It has been observed that hepatocytes directly communicate with HSCs via a panel of secreting factors, including cytokine peptides, miRNA, and lipid molecules.[12] To identify hepatocyte E4BP4‐specific factors that may activate HSCs, we performed RNA‐seq analysis of the liver samples of the 20‐week NASH diet‐fed E4bp4‐LKO cohort and revealed a number of secreted factors downregulated in the liver of NASH diet‐fed E4bp4‐LKO mice including Bmp8b, Opn, Tgfb3, Fbn2, and Gdf15. Here, SPP1 is linked to metabolic dysfunction-associated steatohepatitis.