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Preeclampsia (PE) is a pregnancy-related syndrome characterized by new-onset hypertension and proteinuria after gestational 20 weeks. Oxidative stress, resulting from the imbalance between the production of oxidants and antioxidants in placentas, is recognized as a key pathology of PE. To date, the molecules that regulate antioxidants production remain unclear. CD151, a member of tetraspanins, is an important regulator of many physiological functions. However, the function of CD151 in oxidative stress and its association with pregnancy-related complications are currently unknown. In the present study, we have demonstrated that CD151 was a key regulator of antioxidants in placentas. Compared with the placentas of the controls, the placentas of PE patients exhibited decreased CD151 expression accompanying with decreased antioxidant gene expression (HO-1, NQO-1, GCLC and SOD-1). In vitro , overexpression of CD151 in trophoblast cells could enhance HO-1, NQO-1, GCLC and SOD-1 expression but downregulation of CD151 decreased those antioxidant genes expression, which indicates CD151 is the upstream of antioxidants. Importantly, the phenotype of PE (hypertension and proteinuria) was mimicked in the downregulating CD151 induced mouse model. Moreover, the beneficial effect of CD151 in trophoblast cells was hindered when ERK and Nrf2 signaling were blocked. Overall, our results revealed CD151 might be a new target for PE treatment. Image 1 • CD151 decreases in trophoblasts of placentas from PE patients. • CD151 exerts antioxidative ability via ERK/Nrf2 pathway. • Downregulation of CD151 in pregnant mice mimics the phenomenon of PE. [ABSTRACT FROM AUTHOR]