Metabolism of carbohydrates and lipids andprotein degradation occurs in the liver and contributes tothe body’s homeostasis by secreting a variety of mediators. Any imbalance in this homeostasis due to excess fatconsumption and the pathologic events accompanying lipotoxicity,autophagy dysregulation, endoplasmic reticulumstress, and insulin resistance may cause disturbances in thesecretion of the proteins from the liver and their physiologicmodifi cations and interactions with others. Since the liversecretome plays a role in the regulation of fuel metabolismand infl ammation not only in the liver per se but also inother organs, the proteins belong to the utmost targets fortreating metabolic and infl ammatory diseases (e.g., COVID-19), depending on the available and feasible approaches tocontrolling their biological eff ects. However, in this era,we still come across new liver-derived proteins but are yetunable to entirely understand the pathologic basis underlyingdisease progression. This review aims to provide anupdated overview of liver secretome biology with explanatorymechanisms with regard to the progression of metabolicand infl ammatory liver diseases.