Identification of mitochondria-associated hub genes related to alcohol-associated liver fibrosis progression in aldehyde dehydrogenase 2 deficiency.

BACKGROUND & AIMS: The pathogenesis of alcohol-associated liver fibrosis remains incompletely understood. Aldehyde dehydrogenase 2 (ALDH2) is the primary enzyme responsible for detoxifying ethanol-derived acetaldehyde. Notably, the ALDH2 rs671 variant is carried by approximately 8% of the global population, with a prevalence of 30%-50% in East Asians. This variant reduces ALDH2 enzymatic activity. However, the contribution of impaired ALDH2 function to fibrotic susceptibility and the underlying regulatory molecules remains to be fully elucidated.

METHODS

Blood samples from patients with alcohol-associated liver disease (ALD) were collected for ALDH2 rs671 genotyping, with concurrent assessment of liver stiffness. Global Aldh2 knockout (Aldh2-/ -) and wild-type (WT) mice were treated with ethanol or carbon tetrachloride (CCl4) or a combination of both.

RESULTS

Among 80 patients with ALD, those carrying the ALDH2 rs671 variant (n = 34) exhibited comparable liver fibrosis-related indices to ALDH2 wild-type patients (n = 46) despite significantly lower cumulative alcohol intake. Compared with WT mice, Aldh2-/ - mice treated with ethanol and CCl4 showed exacerbated hepatic fibrosis, with transcriptomic analysis revealing predominant enrichment of differentially expressed genes in mitochondrial pathways, accompanied by reduced hepatic mitochondrial size and redox imbalance. Acyl-CoA synthetase long-chain family member 1 (ACSL1) was identified as a candidate molecule associated with fibrotic progression under ALDH2-deficient conditions. ACSL1 expression was downregulated in liver tissue from ethanol plus CCl4-treated Aldh2-/ - mice, coinciding with elevated hepatic long-chain free fatty acids.

CONCLUSION

This study suggests a potential clinical association between the ALDH2 rs671 variant and increased fibrosis susceptibility in patients with ALD, and identifies ACSL1 as a candidate molecule associated with alcohol-associated fibrotic progression under ALDH2-deficient conditions, providing a basis for future mechanistic studies.

IMPACT AND IMPLICATIONS: This study provides clinical evidence suggesting a potential association between the prevalent ALDH2 rs671 variant and increased susceptibility to alcohol-associated liver fibrosis. Mitochondrial alterations may contribute to fibrotic progression in Aldh2-deficient mice exposed to ethanol and CCl4. ACSL1 was identified as a candidate molecule associated with this process. These findings extend the current understanding of mitochondrial and metabolic alterations involved in ALDH2-related alcohol-associated fibrotic injury and provide a basis for future mechanistic studies.