The endoplasmic reticulum (ER) is a cellular organelle important for regulating calcium homeostasis, lipid metabolism and protein synthesis, post-translational modification and trafficking. Numerous environmental, physiological and pathological insults disturb ER homeostasis, referred to as ER stress, in which a collection of conserved intracellular signaling pathways termed the unfolded protein response (UPR) are activated to maintain ER function for cell survival. However, excessive and/or prolonged UPR activation leads to initiation of self-destruction through apoptosis. Excessive accumulation of lipids and their intermediate products causes metabolic abnormalities and cell death, called lipotoxicity, in peripheral organs, including the pancreatic islets, liver, muscle and heart. Since accumulating evidence links chronic ER stress and defects in UPR signaling to lipotoxicity in peripheral tissues, understanding the role of ER stress in cell physiology is a topic under intense investigation. In this review, we highlight recent findings that link ER stress and UPR signaling to the pathogenesis of peripheral organs due to lipotoxicity.

Numerous environmental, physiological, and pathological insults disrupt protein-folding homeostasis in the endoplasmic reticulum (ER), referred to as ER stress. Eukaryotic cells evolved a set of intracellular signaling pathways, collectively termed the unfolded protein response (UPR), to maintain a productive ER protein-folding environment through reprogramming gene transcription and mRNA translation. The UPR is largely dependent on transcription factors (TFs) that modulate expression of genes involved in many physiological and pathological conditions, including development, metabolism, inflammation, neurodegenerative diseases, and cancer. Here we summarize the current knowledge about these mechanisms, their impact on physiological/pathological processes, and potential therapeutic applications.

Endoplasmic reticulum (ER) stress is known to influence various cellular functions, including cell cycle progression. Although it is well known how ER stress inhibits cell cycle progression at the G1 phase, the molecular mechanism underlying how ER stress induces G2/M cell cycle arrest remains largely unknown. In this study, we found that ER stress and subsequent induction of the UPR led to cell cycle arrest at the G2/M phase by reducing the amount of cyclin B1. Pharmacological inhibition of the IRE1α or ATF6α signaling did not affect ER stress-induced cell cycle arrest at the G2/M phase. However, when the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α) phosphorylation was genetically abrogated, the cell cycle progressed without arresting at the G2/M phase after ER stress. GEO database analysis showed that growth arrest and DNA-damage-inducible protein α (Gadd45α) were induced in an eIF2a phosphorylation-dependent manner, which was confirmed in this study. Knockdown of GADD45α abrogated cell cycle arrest at the G2/M phase upon ER stress. Finally, the cell death caused by ER stress significantly reduced when GADD45α expression was knocked down. In conclusion, GADD45α is a key mediator of ER stress-induced growth arrest via regulation of the G2/M transition and cell death through the eIF2α signaling pathway.

Stress granules are membraneless organelles composed of numerous components including ribonucleoproteins. The stress granules are characterized by a dynamic complex assembly in response to various environmental stressors, which has been implicated in the coordinated regulation of diverse biological pathways, to exert a protective role against stress-induced cell death. Here, we show that stress granule formation is induced by morusin, a novel phytochemical displaying antitumor capacity through barely known mechanisms. Morusin-mediated induction of stress granules requires activation of protein kinase R (PKR) and subsequent eIF2α phosphorylation. Notably, genetic inactivation of stress granule formation mediated by G3BP1 knockout sensitized cancer cells to morusin treatment. This protective function against morusin-mediated cell death can be attributed at least in part to the sequestration of receptors for activated C kinase-1 (RACK1) within the stress granules, which reduces caspase-3 activation. Collectively, our study provides biochemical evidence for the role of stress granules in suppressing the antitumor capacity of morusin, proposing that morusin treatment, together with pharmacological inhibition of stress granules, could be an efficient strategy for targeting cancer.

Ferroptosis is an iron-dependent, lipid-peroxidation-driven form of regulated cell death that is distinct from apoptosis and necroptosis. Its involvement in various diseases highlights the need for reliable detection strategies. We provide a concise guide for ferroptosis detection, outlining key mechanisms, including iron metabolism, lipid remodeling, and antioxidant failure. Cellular, biochemical, genetic, and morphological methods, including viability assays, lipid reactive oxygen species probes, and electron microscopy, have been used to identify ferroptosis in vitro and in vivo. A multiparametric approach is emphasized to ensure the specificity and reproducibility.