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Background information: Tubulointerstitial fibrosis is the end‐point of chronic kidney diseases. Tamoxifen, a selective oestrogen receptor (ER) modulator, attenuates renal fibrosis, by regulating the transforming growth factor (TGF)‐β/Smad signalling. Src and phosphoinositide 3‐kinase (PI3K)/Akt pathways play critical roles in the pathogenesis of renal fibrosis. However, the activation of the non‐canonical TGF‐β signalling in renal fibrosis after treatment with tamoxifen remains unclear. Renal fibrosis was induced by unilateral ureteral obstruction (UUO) in rats. Tamoxifen was orally administered after UUO. Additionally, HK‐2 cells were treated with tamoxifen in the presence or absence of TGF‐β1. The selective ER down‐regulator ICI and ER‐α silencing were used to confirm the involvement of ER‐α on the effect of tamoxifen on TGF‐β1‐stimulated fibrosis in HK‐2 cells. Results: Tamoxifen treatment ameliorated UUO‐induced renal fibrosis as shown by decreased expression of α‐smooth muscle actin (SMA), fibronectin and connective tissue growth factor (CTGF). The phosphorylation of Src, PI3K, Akt, mammalian target of rapamycin (mTOR) and p70S6K significantly decreased in UUO kidneys from tamoxifen‐treated animals. Tamoxifen dose‐dependently suppressed the TGF‐β1‐induced expression of α‐SMA and CTGF, and phosphorylation of Src, PI3K, Akt, mTOR and p70S6K in HK‐2 cells. These anti‐fibrotic effects were reversed by treatment with ICI and silencing of ER‐α. Moreover, inhibition of the PI3K/Akt and mTOR/p70S6K pathways was observed in HK‐2 cells co‐treated with PP1 (a Src kinase inhibitor) and tamoxifen. Conclusions: The anti‐fibrotic effects of tamoxifen are associated with the suppression of Src kinase function via ER‐α, followed by inhibition of the PI3K/Akt and mTOR/p70S6K signalling pathways. Significance: Our findings suggest that tamoxifen is a novel therapeutic option for the prevention and treatment of renal fibrosis. Research Article: Our results demonstrated that phosphorylation of Src kinase in the obstructive kidney medicates renal fibrosis by activation of PI3K/Akt and mTOR/p70S6K signalling pathway, and treatment of tamoxifen has anti‐fibrotic effect on renal fibrosis by suppressing these pathways. In addition, our in vitro results suggested that anti‐fibrotic effect and its downstream signalling pathway were attenuated by tamoxifen in an ER‐α‐dependent manner. However, at present, it remains difficult to determine whether tamoxifen acts as anti‐oestrogenic or oestrogenic effect in our study. [ABSTRACT FROM AUTHOR]