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It is known for its high efficiency, low toxicity, and broad\u2010spectrum activity. Although numerous strategies have been employed to enhance spinosad production, intricate regulation of secondary metabolism and inefficient genetic manipulation impede systematic and comprehensive metabolic engineering in this spinosad\u2010producing strain. In this study, a genome\u2010scale metabolic model (GEM) for\n                    <jats:italic>Sa. spinosa<\/jats:italic>\n                    NHF132 is developed to dissect the intricate secondary metabolic pathways of spinosad biosynthesis, analyzing interactions among precursors, key enzymes, and competing or bypass pathways. Guided by the model, the impact of rhamnose precursor overexpression, gene cluster amplification, short\u2010chain acyl\u2010CoA enhancement, and chassis optimization on spinosad production is systematically evaluated. By integrating these metabolic engineering strategies, engineered strain NHF132\u2010BAC\u2010\n                    <jats:italic>SP43<\/jats:italic>\n                    \u2010NCM achieved a spinosad titer of 1816.8\u00a0mg\u00a0L\n                    <jats:sup>\u22121<\/jats:sup>\n                    , a 553.3% increase over the starting strain, with substantial improvements in yield and product proportion. The model\u2010driven framework for metabolic engineering of complex secondary metabolites in actinomycetes substantially increased spinosad production and offered valuable insights for other complex natural products.\n                  <\/jats:p>","DOI":"10.1002\/advs.202511411","type":"journal-article","created":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T07:40:28Z","timestamp":1758872428000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Model\u2010Guided Systematic Metabolic Engineering for Enhanced Spinosad Biosynthesis in\n                    <i>Saccharopolyspora spinosa<\/i>\n                    NHF132"],"prefix":"10.1002","volume":"12","author":[{"given":"Shuliu","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Bioreactor Engineering (SKLBE) and School of Biotechnology East China University of Science and Technology (ECUST)  Shanghai 200237 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