The present investigation of the role of Sig1R in the activation of cardiac fibroblasts revealed the following major findings illustrated in Figure 9: (1) The expression of Sig1R is decreased in mice heart tissue following TAC operation and in the activation of cardiac fibroblasts induced by TGF-β1; (2) Stimulation of Sig1R attenuates the activation of cardiac fibroblasts and cardiac fibrosis; (3) The IRE1α pathway mediates the role of Sig1R in the activation of cardiac fibroblasts; (4) Stimulation of Sig1R alleviates the autophagic flux impairment in the activation of cardiac fibroblasts. This evidence concerns the gene ERN1 and persistent truncus arteriosus.