Push-pull-block framework for lycopene biosynthesis: a comprehensive review of metabolic engineering strategies in...

Lycopene is a high-value carotenoid widely utilized in food, pharmaceutical, nutraceutical, and cosmetic industries because of its strong antioxidant properties and associated health benefits. Among microbial hosts, Saccharomyces cerevisiae has emerged as a promising platform for sustainable lycopene biosynthesis due to its Generally Recognized as Safe status, well-characterized metabolism, and compatibility with industrial-scale fermentation processes. However, efficient lycopene production in yeast remains constrained by limited precursor availability, metabolic flux imbalance, competing pathways, redox stress, and intracellular toxicity associated with carotenoid accumulation. This review comprehensively summarizes current metabolic engineering strategies for enhancing lycopene biosynthesis in S. cerevisiae through an integrated "push-pull-block" framework. Push strategies focus on increasing precursor supply, acetyl-CoA availability, mevalonate pathway flux, and NADPH regeneration. Pull strategies emphasize pathway optimization through promoter engineering, gene dosage tuning, enzyme scaffolding, and heterologous carotenoid pathway enhancement to improve carbon flux toward lycopene biosynthesis. Block strategies target the suppression of competing sterol pathways, relief of feedback inhibition, and redirection of metabolic resources toward carotenoid accumulation. In addition, emerging approaches involving stress mitigation, lipid droplet engineering, adaptive laboratory evolution, dynamic regulation, controlled fermentation, and multi-omics-guided systems metabolic engineering are discussed as next-generation solutions for improving industrial lycopene production. Collectively, this review provides a systems-level perspective on current advances and future opportunities in engineering S. cerevisiae as an efficient microbial cell factory for sustainable lycopene biosynthesis.