Protection from thiol reductive stress through an autoinhibitory hypoxia response pathway in Caenorhabditis elegans

Abstract Cellular redox homeostasis depends on a finely tuned balance between oxidizing and reducing conditions, and disturbances in this balance lead to oxidative or reductive stress. While oxidative stress and its pathological outcomes are well studied, the molecular mechanisms underlying cellular responses to reductive stress remain poorly understood. Using Caenorhabditis elegans as a model, we investigate thiol reductive stress induced by dithiothreitol (DTT) and uncover a critical protective role for the hypoxia response pathway. We identify RHY-1, a membrane-associated acyltransferase and known negative regulator of the hypoxia-inducible factor HIF-1, as essential for survival under thiol reductive stress. Notably, rhy-1 is a direct transcriptional target of HIF-1, and overexpression of rhy-1 fully rescues the sensitivity of hif-1 loss-of-function mutants to DTT. We demonstrate that RHY-1 functions in an autoinhibitory feedback loop, where elevated RHY-1 levels suppress activation of the hypoxia response pathway even during reductive stress. Together, our findings establish RHY-1 as both a regulatory and effector component of the hypoxia response pathway that mediates cellular protection against thiol reductive stress.