Abstract: SA-PO0255
Structure-Guided Discovery of an Endogenous CYP7B1 Agonist for Ischemic AKI
Session Information
- AKI: Mechanisms - Cell Signaling
October 24, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Zhang, Yilin, Southeast University, Nanjing, Jiangsu, China
- Liu, Bi-Cheng, Southeast University, Nanjing, Jiangsu, China
Background
Human cytochrome P450 7B1 (CYP7B1) is involved in oxysterol metabolism and cholesterol homeostasis. It catalyzes the hydroxylation of side-chain–oxidized sterols, including 25- and 27-hydroxycholesterol, thereby regulating their cellular accumulation and downstream signaling. Studies have implicated this enzyme as an early and functionally important target in ischemic acute kidney injury (AKI), but there are no known selective agonists for CYP7B1 and no enzymatic structures available to guide therapeutic development.
Methods
We combined structure-based modeling, molecular docking, and binding energy analyses to identify candidate CYP7B1 modulators, followed by biochemical, cellular, and in vivo validation in ischemic AKI models.
Results
Here, we established an integrated structure-enabled pharmacological platform to identify and characterize interactions between CYP7B1 and endogenous bile acid derivatives. Human CYP7B1 was modeled using deep learning–based structure prediction and used in conjunction with heme-coordination–aware molecular docking, binding free energy estimation, and quantitative pharmacological prioritization to interrogate a focused library of hydroxylated bile acids as candidate functional modulators. Through this approach, taurohyodeoxycholic acid (THDCA) was identified as a high-affinity CYP7B1 ligand. In silico analyses predicted that THDCA binds within the CYP7B1 catalytic pocket, with its hydroxyl moiety directly coordinating the heme iron-an interaction geometry consistent with stable target engagement, enzymatic activation, and selectivity among related P450 enzymes. Further biochemical and cellular assays confirmed that THDCA enhances CYP7B1 enzymatic activity and restores oxysterol metabolic flux in injured tubular epithelial cells. Mechanistically, THDCA-mediated CYP7B1 activation reduced pathological accumulation of 27-hydroxycholesterol, suppressed lipid peroxidation, and attenuated ferroptsis following ischemic stress. In vivo, systemic administration of THDCA significantly rescued renal function, tubular integrity, and survival in CYP7B1-deficient AKI mouse models, without observable off-target toxicity.
Conclusion
Together, selective activation of CYP7B1 will advance understanding of the role of oxysterol metabolism in ischemic AKI and provide a therapeutic strategy for renal ischemic injury.