Engineering Squalene Biosynthesis: Multi-level Metabolic Strategies for Future Foods

Squalene, a high-value food ingredient, faces unsustainable supply challenges. Microbial metabolic engineering offers a sustainable alternative, but achieving high-yield production requires systematic optimization beyond conventional approaches. This review provides a unique framework categorizing cutting-edge strategies from molecular to cellular and systemic levels: enzyme engineering, static/dynamic metabolic control, metabolic channeling, subcellular compartmentalization, cofactor engineering, lipid droplet management, membrane transport, and adaptive laboratory evolution. We further discuss integrating artificial intelligence and process intensification to bridge the gap between laboratory innovation and industrially viable, sustainable squalene biomanufacturing for the future food industry.