In conclusion, this study identifies a Nox4‐dependent stress pathway that protects against RCD through spatially delimited redox signaling at the MAM to inhibit the calcium release activity of InsP3R. The findings provide a molecular insight into the regulation of the pathway in somatic cells and may be especially relevant for post‐mitotic cells like cardiomyocytes that are prone to frequent death‐promoting stresses (such as myocardial ischemia and infarction) in humans. The gene discussed is NOX4; the disease is infarction.