The endoplasmic reticulum (ER) is an organelle that orchestrates the production and proper assembly of an extensive types of secretory and membrane proteins. Endoplasmic reticulum stress is conventionally related to prolonged disruption in the protein folding machinery resulting in the accumulation of unfolded proteins in the ER. This disruption is often manifested due to oxidative stress, Ca²⁺ leakage, iron imbalance, disease conditions which in turn hampers the cellular homeostasis and induces cellular apoptosis. A mild ER stress is often reverted back to normal. However, cells retaliate to acute ER stress by activating the unfolded protein response (UPR) which comprises three signaling pathways, Activating transcription factor 6 (ATF6), inositol requiring enzyme 1 alpha (IRE1α), and protein kinase RNA-activated-like ER kinase (PERK). The UPR response participates in both protective and pro-apoptotic responses and not much is known about the mechanistic aspects of the switch from pro‐survival to pro‐apoptosis. When ER stress outpaces UPR response then cell apoptosis prevails which often leads to the development of various diseases including cardiomyopathies. Therefore, it is important to identify molecules that modulate the UPR that may serve as promising tools towards effective treatment of cardiovascular diseases. In this review, we elucidated the latest advances in construing the contribution imparted by the three arms of UPR to combat the adverse environment in the ER to restore cellular homeostasis during cardiomyopathies. We also summarized the various therapeutic agents that plays crucial role in tilting the UPR response towards pro-survival.

内质网 (ER) 是一种细胞器，可协调大量分泌蛋白和膜蛋白的产生和正确组装。内质网应激通常与蛋白质折叠机制的长期破坏有关，导致未折叠蛋白质在 ER 中积累。这种破坏通常表现为氧化应激，Ca ²⁺渗漏、铁失衡、疾病状况反过来阻碍细胞稳态并诱导细胞凋亡。轻微的 ER 压力通常会恢复正常。然而，细胞通过激活未折叠蛋白反应 (UPR) 对急性 ER 应激进行报复，该反应包括三个信号通路，激活转录因子 6 (ATF6)、肌醇需要酶 1 α (IRE1α) 和蛋白激酶 RNA 激活样 ER 激酶（振作）。UPR 反应参与保护性和促凋亡反应，关于从促生存到促凋亡的转变的机制方面知之甚少。当 ER 压力超过 UPR 反应时，细胞凋亡就会盛行，这通常会导致各种疾病的发展，包括心肌病。所以，重要的是要确定调节 UPR 的分子，这些分子可以作为有效治疗心血管疾病的有希望的工具。在这篇综述中，我们阐明了在解释 UPR 的三个分支对对抗 ER 中的不利环境以恢复心肌病期间的细胞稳态的贡献方面的最新进展。我们还总结了各种治疗药物，这些药物在使 UPR 反应向促生存倾斜方面发挥着关键作用。