Cystathionine gamma‐lyase‐mediated hypoxia inducible factor 1‐alpha expression drives clear cell ovarian cancer progression

Clear cell ovarian cancer (CCOC) is the second most common ovarian cancer subtype, accounting for 5%-11% of ovarian cancers in North America. Late-stage 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-lyase (CTH). CTH is a key enzyme in the transsulfuration pathway and serves as a marker of ciliated cells derived from the Müllerian tract. CTH plays a pivotal role in de novo cysteine synthesis, which is essential for glutathione (GSH) production and redox homeostasis. Using an array of molecular tools and cancer models, including in vivo 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-alpha (HIF1α) expression, independently of hydrogen sulfide (H₂S) production. Re-expression of HIF1α in CTH KO cells fully restored metastatic capacity in in vivo models. Co-expression of CTH and HIF1α proteins was also observed in human CCOC samples. Importantly, targeting CTH in CCOC significantly reduced its metastatic potential in in vivo 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-expressing cancers. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.