Abstract: SA-PO0024
Metabolic Dysregulation of 27-Hydroxycholesterol Sensitizes Proximal Tubular Epithelial Cells to Ferroptosis in Ischemic AKI
Session Information
- Intelligent Imaging and Omics: Phenotyping and Risk Stratification
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Artificial Intelligence, Digital Health, and Data Science
- 300 Artificial Intelligence, Digital Health, and Data Science
Authors
- Zhang, Yilin, Southeast University, Nanjing, China
- Wang, Bo, Southeast University, Nanjing, China
- Wang, Bin, Southeast University, Nanjing, China
- Liu, Bi-Cheng, Southeast University, Nanjing, China
Group or Team Name
- Liu Lab.
Background
Cell death plays a pivotal role in ischemic acute kidney injury, with metabolic dysfunction emerging as a key contributor. However, the mechanism by which how metabolism imbalance initiates renal tubular cell death is poorly understood.
Methods
We performed single-cell spatial transcriptomics and metabolomics to analyze kidneys from a UIR mouse model. Cell types and PT states were identified through clustering and gene expression. Pseudotime and SCENIC analyses revealed PT transitions and key regulators. Using REINVENT 4.0, we AI-optimized a Cyp7b1-targeting compound. Validation was conducted via WB, IF and IHC.
Results
We identified 13 renal cell types and the dynamic changes during AKI-to-CKD transition: PTs declined on day1 post-AKI and recovered by day3. PSTs showed the highest injury via spatiotemporal profiling, and subclustering revealed 10 subtypes. Among them, PST-5 had the highest apoptosis and ferroptosis scores, likely originating from metabolically active PST-4, suggesting lipid reprogramming drives cell death.
Lipidomics showed elevated 25-hydroxycholesterol (25-OHC) and 27-hydroxycholesterol (27-OHC) post-AKI, which induced ferroptosis in HK-2 cells. Cyp7b1, a key enzyme metabolizing oxysterols, was significantly downregulated early in AKI. 27-OHC activated ERα and Hmox1, promoting ferroptosis. Cyp7b1 overexpression reduced injury by clearing 27-OHC.
According to the findings above, we identified THDCA as a Cyp7b1 activator via LINCSL1000. Using REINVENT 4.0 AI, it was optimized for Cyp7b1 binding and selected TA516-50-8 for validation.
Conclusion
We highlights the Cyp7b1/27-HC axis as a driver of ferroptosis in early AKI and targeting 27-HC as a potential therapy. We also demonstrate AI-enabled optimization of Cyp7b1 modulators for drug development.
Funding
- Government Support – Non-U.S.