Taken together, our observation implies that high-fat diet leads to lipid metabolism disorders in NAFLD model rats, oxidative stress, the opening of apoptosis pathways (Bax, ATF4, and Caspase-3), leading to hepatocyte apoptosis, and further activation of endoplasmic reticulum stress proteins (GRP78, PERK, eIF2α, CHOP, JNK, and p-IRE1/IRE1). This evidence concerns the gene ERN1 and metabolic dysfunction-associated steatotic liver disease.