Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most common liver disease worldwide. Two nuclear receptors (NR), peroxisome proliferator-activated receptor alpha (PPARα) and estrogen-related receptor alpha (ERRα), involved in hepatic energy metabolism are druggable targets against MASLD. Recently, a close functional interconnection was described. Therefore, we studied whether simultaneous pharmacological modulation of PPARα and ERRα can ameliorate MASLD.