CXCL6 exacerbates metabolic dysfunction-associated steatohepatitis by suppressing LPIN1-mediated fatty acid oxidation in hepatocytes.

Progression of hepatic steatosis to metabolic dysfunction-associated steatohepatitis (MASH) is driven by impaired fatty acid (FA) oxidation and subsequent hepatocyte lipotoxicity. While MASH is characterized by upregulation of the neutrophil chemoattractant CXCL6, which functions through CXCR2, the direct impact of this pathway on hepatocyte FA metabolism during MASH progression remains unclear. Here, we demonstrate that hepatic overexpression of Cxcl5 (the murine homolog of CXCL6) inhibits hepatocyte FA oxidation and promotes MASH progression in mice. In contrast, Cxcl5 deficiency conferred protection against diet-induced MASH by reducing hepatic FA levels and restoring the expression of LPIN1, a transcriptional coactivator of PPARα, thereby normalizing FA metabolic gene expression. Mechanistically, CXCL6 activated JNK, leading to the inhibitory phosphorylation of the glucocorticoid receptor (GR). This blockade prevented GR-dependent activation of the LPIN1 promoter, thereby suppressing the LPIN1-PPARα axis in hepatocytes. Lpin1 knockdown reversed the protective phenotype in Cxcl5-deficient mice, confirming that LPIN1 suppression is the essential driver of CXCL6-mediated MASH progression. Consistently, human MASH samples exhibited reduced LPIN1 expression, which inversely correlated with CXCL6 expression. In conclusion, beyond its canonical role in neutrophil recruitment, CXCL6 promotes MASH progression by inhibiting the GR-LPIN1-PPARα axis in hepatocytes, resulting in impaired FA oxidation and lipotoxicity.