biostudies-literatureRaviScience and Engineering Research BoardDepartment of Biotechnology, Government of West BengalODCDC CDC HHSNIH HHSe114093https://www.ebi.ac.uk/biostudies/studies/S-EPMC10646554biostudies-literatureUnknown42(22)Owing to their capability to disrupt the oxidative protein folding environment in the endoplasmic reticulum (ER), thiol antioxidants, such as dithiothreitol (DTT), are used as ER-specific stressors. We recently showed that thiol antioxidants modulate the methionine-homocysteine cycle by upregulating an S-adenosylmethionine-dependent methyltransferase, rips-1, in Caenorhabditis elegans. However, the changes in cellular physiology induced by thiol stress that modulate the methionine-homocysteine cycle remain uncharacterized. Here, using forward genetic screens in C. elegans, we discover that thiol stress enhances rips-1 expression via the hypoxia response pathway. We demonstrate that thiol stress activates the hypoxia response pathway. The activation of the hypoxia response pathway by thiol The EMBO journalThiol reductive stress activates the hypoxia response pathway.PMC10646554BT/RLF/Re‐entry/50/2020P40 OD010440SRG/2020/000022Singh JRaviBhattacharyya SKumar AfalseThiol reductive stress activates the hypoxia response pathway.Owing to their capability to disrupt the oxidative protein folding environment in the endoplasmic reticulum (ER), thiol antioxidants, such as dithiothreitol (DTT), are used as ER-specific stressors. We recently showed that thiol antioxidants modulate the methionine-homocysteine cycle by upregulating an S-adenosylmethionine-dependent methyltransferase, rips-1, in Caenorhabditis elegans. However, the changes in cellular physiology induced by thiol stress that modulate the methionine-homocysteine cycle remain uncharacterized. Here, using forward genetic screens in C. elegans, we discover that thiol stress enhances rips-1 expression via the hypoxia response pathway. We demonstrate that thiol stress activates the hypoxia response pathway. The activation of the hypoxia response pathway by thiol 2023-01-01T00:00:00Z2023 Nov2026-06-06T22:14:45.06Z2025-04-04T00:39:08.061ZS-EPMC106465543790246410.15252/embj.2023114093