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Late\u2010stage CCOC is associated with a worse prognosis compared to other ovarian cancer histotypes, a challenge that has seen limited progress in recent decades. CCOC typically originates within the toxic microenvironment of endometriotic ovarian cysts and is characterized by its intrinsic chemoresistance, a strong hypoxic signature, and abundant expression of cystathionine gamma\u2010lyase (CTH). CTH is a key enzyme in the transsulfuration pathway and serves as a marker of ciliated cells derived from the M\u00fcllerian tract. CTH plays a pivotal role in <jats:italic>de novo<\/jats:italic> cysteine synthesis, which is essential for glutathione (GSH) production and redox homeostasis. Using an array of molecular tools and cancer models, including <jats:italic>in vivo<\/jats:italic> studies, we demonstrated that CTH expression was induced under various stress conditions, such as exposure to endometriotic cyst content and hypoxia. This induction enables cell survival and creates a differentiation state manifested by CCOC that potentiates tumor progression and metastasis. In addition to regulating redox homeostasis, CTH enhances hypoxia inducible factor 1\u2010alpha (HIF1\u03b1) expression, independently of hydrogen sulfide (H<jats:sub>2<\/jats:sub>S) production. Re\u2010expression of HIF1\u03b1 in <jats:italic>CTH<\/jats:italic> KO cells fully restored metastatic capacity in <jats:italic>in vivo<\/jats:italic> models. Co\u2010expression of CTH and HIF1\u03b1 proteins was also observed in human CCOC samples. Importantly, targeting CTH in CCOC significantly reduced its metastatic potential in <jats:italic>in vivo<\/jats:italic> models and enhanced sensitivity to chemotherapy. These findings underscore that CTH is both a defining feature of CCOC and a promising therapeutic target, not only for CCOC patients but also for those with other CTH\u2010expressing cancers. \u00a9 2025 The Author(s). <jats:italic>The Journal of Pathology<\/jats:italic> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.6433","type":"journal-article","created":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T07:28:48Z","timestamp":1747294128000},"page":"352-367","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Cystathionine gamma\u2010lyase\u2010mediated hypoxia inducible factor 1\u2010alpha expression drives clear cell ovarian cancer progression"],"prefix":"10.1002","volume":"266","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3202-6171","authenticated-orcid":false,"given":"Amal 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