Siah-1 is Critical for Hypoxia-Induced Lifespan Extension in Caenorhabditis elegans by Regulating the Expression of SKN-1

Introduction: Hypoxia has been shown to extend lifespan in Caenorhabditis elegans through mechanisms involving HIF-1 and DAF-16, but the interplay with SKN-1/Nrf, a key regulator of oxidative stress responses, remains complex. Studies have shown that SKN-1 reduced lifespan when overexpressed in hypoxic environments. However, the mechanism behind SKN-1 regulation under hypoxia is largely unknown. Objective: This study aims to elucidate the hypoxic regulation of SKN-1, particularly by the E3 ubiquitin ligase Siah-1. Results: Under normoxia (O2= 21%), SKN-1 extended the lifespan of C. elegans and its stability was regulated by WDR-23. However, in hypoxic environment (O2= 1%), SKN-1 was detrimental to lifespan. Genetic and chemical inhibitions of Siah-1 revealed that SKN-1 stability in hypoxic environment was regulated by Siah-1. The results showed that the protein levels of Siah-1 were elevated under hypoxia. Under low oxygen conditions, Siah-1 attenuated the transcriptional activity of SKN-1, as shown by the reduced gcs-1, gss-1, and sod-3 mRNA expression and elevated reactive oxygen species levels. Mechanistic studies using kinase mutant worms revealed that PMK-1 was critical for this effect. Conclusion: The present study identifies Siah-1 as a novel mediator linking hypoxic signaling to SKN-1-dependent transcriptional programs, providing insights into conserved mechanisms of stress adaptation and aging. This work underscores the importance of ubiquitin-mediated regulatory nodes in coordinating longevity pathways under environmental stressors.