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Lincomycin industrially produced by <i>Streptomyces lincolnensis</i> can be adopted to treat infections caused by Gram-positive bacteria. SLCG_Lrp, a transcriptional regulator of the Lrp family, was first identified to positively regulate lincomycin biosynthesis. However, the regulatory role of SLCG_Lrp is yet to be elucidated. This study utilized RNA-seq for comparing the transcriptome profile of original-strain LCGL and the Δ<i>SLCGL_Lrp</i> mutant. A total of 244 genes comprising 116 downregulated and 128 upregulated genes were differentially expressed between LCGL and Δ<i>SLCGL_Lrp</i>. An in-depth analysis revealed that SLCG_Lrp promotes nitrate assimilation but inhibits fatty acid metabolism, as well as directly regulates five regulators participating in the modulation of multiple cellular processes. With individual inactivation of those regulatory genes in <i>S. lincolnensis</i> LCGL, we confirmed the FadR transcriptional regulator SLCG_2185 was obviously correlated with lincomycin production and found it to transcriptionally stimulate the lincomycin biosynthetic cluster. Furthermore, <i>SLCG_2185</i> overexpression in the high-yield <i>S. lincolnensis</i> LA219X promoted lincomycin production by 17.8%, and <i>SLCG_2185</i> being co-overexpressed with <i>SLCG_Lrp</i> in LA219X increased lincomycin production by 28.1% compared to LA219X. Therefore, this investigation not only provides a direction for further investigations regarding the regulation mechanism of SLCG_Lrp, but also provides a basis for guiding the further improvement of lincomycin levels.