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Abstract   Aims  Previous reports indicated that the Slit2–Robo signalling pathway is involved in embryonic heart development and fibrosis in other solid organs, but its function in adult cardiac fibrosis has not been investigated. Here, we investigate the role of the Slit2–Robo1 signalling pathway in cardiac fibrosis.    Methods and results  The right atrial tissue samples were obtained from patients with valvular heart disease complicated by atrial fibrillation during heart valve surgery and from healthy heart donors. The fibrotic animal model is created by performing transverse aortic constriction (TAC) surgery. The Robo1, Slit2, TGF‐β1, and collagen I expression levels in human and animal samples were evaluated by immunohistochemistry and western blot analysis. Echocardiography measured the changes in heart size and cardiac functions of animals. Angiotensin II (Ang II),  Slit2‐siRNA ,  TGF‐β1‐siRNA , recombinant Slit2, and recombinant TGF‐β1 were transfected to cardiac fibroblasts (CFs) respectively to observe their effects on collagen I expression level. The right atrial appendage of patients with valvular heart disease complicated by atrial fibrillation found significantly up‐regulated Slit2, Robo1, TGF‐β1, and collagen I expression levels. TAC surgery leads to heart enlargement, cardiac fibrosis, and up‐regulation of Slit2, Robo1, TGF‐β1, and collagen I expression levels in animal model. Robo1 antagonist R5 and TGF‐β1 antagonist SB431542 suppressed cardiac fibrosis in TAC mice. Treatment with 100 nM Ang II in CFs caused significantly increased Slit2, Robo1, Smad2/3, TGF‐β1, collagen I, PI3K, and Akt expression levels. Transfecting  Slit2‐siRNA  and  TGF‐β1‐siRNA , respectively, into rat CFs significantly down‐regulated Smad2/3 and collagen I expression, inhibiting the effects of Ang II. Recombinant Slit2 activated the TGF‐β1/Smad signalling pathway in CFs and up‐regulated Periostin, Robo1, and collagen I expression.    Conclusions  The Slit2–Robo1 signalling pathway interfered with the TGF‐β1/Smad pathway and promoted cardiac fibrosis. Blockade of Slit2–Robo1 might be a new treatment for cardiac fibrosis.

Crosstalk between the activated Slit2–Robo1 pathway and TGF‐β1 signalling promotes cardiac fibrosis