The condition of ischemia and reperfusion (I/R) injury remains one of the significant pathological processes in diseases, including stroke and myocardial infarction, involving multifaceted molecular mechanisms: signaling pathways in cellular survival and oxidative stress response as well as metabolic responses. The Sigma-1 receptor is an important key modulator for many physiological and pathological processes, including neurotransmitter receptor/ligand as well as ion channels, modulating their respective functions under activation conditions of the receptor by stress or disease states. This review emphasizes evidence indicating the critical role of S1R in the therapeutics of ischemia. Angiogenic pathways, such as Vascular Endothelial Growth Factor (VEGF), Tropomyosin Receptor Kinase B (TrKB), and Epidermal Growth Factor (EGF), are considered to promote survival. The inflammatory pathways, which include Mitogen-Activated Protein Kinase (MAPK), Phosphoinositide 3-Kinase/Protein Kinase B (PI3K/AKT), Extracellular Signal-Regulated Kinase (ERK), and Mechanistic Target of Rapamycin (mTOR), improve cell survival and minimize apoptosis, with subsequent tissue repair in myocardial and cerebral ischemia. Oxidative stress responses mediated through Nuclear Factor Erythroid 2-Related Factor 2/Heme Oxygenase-1 (Nrf2/HO-1), Inositol-Requiring Enzyme 1 (IRE-1), and Protein Kinase R-like Endoplasmic Reticulum Kinase (PERK) pathways are required to counter ischemia-induced oxidative damage. Beyond these, further pathways include those of Protein Kinase A (PKA), Protein Kinase C (PKC), and Insulin-Like Growth Factor 1 (IGF-1), controlling cell survival, metabolism, ion homeostasis, and mitochondrial function. Targeting these pathways, particularly through S1R, presents promising therapeutic avenues for managing ischemic injuries.
