Metabolic dysfunction-associated steatotic liver disease (MASLD) progresses from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH), representing a critical transition in disease progression. We investigated the hepatocyte-intrinsic role of Cxcl5, the murine homolog of human CXCL6, using gain- and loss-of-function approaches. Hepatic Cxcl5 overexpression promoted steatosis-to-MASH transition in high-fat diet–fed mice with increased hepatocellular injury, inflammation, and fibrosis, whereas Cxcl5 deficiency protected against AMLN diet–induced MASH. Transcriptomic and in vitro analyses showed that Cxcl5-deficient livers and hepatocytes exhibited upregulation of Lpin1, enhanced expression of fatty acid oxidation genes, and increased PPARα activation, while recombinant CXCL6/CXCL5 suppressed LPIN1 and PPARα expression. Mechanistically, CXCL6 activated JNK and induced inhibitory phosphorylation of the glucocorticoid receptor (GR), thereby attenuating GR-dependent LPIN1 promoter activity. Lpin1 knockdown reversed the protective phenotype of Cxcl5-deficient mice. Consistently, human MASH livers displayed reduced LPIN1 expression and an inverse correlation between LPIN1 and CXCL6 expression. Collectively, the CXCL6 axis drives MASH progression by inhibiting GR–LPIN1–PPARα–mediated fatty acid oxidation, promoting lipotoxicity and inflammation, and represents a potential therapeutic target against MASH transition in MASLD.