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The in vitro scavenging activity of Tomato Seed Protein Isolate (TSPI) against free radicals as well as its reducing power was determined. Moreover, the possible protective effect and the mechanisms involved in the action of the protein isolate against the oxidative stress in LPS-induced RAW264.7 cells were determined. The results showed that the protein isolate scavenged DPPH, ABTS+ with IC50 values of 40.89 and 18.45 µg of protein/mL. Moreover, the reducing power activity of TSPI was 0.58. As regards to the antioxidant effects in LPS-induced RAW264.7 cells, tomato seed protein treatment attenuated increasing of ROS and NO levels. At 1000 µg/mL of TSPI, ROS and NO levels decreased up to 74.01 and 63.49 %. The isolate could increase the mRNA and protein expression of Nrf2 signaling related genes especially Hmox-1. These findings provide additional evidence that TSPI may be useful for reducing the oxidative damages by the activation of Nrf2 signaling.