Engineered Microbial Production of Sesquiterpenoids: Recent Advances and Prospects

Sesquiterpenoids have a wide range of functions, including anti-inflammatory, antitumor, antioxidant, and immune-enhancing properties, rendering them valuable for applications in cosmetics, pharmaceuticals, and fragrances. Recent advances in the microbial synthesis of sesquiterpenoids have emerged as a promising alternative to traditional plant extraction and chemical synthesis due to their enhanced efficiency, environmental sustainability, and cost-effectiveness. Significant progress in metabolic engineering, enzyme engineering, and microbial fermentation techniques has substantially improved sesquiterpenoid accumulation in microbial hosts. This review systematically summarizes current advances in the biosynthesis of four representative sesquiterpenoids, with a detailed analysis of their biosynthetic pathways categorized into four functional modules. Furthermore, state-of-the-art engineering strategies are critically reviewed, encompassing metabolic pathway optimization, flux balancing, enzyme engineering, host strain selection, promoter/copy number regulation, cofactor recycling, subcellular compartmentalization, substrate feeding optimization, and fermentation process control. Finally, we propose future directions for developing customized microbial cell factories through rational design and systems-level optimization to achieve high-efficiency sesquiterpenoid production.