REVIEW article
Front. Oncol.
Sec. Cancer Genetics
Volume 15 - 2025 | doi: 10.3389/fonc.2025.1610915
CHAC1 in Urological Tumors: Contextual Dualism and Therapeutic Implications
Provisionally accepted
Deyu Wang1,2
Yongquan Wan1,2
Yunxiang Li1,2*Yuan Ren2Jiakai Ma1,2Si Ge2Ziqiang Zeng2Zuoping Wang1,2Lei Zhen1,2- 1North Sichuan Medical College, Nanchong, China
- 2Department of Urology, Nanchong Central Hospital, Nanchong, Shanxi Province, China
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CHAC1, a glutathione-degrading enzyme, governs context-dependent pathophysiological processes in urological malignancies through modulation of endoplasmic reticulum stress and ferroptotic pathways. In clear cell renal cell carcinoma (ccRCC), CHAC1 exhibits stage-specific functional duality: downregulation in early-stage tumors correlates with adverse prognosis (suggesting tumor-suppressive activity), whereas elevated expression in advanced ccRCC (G3-G4/Stage III-IV) associates with increased mortality (indicating adaptive pro-survival adaptation). For prostate cancer, CHAC1 potentiates docetaxel cytotoxicity via coordinated induction of endoplasmic reticulum stress and ferroptosis, yet its suppression by cancer-associated fibroblast-derived exosomal miR-432-5p establishes therapy-reinforced chemoresistance. Mechanistically, CHAC1 intersects critical pathways by regulating redox homeostasis through glutathione catabolism, mediating potential crosstalk with androgen receptor signaling, and serving as an independent prognostic determinant in ccRCC (FPTOS_score model: HR = 2.028, 95% CI: 1.640-2.507). Notably, current evidence reveals no established link between CHAC1 and urothelial carcinoma pathogenesis. Further elucidation of CHAC1's mechanistic intricacies and therapeutic targeting (e.g., CHAC1 agonists, exosomal miRNA antagonists) may advance precision management of urological tumors.
Keywords: CHAC1, Glutathione metabolism, ferroptosis, Endoplasmic Reticulum Stress, prognostic biomarker, Drug Resistance
Received: 13 Apr 2025; Accepted: 18 Jul 2025.
Copyright: © 2025 Wang, Wan, Li, Ren, Ma, Ge, Zeng, Wang and Zhen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Yunxiang Li, North Sichuan Medical College, Nanchong, China
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