---
title: "Macrophage-Derived 25-Hydroxycholesterol Potentiates Statin-Associated Acute Kidney Injury"
id: "biorxiv-2-macrophage-derived-25-hydroxycholesterol-drives-statin-associated-acute-kidney"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-2-macrophage-derived-25-hydroxycholesterol-drives-statin-associated-acute-kidney"
content_type: "clinical_feed_article"
specialty: "Nephrology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.10.16.759612v1?rss=1"
published_at: "2026-10-22T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Macrophage-Derived 25-Hydroxycholesterol Potentiates Statin-Associated Acute Kidney Injury
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-2-macrophage-derived-25-hydroxycholesterol-drives-statin-associated-acute-kidney
- **Specialty:** [Nephrology](https://medichelpline.com/clinical-feed/nephrology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.10.16.759612v1?rss=1)
- **Published At:** 2026-10-22T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- The investigators tested whether macrophage-derived **25-hydroxycholesterol** (25‑HC) increases susceptibility to **statin**-induced **acute kidney injury** (AKI) using cell, mouse, and organoid models. - In vitro, proximal tubular cells exposed to atorvastatin or fluvastatin showed increased cell death when combined with 25‑HC; the source did not report specific drug concentrations or exposure durations. - A low-dose lipopolysaccharide (LPS) challenge produced AKI in statin-treated mice, consistent with an interaction between inflammation and statin exposure in vivo; detailed mouse numbers and strain information were not provided in the source. - Mechanistic data indicated that impaired protein prenylation disrupted the autophagosome–lysosome pathway in proximal tubular cells, linking statin effects on prenylation to defective autophagy and cell injury. - Mevalonate supplementation attenuated AKI in the reported models by restoring protein prenylation; macrophage/monocyte depletion likewise reduced AKI, attributed to lowering cellular sources of 25‑HC. - Human induced pluripotent stem cell-derived kidney organoids exposed to combined fluvastatin and 25‑HC exhibited increased **KIM-1** expression, providing a human-relevant signal of tubular injury; the source did not report organoid experimental parameters in depth. - The authors propose that elevated macrophage-derived 25‑HC in infection, inflammation, or major surgery may increase statin-associated AKI risk and suggest mitigation strategies; the report did not include clinical patient data or prospective human safety outcomes. - The team disclosed a related patent application; specific clinical recommendations or regulatory steps were not described in the manuscript.
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Chul Hoon Kim 1 Yonsei University College of Medicine; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Chul%2BHoon%2BKim%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Kim%20CH&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AChul%2BHoon%2BKim%2B) * [ORCID record for Chul Hoon Kim](http://orcid.org/0000-0002-7360-429X "Open in new tab") * For correspondence: kimhoon@yuhs.ac Hye Jin Wang 1 Yonsei University College of Medicine; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Hye%2BJin%2BWang%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Wang%20HJ&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AHye%2BJin%2BWang%2B) Yuri Cho 1 Yonsei University College of Medicine; 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* [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Beom%2Bseok%2BKim%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Kim%20BS&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ABeom%2Bseok%2BKim%2B) * [ORCID record for Beom seok Kim](http://orcid.org/0000-0002-5732-2583 "Open in new tab") * [Abstract](https://www.biorxiv.org/content/10.64898/2026.10.16.759612v1)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_art/node:5894139/1) * [Info/History](https://www.biorxiv.org/content/10.64898/2026.10.16.759612v1.article-info)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_info/node:5894139/1) * [Metrics](https://www.biorxiv.org/content/10.64898/2026.10.16.759612v1.article-metrics)[](https://www.biorxiv.org/panels_ajax_tab/article_tab_metrics/node:5894139/1) * [ Preview PDF](https://www.biorxiv.org/content/10.64898/2026.10.16.759612v1.full.pdf+html)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_pdf/node:5894139/1) ![Loading](https://www.biorxiv.org/sites/all/modules/contrib/panels_ajax_tab/images/loading.gif) ## 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. ### Competing Interest Statement Yonsei University College of Medicine has filed a patent application (US Pat. App. No. 16/761764), "Pharmaceutical Composition for Preventing or Treating Adverse Drug Reactions by Statin," related to this work. BSK, CHK, and JY are listed as inventors on this application. All other authors declare that they have no competing interests. Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a [CC-BY-ND 4.0 International license](http://creativecommons.org/licenses/by-nd/4.0/). bioRxiv and medRxiv thank the following for their generous financial support: > The Chan Zuckerberg Initiative, Cold Spring Harbor Laboratory, the Sergey Brin Family Foundation, California Institute of Technology, Centre National de la Recherche Scientifique, Fred Hutchinson Cancer Center, Imperial College London, Massachusetts Institute of Technology, Stanford University, The University of Edinburgh, University of Washington, and Vrije Universiteit Amsterdam. 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[ Download PDF](https://www.biorxiv.org/content/10.64898/2026.10.16.759612v1.full.pdf) Print/Save Options [Download PDF](https://www.biorxiv.org/content/biorxiv/early/2026/10/22/2026.10.16.759612.full.pdf)Full Text & In-line FiguresXML [More Info](https://www.biorxiv.org/about/FAQ#PrintOptions "More Information on Print/Save Options") [ Email](https://www.biorxiv.org/ "Email this Article") [ Share](https://www.biorxiv.org/) Macrophage-Derived 25-Hydroxycholesterol Drives Statin-Associated Acute Kidney Injury Chul Hoon Kim, Hye Jin Wang, Yuri Cho, Jung Ho Lee, Jongjin Yoon, Hye-Youn Kim, Youngrak Jung, Haebeen Lee, Hoon Young Choi, June-Yong Lee, Heon Yung Gee, Beom seok Kim bioRxiv 2026.10.16.759612; doi: https://doi.org/10.64898/2026.10.16.759612 This article is a preprint and has not been certified by peer review [[what does this mean?](https://www.biorxiv.org/about/FAQ#unrefereed)]. 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