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Epirubicin, a clinically important anthracycline-type antitumor drug, is industrially produced through a tedious chemical semisynthetic process. Here, we developed an engineered Streptomyces peucetius through a combinatorial strategy of strain mutation and metabolic engineering for efficient epirubicin biosynthesis. First, S. peucetius SIPI-DU-1557, which overproduces doxorubicin, was cultured through a doxorubicin-resistant screening method, and used as a host strain for genetic modification. Next, EvaE from Amycolatopsis orientalis, found through protein sequence comparisons of various exogenous TDP-4-ketoreductases, increased epirubicin production significantly. Subsequently, metabolic engineering strategies were used to enhance epirubicin production by co-expressing key biosynthesis pathway genes, dnrS/dnrQ and desIII/desIV, to strengthen metabolic flux toward epirubicin. The final epirubicin concentrations were 270 mg/L and 252 mg/L in the flask and 5 L fermenter, respectively. These are the highest levels reported, and show that the engineered S. peucetius has potential industrial application in green epirubicin production by direct fermentation with renewable resources.