["Journal of Cellular Physiology, Volume 241, Issue 4, April 2026. ", "\nABSTRACT\nDyslipidemia, characterized by an excessive amount of lipids in the bloodstream, is a significant risk factor for metabolic disorders and cardiovascular diseases (CVDs). Maternal supraphysiological hypercholesterolemia (MSPH) is associated with increased maternal levels of total cholesterol (TC) and low‐density lipoprotein (LDL). This condition has been linked to negative consequences on the fetoplacental vasculature, including increased atherosclerosis development in the fetal aorta and later in children and adolescents. This study aims to determine whether the high cholesterol levels associated with MSPH affect lysosomal and mitochondrial functions in the syncytiotrophoblast (STB), considering the increased free cholesterol levels previously reported in primary human trophoblast (PHT) cells from MSPH pregnancies. Total cholesterol levels were measured in placental tissues and BeWo cells. Lysosomal mass, size, and activity, as well as mitochondrial mass, function, and morphology, were assessed in BeWo cells and placentas. Our results revealed that placental tissues from MSPH pregnancies and BeWo cells treated with oxidized (ox‐LDL) exhibited increased free cholesterol levels and higher expression of cholesterol transport proteins. Treatment of BeWo cells with ox‐LDL also led to an increase in lysosomal mass and size, accompanied by a decrease in lysosomal activity. Conversely, ox‐LDL treatment induced mitochondrial fragmentation in BeWo cells, together with reduced ATP production and diminished mitochondrial membrane potential. Similar alterations in lysosomes and mitochondria were observed in the placenta of patients with a history of MSPH. MSPH‐related high cholesterol levels induced by ox‐LDL impair lysosomal and mitochondrial functions in the STB, potentially contributing to cellular dysfunction observed in MSPH. This study highlights the importance of understanding the underlying mechanisms of MSPH to improve maternal and fetal health outcomes."]