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

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 translational candidate for its management. This study was registered at chictr.org.cn (ChiCTR2500106709).

ORGANISM(S): Mus musculus

PROVIDER: GSE316128 | GEO | 2026/01/16

REPOSITORIES: GEO

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