The main findings of the present study are as follows: (1) Myeloid cell-derived MYDGF inhibited inflammation and attenuated hepatic de novo lipid synthesis to protect against NAFLD; (2) myeloid cell-derived MYDGF serves as a molecular messenger that mediates crosstalk between the bone marrow and liver to regulate liver fat metabolism; (3) MYDGF inhibits the inflammation of KCs; and (4) the IKKβ/NF-κB signaling pathway is involved in the beneficial effects of MYDGF on NAFLD. Here, MYDGF is linked to metabolic dysfunction-associated steatotic liver disease.