Macrophage-Derived 25-Hydroxycholesterol Drives Statin-Associated Acute Kidney Injury
- 1Yonsei University College of Medicine
Abstract
Although acute kidney injury (AKI) has been implicated as a potential adverse effect of statin therapy, experimental evidence supporting this association remains limited. Here, we investigated whether elevated levels of 25-hydroxycholesterol (25-HC), an oxysterol produced by activated macrophages and monocytes, increase susceptibility to statin-induced AKI. We found that atorvastatin and fluvastatin induced cell death in proximal tubular cells when combined with 25-HC. Consistently, administration of low-dose lipopolysaccharide triggered AKI in statin-treated mice. Mechanistically, impaired protein prenylation disrupted the autophagosome-lysosome pathway in proximal tubular cells. AKI was attenuated by mevalonate supplementation, which restored protein prenylation, and by macrophage/monocyte depletion, which reduced the cellular sources of 25-HC. Furthermore, combined exposure to fluvastatin and 25-HC increased kidney injury molecule-1 (KIM-1) expression in human induced pluripotent stem cell-derived kidney organoids. Together, these findings suggest that elevated macrophage-derived 25-HC under conditions of infection, inflammation, or major surgery may increase susceptibility to statin-induced AKI. Our study identifies a previously unrecognized interaction between statins and 25-HC and suggests potential strategies to mitigate kidney injury while preserving the therapeutic benefits of statins.
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BibTeX
@misc{kim2026macrophagederived,
title = {{Macrophage-Derived 25-Hydroxycholesterol Drives Statin-Associated Acute Kidney Injury}},
author = {C. H. Kim and H. J. Wang and Y. Cho and J. H. Lee and J. Yoon and H.-Y. Kim and Y. Jung and H. Lee and H. Y. Choi and J.-Y. Lee and H. Y. Gee and B. s. Kim},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.16.759612},
url = {https://www.biorxiv.org/content/10.64898/2026.10.16.759612v1},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - Macrophage-Derived 25-Hydroxycholesterol Drives Statin-Associated Acute Kidney Injury
AU - C. H. Kim
AU - H. J. Wang
AU - Y. Cho
AU - J. H. Lee
AU - J. Yoon
AU - H.-Y. Kim
AU - Y. Jung
AU - H. Lee
AU - H. Y. Choi
AU - J.-Y. Lee
AU - H. Y. Gee
AU - B. s. Kim
PY - 2026
DA - 2026/10/16
PB - bioRxiv
DO - 10.64898/2026.10.16.759612
UR - https://www.biorxiv.org/content/10.64898/2026.10.16.759612v1
AB - Although acute kidney injury (AKI) has been implicated as a potential adverse effect of statin therapy, experimental evidence supporting this association remains limited. Here, we investigated whether elevated levels of 25-hydroxycholesterol (25-HC), an oxysterol produced by activated macrophages and monocytes, increase susceptibility to statin-induced AKI. We found that atorvastatin and fluvastatin induced cell death in proximal tubular cells when combined with 25-HC. Consistently, administration of low-dose lipopolysaccharide triggered AKI in statin-treated mice. Mechanistically, impaired protein prenylation disrupted the autophagosome-lysosome pathway in proximal tubular cells. AKI was attenuated by mevalonate supplementation, which restored protein prenylation, and by macrophage/monocyte depletion, which reduced the cellular sources of 25-HC. Furthermore, combined exposure to fluvastatin and 25-HC increased kidney injury molecule-1 (KIM-1) expression in human induced pluripotent stem cell-derived kidney organoids. Together, these findings suggest that elevated macrophage-derived 25-HC under conditions of infection, inflammation, or major surgery may increase susceptibility to statin-induced AKI. Our study identifies a previously unrecognized interaction between statins and 25-HC and suggests potential strategies to mitigate kidney injury while preserving the therapeutic benefits of statins.
ER -