Cholesterol: an ancient ally or modern menace?

Abstract Cholesterol, an essential sterol for cellular membranes, has been central to the evolutionary and biological story of life. Its origin, tied to Earth’s Great Oxidation Event over 2 billion years ago, enabled early eukaryotic cells to stabilize their membranes by maintaining stability, fluidity and selective permeability. These properties facilitated the emergence of multicellularity and complex tissues, particularly by enabling the formation of lipid rafts, cholesterol-enriched microdomains essential for protein organization, signalling and intracellular communication. This structural and functional refinement also supported the evolution of organelles, along with dynamic processes that drove key evolutionary transitions, paving the way for the development of complex life and, ultimately, the advancement of brain function. In vertebrates, cholesterol became indispensable for synthesizing steroid hormones, vitamin D and bile acids, enabling adaptation to diverse environments. For Neanderthals and Homo sapiens, its metabolic versatility was critical in the immune system development, central nervous system evolution, energy storage and reproduction. However, as human lifestyles shifted from hunter–gatherer diets to agriculture and modern processed foods, the balance of cholesterol uptake, usage and elimination has been disrupted. This mismatch contributed to widespread issues related to cholesterol metabolism, notably atherosclerosis and cardiovascular diseases, as excess cholesterol in the bloodstream accumulates in arterial walls, leading to plaque formation, inflammation and vascular obstruction. Rapidly, these conditions have become some of the most relevant health challenges for modern humans. The role of cholesterol extends to oncogenesis, where its influence on membrane dynamics becomes critical. Tumour cells manipulate cholesterol-rich domains to amplify growth factor signalling and evade apoptosis, facilitating uncontrolled proliferation and metastasis. Moreover, cancer cells upregulate cholesterol biosynthesis and uptake to sustain their heightened metabolic demands, linking dysregulated cholesterol pathways to tumour progression. Although this review does not aim to provide an exhaustive account of the appearance and evolution of cholesterol across all forms of life on Earth, it outlines the evolutionary trajectory for this molecule, from its primordial roles in early cellular systems to its dual functions in human physiology and disease. By situating cholesterol within both deep evolutionary history and contemporary biomedical contexts, this review highlights cholesterol as a key molecular participant in the major biological transitions that shaped life, while also underscoring its relevance to modern health challenges. In doing so, it offers a cross-disciplinary perspective that bridges fundamental evolutionary biology with current biomedical science.