Abstract: TH-PO0214
Mitochondrial ROS-Driven Ferroptosis via the Cystine/Glutamate Antiporter (xCT)-Glutathione (GSH) Axis in Unilateral Ureteral Obstruction
Session Information
- CKD: Mechanisms of Injury and Fibrosis - 1
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2203 CKD (Non-Dialysis): Mechanisms
Authors
- Kim, Won, Jeonbuk National University Medical School, Jeonju-si, Jeollabuk-do , Korea (the Republic of)
- Park, Woong, Jeonbuk National University Medical School, Jeonju-si, Jeollabuk-do , Korea (the Republic of)
- Jung, Yujin, Jeonbuk National University Medical School, Jeonju-si, Jeollabuk-do , Korea (the Republic of)
- Lee, Jiha, Jeonbuk National University Medical School, Jeonju-si, Jeollabuk-do , Korea (the Republic of)
Background
Unilateral ureteral obstruction (UUO) is a well-established model of renal fibrosis characterized by tubular injury and oxidative stress. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a critical mechanism in kidney disease. However, the upstream regulatory mechanisms linking mitochondrial ROS (mtROS) and the xCT–GSH antioxidant axis to ferroptosis in UUO remain unclear. Piperazine erastin (PE), an analog of erastin, provides a useful tool to interrogate this pathway.
Methods
Male C57BL/6 mice were divided into Sham, UUO, PE, and UUO+PE groups. UUO was induced by unilateral ureteral ligation, and PE (10 mg/kg) was administered intraperitoneally for 7 days. Renal tissues were analyzed for total and mitochondrial ROS using DCFH-DA and MitoSOX staining. Ferroptosis-related markers including GPX4 and SLC7A11 (xCT) were evaluated by Western blotting. GSH levels were quantified to assess redox status. mRNA expression of Ptgs2, Ho-1, and Acsl4 was measured by qRT-PCR. Tubular injury and interstitial fibrosis were assessed histologically.
Results
UUO significantly increased ROS and mtROS levels compared to sham controls, which were further exacerbated by PE treatment. PE administration markedly suppressed SLC7A11 expression and reduced intracellular GSH levels, accompanied by a further decrease in GPX4 expression in the UUO+PE group. Among ferroptosis-associated genes, Ptgs2 expression was significantly upregulated following PE treatment. Although tubular injury and fibrosis were increased in UUO mice, PE treatment showed a trend toward further aggravation without statistical significance.
Conclusion
Our findings suggest that PE exacerbates ferroptosis in UUO by disrupting the xCT–GSH–GPX4 axis and enhancing mitochondrial ROS accumulation. These results support a model in which mtROS-driven redox imbalance promotes ferroptotic signaling in obstructive nephropathy. Targeting the mtROS–xCT–GSH axis may represent a potential therapeutic strategy to mitigate renal fibrosis progression.
Funding
- Government Support – Non-U.S.