Inter-organ crosstalk has gained more and more attention recently. However, the mechanisms under this remain incompletely understood. Here, we revealed an endocrine pathway regulated by skeletal muscle IRF4 that manipulates liver pathology. Skeletal muscle specific IRF4 knockout (F4MKO) mice showed ameliorated liver steatosis, inflammation, and fibrosis, without changes in body weight on nonalcoholic steatohepatitis (NASH) diet. Proteomics analysis of serum suggested that follistatin-like protein 1 (FSTL1) might link the communication between muscle and liver. Dual luciferase assays showed that IRF4 could transcriptionally regulate FSTL1 and reconstitution of FSTL1 expression in muscle of F4MKO mice was sufficient to restore the liver pathology. Furthermore, co-culture experiments verified that different receptors contribute to FSTL1’s function in different cell types of liver. Finally, we found serum FSTL1 level was positively correlated with NASH progression in human. These data unveiled a signaling pathway from skeletal muscle to liver via IRF4-FSTL1-DIP2A/CD14 in the pathogenesis of NASH.