Abstract: TH-PO0248
Novel Insights into the Interplay Between Ferroptosis and PANoptosis Under Uremic Toxin Stress in the Progression of CKD
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
- Liu, Shing-Hwa, National Taiwan University, Taipei City, Taiwan
- Tsai, Li Ting, National Taiwan University, Taipei City, Taiwan
- Liu, Chieh-Yun, National Taiwan University, Taipei City, Taiwan
- Wu, Cheng-Tien, China Medical University Hospital, Taichung City, Taiwan
- Chiang, Chih-Kang, National Taiwan University, Taipei City, Taiwan
Background
Chronic kidney disease (CKD) is a major global health burden. Uremic toxins, including indoxyl sulfate (IS) and p-cresyl sulfate (PCS), are key contributors to CKD-associated renal injury by driving oxidative stress, inflammation, and anemia. However, their effects on the regulation of ferroptosis and PANoptosis (a coordinated form of pyroptosis, apoptosis, and necroptosis) in the kidney during CKD progression remain poorly understood. This study aimed to investigate the impact of uremic toxins on renal iron homeostasis, ferroptosis, and PANoptosis using experiments of in vitro and in vivo.
Methods
Gene expression analysis of renal tissues from patients with CKD was conducted using publicly available NCBI datasets. An adenine-induced CKD mouse model, with or without oral sorbent AST-120 treatment to modulate uremic toxin burden, was employed. In in vitro experiments, human HK-2 and rat NRK-52E renal tubular epithelial cells were exposed to uremic toxins (IS and PCS) treated with or without ferroptosis inhibitors deferoxamine (DFO; iron chelator) and ferrostatin-1 (Fer-1; lipid peroxidation inhibitor).
Results
Gene expression analysis of renal tissues from CKD patients using publicly available NCBI datasets revealed coordinated activation of ferroptosis- and PANoptosis-associated gene programs, implicating these pathways in CKD progression. AST-120 attenuated renal injury, fibrosis, and senescence in adenine-induced CKD mice (p<0.05, n=6). Mechanistically, uremic toxins were involved in the disruption of renal iron metabolism, resulting in zinc protoporphyrin (ZnPP) accumulation, intracellular iron overload, ferroptosis, and PANoptosis in the kidneys of CKD mice (p<0.05, n=6). Both IS and PCS interfered with iron metabolism and induced ferroptosis in both renal tubular cell lines, which could be reversed by DFO treatment (p<0.05, n=6). Both IS and PCS could also induce PANoptosis (p<0.05, n=6) in both renal tubular cell lines. Fer-1 attenuated ferroptotic stress and reduced PANoptosis-associated signaling in renal tubular cells (p<0.05, n=6), supporting a mechanistic framework in which ferroptosis functions upstream to drive PANoptosis through iron-dependent lipid peroxidation.
Conclusion
These findings uncover an iron dysregulation linking uremic toxin-induced ferroptosis-driven PANoptosis during CKD progression.
Funding
- Government Support – Non-U.S.