Macrophage-Derived 25-Hydroxycholesterol Drives Statin-Associated Acute Kidney Injury

Kim, C. H.; Wang, H. J.; Cho, Y.; Lee, J. H.; Yoon, J.; Kim, H.-Y.; Jung, Y.; Lee, H.; Choi, H. Y.; Lee, J.-Y.; Gee, H. Y.; Kim, B. s.

doi:10.64898/2026.10.16.759612

bioRxiv · 10.64898/2026.10.16.759612

Macrophage-Derived 25-Hydroxycholesterol Drives Statin-Associated Acute Kidney Injury

Kim, C. H.·Wang, H. J.·Cho, Y.·Lee, J. H.·Yoon, J.·Kim, H.-Y.·Jung, Y.·Lee, H.·Choi, H. Y.·Lee, J.-Y.·Gee, H. Y.·Kim, B. s.

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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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Kim, C. H., Wang, H. J., Cho, Y., Lee, J. H., Yoon, J., Kim, H.-Y., Jung, Y., Lee, H., Choi, H. Y., Lee, J.-Y., Gee, H. Y., Kim, B. s.. 2026-10-22. Macrophage-Derived 25-Hydroxycholesterol Drives Statin-Associated Acute Kidney Injury. https://doi.org/10.64898/2026.10.16.759612

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