In addition to Sig-1R roles in heart physiology, growing evidence points to the cardioprotective effects of Sig-1R signaling modulation in preclinical models of cardiac injury, including myocardial IRI, HF, hypertrophy, cardiac fibrosis, cardiomyopathy, depression, ER stress, and cardiovascular complications associated with SARS-CoV-2 infection (Figure 6) [177]. The gene discussed is SIGMAR1; the disease is major depressive disorder.