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Heavy metal pollution is widespread and persistent, and causes serious harm to the environment. <i>Pseudomonas putida</i>, a representative environmental microorganism, has strong resistance to heavy metals due to its multiple efflux systems. Although the functions of many efflux systems have been well-studied, the relationship between them remains unclear. Here, the relationship between the Czc and Cad systems that are predominantly responsible for cadmium efflux in <i>P. putida</i> KT2440 is identified. The results demonstrated that CzcR3, the response regulator of two-component system CzcRS3 in the Czc system, activates the expression of efflux pump genes <i>czcCBA1</i> and <i>czcCBA2</i> by directly binding to their promoters, thereby helping the strain resist cadmium stress. CzcR3 can also bind to its own promoter, but it has only a weak regulatory effect. The high-level expression of <i>czcRS3</i> needs to be induced by Cd²⁺, and this relies on the regulation of CadR, a key regulator in the Cad system, which showed affinity to <i>czcRS3</i> promoter. Our study indicates that the Cad system is involved in the regulation of the Czc system, and this relationship is important for maintaining the considerable resistance to cadmium in <i>P. putida</i>.