A preclinical candidate of cyclophilin D inhibition improves alcohol-associated liver injury

  • Cell Rep Med. 2026 Mar 17;7(3):102654. doi: 10.1016/j.xcrm.2026.102654.
Zhaoyi Che  1 ,  Zhihui Luo  2 ,  Dong Xiao  3 ,  Fashu Ma  3 ,  Haoxiong Zhou  4 ,  Yali Song  5 ,  Shanshan Guo  3 ,  Yuan Yuan  6 ,  Hao Wang  1 ,  Ching-Pong Mak  3 ,  Kwok-Fai So  7 ,  Jia Xiao  8
Affiliations
  • 1. Department of Anesthesiology and Clinical Research Institute, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China.
  • 2. Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, China.
  • 3. Farsight Medical Technology (Shanghai) Co., Ltd., Shanghai 201210, China.
  • 4. Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.
  • 5. Department of Ultrasound, Huadu District People's Hospital of Guangzhou, Guangzhou 510800, China.
  • 6. Aier Institute of Ophthalmology, Central South University, Changsha 410015, China.
  • 7. Joint International Research Laboratory of CNS Regeneration, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, China.
  • 8. Department of Anesthesiology and Clinical Research Institute, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China; School of Life and Health Sciences, University of Health and Rehabilitation Sciences, Qingdao 266300, China. Electronic address: [email protected].
PMID: 41850244 DOI: 10.1016/j.xcrm.2026.102654
Abstract

Currently, no therapies are approved for alcohol-associated liver disease (ALD). Here, we identify Cyclophilin D (CypD) as a critical mediator in the progression of ALD. We observe elevated expression of CypD in ALD patients and a corresponding mouse model. Hepatocyte-specific knockout of CypD mitigates hepatic mitochondrial dysfunction, steatosis, inflammation, and oxidative stress. Conversely, overexpression of CypD exacerbates hepatic mitochondrial stress. In vivo and in vitro experiments demonstrate that a CypD inhibitor, RN-0001, effectively and safely alleviates hepatic damage induced by ethanol exposure; these protective effects are absent in CypD-deficient mice. Biophysical assays indicate that RN-0001 directly binds to CypD. Additionally, absorption, distribution, metabolism, excretion, and toxicity (ADMET) tests and first-in-human phase I clinical trial identify RN-0001 as a promising translational candidate for ALD therapy. Collectively, our study highlights the pathological role of CypD in ALD and introduces a preclinical candidate for its management. This study was registered at chictr.org.cn (ChiCTR2500106709).

Keywords
alcohol-associated liver disease; cyclophilin D; mitochondrial dysfunction; preclinical candidate.
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