2. Academic Validation
  3. Unveiling hepatic Krüppel-like factor 15 as the key regulator of cyclosporine A metabolism and adverse effects

Unveiling hepatic Krüppel-like factor 15 as the key regulator of cyclosporine A metabolism and adverse effects

  • Drug Metab Dispos. 2025 Jul 29;53(9):100136. doi: 10.1016/j.dmd.2025.100136.
Xiaohua Guo 1,  Bingxia Wen 2,  Shilin Li 3,  Zhuangqi Shi 2,  Shi Chen 4,  Wanqing Hou 1,  Mengtong Xu 2,  Mengqing Kang 2,  Yuanxin Ma 2,  Tangxin Gao 5,  Suowen Xu 6,  Ku-Geng Huo 7,  Shuxin Han 8
Affiliations

Affiliations

  • 1 Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang, China; Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China; Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, China.
  • 2 Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang, China.
  • 3 Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang, China; Department of Clinical Medicine Research Center, Dazhou Central Hospital, Dazhou, Sichuan, China.
  • 4 Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, Anhui, China.
  • 5 Lantu Biopharma, Guangzhou, Guangdong, China.
  • 6 Department of Endocrinology, Institute of Endocrine and Metabolic Disease, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, China.
  • 7 Cyagen Biosciences (Guangzhou) Inc, Guangzhou, Guangdong, China.
  • 8 Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang, China; Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China; Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, China. Electronic address: hansx@xju.edu.cn.
PMID: 40885107 DOI: 10.1016/j.dmd.2025.100136
Abstract

Cyclosporine A (CsA) is a widely used immunosuppressant for posttransplantation and autoimmune diseases, but its clinical application is limited by severe hepatorenal toxicity. Krüppel-like factor 15 (KLF15), a key regulator of xenobiotic metabolism, has been shown to modulate the metabolism of acetaminophen and rifampicin and play a role in the associated drug-induced liver toxicity. However, its role in CsA metabolism and CsA-induced hepatorenal injury remains unclear. This study aimed to investigate whether hepatic KLF15 regulates CsA metabolism and serves as a potential therapeutic target for mitigating CsA-induced hepatorenal toxicity. KLF15 broadly suppressed the CsA detoxification pathways by inhibiting key metabolic Enzymes and transporters. Inhibition of hepatic KLF15 enhanced CsA detoxification, reduced CsA accumulation, and prevented hepatorenal injury. Notably, both AAV-shKlf15 and PXR agonist treatment demonstrated protective effects even after CsA-induced organ damage had occurred. These findings highlight KLF15 as a critical regulator of CsA metabolism and a promising therapeutic target for preventing or treating CsA-induced hepatorenal toxicity. The study provides preclinical evidence supporting further exploration of KLF15 modulation in clinical settings. SIGNIFICANCE STATEMENT: Hepatic Krüppel-like factor 15 is critical in regulating the metabolism of acetaminophen, rifampicin, and cyclosporine A, drugs used for pain relief, Antibiotics, and immune system regulation, respectively. It may serve as a potential therapeutic target for liver and kidney damage induced by these drugs.

Keywords

Cyclosporine A; Drug metabolism; Krüppel-like factor 15; Liver and kidney injury.

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