Ceramide kinase suppresses ferroptosis and protects against alcohol-associated liver disease through the p38 MAPK-HSPB1 pathway.

BACKGROUND: Alcohol-associated liver disease (ALD) is characterized by progressive liver injury, which is influenced by aberrant oxidative stress, ferroptosis, and sphingolipid metabolism. Although the inhibition of hepatic ceramide production has shown promise in ALD management, the specific roles of ceramide kinase (CERK) and its metabolite ceramide-1-phosphate in ALD pathogenesis and ferroptosis have not been fully explored. METHODS: To investigate the role of CERK in ALD, we established an alcohol-induced liver injury model using the Gao-binge protocol in C57BL/6 wild-type, Cerk knockout, and Cerk overexpression mice. The molecular mechanisms underlying CERK-regulated ALD were identified and characterized through liver transcriptomics and pharmacological inhibition of CERK. RESULTS: Alcohol consumption significantly increased the expression of CERK in the liver. Functional studies demonstrated that CERK mitigates alcohol-induced liver injury by attenuating oxidative stress and ferroptosis both in vivo and in vitro. Mechanistically, these effects were mediated through the activation of heat shock protein beta-1 via the p38 mitogen-activated protein kinase signaling pathway, highlighting HSPB1's role in suppressing oxidative stress and ferroptosis. CONCLUSIONS: Our findings indicated that enhancing CERK expression or activity may represent a novel therapeutic strategy for mitigating alcohol-induced liver injury. This approach could offer a promising avenue for treating ALD and its associated ferroptotic damage.