Supplementary material from "Cholesterol: An Ancient Ally or Modern Menace?"

Cholesterol has played a central role in the evolution of life by becoming a key structural component of cellular membranes. Its emergence, linked to the Great Oxidation Event over two billion years ago, enabled early eukaryotic cells to achieve membrane stability, controlled fluidity, and selective permeability. These properties supported the development of organelles, multicellularity, and complex tissues, particularly through the formation of lipid rafts that organise proteins and facilitate signalling and intracellular communication. This molecular innovation was fundamental for major evolutionary transitions and the later expansion of brain function. In vertebrates, cholesterol became essential for synthesising steroid hormones, vitamin D, and bile acids, contributing to physiological adaptation across diverse environments. In humans, its metabolic versatility supported immune function, energy management, and reproduction. However, modern lifestyles and dietary shifts have disrupted cholesterol homeostasis, contributing to atherosclerosis and cardiovascular diseases through arterial cholesterol accumulation and inflammation. Cholesterol also influences oncogenesis, as tumour cells exploit cholesterol-rich membrane domains and increase cholesterol synthesis and uptake to sustain growth and metastasis. This review traces the evolutionary trajectory of cholesterol and highlights its dual role in supporting complex life while contributing to major human diseases, linking evolutionary biology with contemporary biomedical relevance.