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Microcystis blooms and their secondary metabolites microcystins (MCs) occurred all over the world, which have damaged aquatic ecosystems and threatened public health. Techniques to reduce the Microcystis blooms and MCs are urgently needed. This study aimed to investigate the algicidal and inhibitory mechanisms of a red pigment prodigiosin (PG) against the growth and MC-producing abilities of Microcystis aeruginosa (M. aeruginosa). The numbers of Microcystis cells were counted under microscope. The expression of microcystin synthase B gene (mcyB) and concentrations of MCs were determined by quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme linked immunosorbent assay (ELISA) methods, respectively. The inhibitory effects of PG against M. aeruginosa strain FACHB 905 with 50% algicidal concentration (LC 50) at 120 h was 0.12 μg/mL. When M. aeruginosa cells exposed to 0.08 μg/mL, 0.16 μg/mL, 0.32 μg/mL PG, the expression of mcyB of M. aeruginosa was down-regulated 4.36, 8.16 and 18.51 times lower than that of the control at 120 h. The concentrations of total MC (TMC) also were 1.66, 1.72 and 5.75 times lower than that of the control at 120 h. PG had high algicidal effects against M. aeruginosa , with the activities of superoxide dismutase (SOD) initially increased and then decreased after 72 h, the contents of malondialdehyde (MDA) increase, the expression of mcyB gene down-regulation, and MCs synthesis inhibition. This study was first to report the PG can simultaneously lyse Microcystis cells, down-regulate of mcyB expression and inhibit MCs production effectively probably due to oxidative stress, which indicated PG poses a great potential for regulating Microcystis blooms and MCs pollution in the environment. Image 1 • PG has high algicidal effects against Microcystis aeruginosa. • PG down-regulates mcyB expression and reduces MCs production effectively. • The algicidal and inhibitory mechanisms of PG against Microcystis sp. are related to oxidative stress. PG poses a great potential for regulating Microcystis blooms and MCs pollution by simultaneously lysing M. aeruginosa and inhibiting the synthesis of MCs. [ABSTRACT FROM AUTHOR]