addition, KLF-1 and KLF-2 had opposing effects on lipid accumulation independently of SBP-1. They regulated the expression of lipophagy-related genes unc-51, atg-9, and lipl-1 in opposite directions.
Why it matters
The study reveals an upstream transcriptional network that coordinates lipid storage with antioxidant defenses. Mapping how lipid homeostasis directly controls SKN-1 and Nrf factor activity helps clarify how metabolic networks sustain cellular resilience and regulate longevity.
Caveats
This work was performed exclusively in the invertebrate Caenorhabditis elegans, with key longevity phenotypes examined in germline-deficient models. Whether these Krüppel-like factors exert comparable control over mammalian Nrf signaling and lifespan remains to be tested.
- Disabled macroautophagy
- Loss of proteostasis
- Autophagy
- Lipid and ceramide metabolism
- NRF2–KEAP1 antioxidant response
- Oxidative stress and ROS signalling
- atg-9
- klf-1
- klf-2
- lipl-1
- skn-1
- unc-51
The paper
Krüppel-like factors regulate lipid homeostasis to modulate SKN-1/Nrf activity, oxidative stress resistance and longevity
Castillo-Quan JI, McCarty A, Kurdeikaite U et al.
Genetics · 29 Sep 2026