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.