Metabolic Dysregulation of 27-Hydroxycholesterol Sensitizes Proximal Tubular Epithelial Cells to Ferroptosis in Ischemic Acute Kidney Injury

  • J Am Soc Nephrol. 2026 Mar 1;37(3):445-459. doi: 10.1681/ASN.0000000857.
Yi-Lin Zhang  1 ,  Xin-Yan Li  1 ,  Tao-Tao Tang  1 ,  Qin Yang  1 ,  Bo Wang  1 ,  Zuo-Lin Li  1 ,  Yi Wen  1 ,  Qiu-Li Wu  1 ,  Lin-Li Lv  1 ,  Ye Feng  1  2 ,  Xiong-Zhong Ruan  3 ,  John Ci-Jiang He  2 ,  Bin Wang  1 ,  Bi-Cheng Liu  1
Affiliations
  • 1. Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China.
  • 2. Department of Medicine, Icahn School of Medicine at Mount Sinai, Division of Nephrology, New York, New York.
  • 3. Key Laboratory of Molecular Biology on Infectious Diseases, Centre for Lipid Research, Ministry of Education, Chongqing Medical University, Chongqing, China.
PMID: 40952808 DOI: 10.1681/ASN.0000000857
Abstract

Key Points:

  1. Integrated single-cell spatial transcriptomics and metabolomics identified Cholesterol reprogramming as a driver of Ferroptosis in proximal tubules.

  2. Targeting the Cyp7b1/27-hydroxycholesterol axis efficiently alleviated ferroptosis-induced proximal tubule injury during ischemic AKI.

Background: Cell death plays a pivotal role in ischemic AKI, with metabolic dysfunction emerging as a key contributor. However, the mechanism by which metabolism imbalance initiates renal tubular cell death is poorly understood.

Methods: We combined single-cell spatial transcriptomics and metabolomics to characterize the function and metabolites of murine renal proximal cell subpopulations during ischemic AKI to CKD transition.

Results: Ferroptosis was identified as the predominant mode of cell death in severely injured proximal straight tubules after AKI. Additional investigation revealed a critical deficiency in Cyp7b1, an enzyme responsible for metabolizing 27-hydroxycholesterol (27-HC) into 7α,27-dihydroxycholesterol, resulting in substantial 27-HC accumulation in proximal tubular cells during the early phase of ischemic AKI. Mechanistically, 27-HC acts as an endogenous ligand for Estrogen receptor α, inducing downstream Hmox1 activation and thereby potentiating Ferroptosis susceptibility in proximal tubular cells. Notably, adeno-associated virus–mediated Cyp7b1 overexpression in a murine ischemia-reperfusion injury model attenuated Ferroptosis by enhancing 27-HC degradation, effectively mitigating ischemic AKI progression. These findings underscore the pivotal role of the Cyp7b1/27-HC axis in this pathologic context.

Conclusions: Our study delineated a unique mechanism of Cyp7b1/27-HC axis in proximal tubular cell Ferroptosis in early AKI.

Keywords
AKI; cell death; ischemia-reperfusion; lipids; metabolism; metabolomics.
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