Integrated multi-omics identification and experimental validation of ACSL4-associated ferroptotic lipid remodeling in drug-induced acute liver failure.

BACKGROUND

Acute liver failure due to Drug-induced liver injury (DILI-ALF) is a life-threatening syndrome with rapid progression and high mortality. Although oxidative stress and lipid peroxidation are implicated, the molecular mechanisms underlying DILI-ALF remain incompletely understood. This study aimed to explored the molecular mechanisms of DILI-ALF.

METHODS

We performed an integrated analysis combining proteomic profiling of liver tissues from patients with DILI-ALF, reanalysis of public single-cell transcriptomic data, and experimental validation in human liver tissues and an acetaminophen (APAP)-induced liver failure model. Lipid peroxidation, ultrastructural changes, and ACSL4 expression were assessed using biochemical assays, transmission electron microscopy, western blotting, immunohistochemistry.

RESULTS

Proteomic analysis revealed significant enrichment of lipid peroxidation and ferroptosis-related pathways in DILI-ALF, with ACSL4 identified as a prominently dysregulated molecule. Single-cell transcriptomic analysis further showed increased ACSL4 expression in specific hepatocytes populations during DILI-ALF. In liver tissues from patients with DILI-ALF, increased ACSL4 expression was accompanied by elevated malondialdehyde and lipid peroxide levels, as well as mitochondrial abnormalities consistent with ferroptosis-associated injury. Similar findings were observed in APAP-induced mouse livers, whereas inhibition of ACSL4 could significantly attenuated levels of lipid peroxidation and liver injury.

CONCLUSION

These study identifies and validates an ACSL4-associated ferroptotic lipid peroxidation signature and support the involvement of ferroptosis-related lipid remodeling in the pathogenesis of in DILI-ALF. ACSL4 may represent a potential biomarker and therapeutic target for this severe condition.