Jiedu Huayu suppress ferroptosis induced by 5-lipoxygenase-dependent peroxidation in acute liver failure

Jiedu Huayu Granules (JDHY), a compound formula of six traditional Chinese herbal medicines, has been used for nearly twenty years to treat acute liver failure (ALF) with good clinical efficacy. Its underlying drug mechanisms warrant in-depth exploration.

This study aims to investigate the inhibitory effects and mechanisms of JDHY on D-Galactosamine + Lipopolysaccharides (D-GalN + LPS)-induced ALF cell and animal models in mice.

The 10 mg/mL D-GalN+1 μg/mL LPS-induced ALF cell model in mice was established according to previous methods, and 15 % JDHY-containing serum was used for intervention. Transcriptomics and proteomics analyses were employed to explore the effective mechanism of JDHY in treating ALF, and verification was carried out at the cell and animal levels based on the omics results.

Transcriptomics revealed JDHY anti-ALF mechanism involves ferroptosis. Proteomics suggested 5-lipoxygenase (5-LOX) mediates JDHY anti-ferroptotic effects. Crucially, 5-LOX subcellular localization influences its activity: cytoplasmic retention exacerbates ALF oxidative stress and ferroptosis, which ferroptosis inhibitor Fer-1 significantly attenuated. Mechanistically, cAMP-PKA pathway activation promotes 5-LOX nuclear-to-cytoplasmic translocation. Conversely, JDHY inhibited cAMP-PKA expression, facilitated 5-LOX nuclear reflux, and alleviated ferroptosis-mimicking PKA siRNA effects. In addition, JDHY inhibition of ALF ferroptosis might be multifaceted, as we also found that it promoted the expression levels of Slc7a11, GSH, and GPX4, indirectly improving the antioxidant capacity of cells.

JDHY suppresses 5-LOX-catalyzed lipid peroxidation via negative feedback regulation of the cAMP-PKA pathway, mitigating ALF-associated ferroptosis. Moreover, the data provided in this paper suggest that 5-LOX can serve as a potential target for inhibiting ALF ferroptosis, providing a scientific basis for the clinical prevention and treatment of ALF.