Stanniocalcin-1 Attenuates Cardiac Fibrosis Post Ischemia-Reperfusion Injury by Targeting the DOCKER Domain of Dedicator of Cytokinesis 1.

Cardiac fibrosis is a pivotal pathological process driving heart failure following ischemia-reperfusion (I/R) injury. STC1 (stanniocalcin-1), a conserved glycoprotein with mitochondrial regulatory functions, remains unexplored in myocardial fibrosis. This study investigates the mechanistic role of cardiomyocyte-derived STC1 in cardiac fibrosis. Mouse models of myocardial I/R injury were established by left anterior descending coronary artery ligation followed by 24-hour reperfusion. Cardiac-specific STC1 knockdown (adeno-associated virus 9-shSTC1) or overexpression (adeno-associated virus 9-STC1) preceded I/R injury induction. Cardiac function was assessed via echocardiography, and fibrosis was quantified histologically (Masson's trichrome, Sirius red) and molecularly (α-SMA [alpha smooth muscle actin], COL1A1 [collagen type I alpha 1 chain], COL3A1 [collagen type III alpha 1 chain], Smad2 [SMAD family member 2]). In vitro, cardiomyocyte-derived conditioned medium was applied to TGF-β (transforming growth factor beta)-stimulated fibroblasts, supplemented with recombinant STC1 for rescue assays. Protein-protein interactions were analyzed via coimmunoprecipitation and domain-deletion mutants. STC1 deficiency exacerbated post-I/R cardiac dysfunction and fibrosis, accompanied by elevated α-SMA, COL1A1, and phosphorylated-Smad2 levels. Conversely, STC1 overexpression attenuated I/R-induced functional decline and fibrosis. In addition, cardiomyocyte-derived STC1 suppressed TGF-β-driven fibroblast activation and Smad2 nuclear translocation. Mechanistically, STC1 directly interacted with the DOCKER domain of DOCK1 (dedicator of cytokinesis 1), disrupting DOCK1/RAC1-GTP (Rac family small GTPase 1 bound to guanosine triphosphate) signaling. Genetic ablation of the DOCKER domain abolished STC1's antifibrotic effects, restoring RAC1-GTP activity and fibrosis markers. Cardiomyocyte-derived STC1 mitigates cardiac fibrosis post I/R by targeting the DOCK1/RAC1 axis via its interaction with the DOCKER domain. These findings identify STC1-DOCK1 as a novel therapeutic pathway for ischemic heart failure.