The endoplasmic reticulum (ER) is crucial for protein quality control, and disruptions in its function can lead to various diseases. ER stress triggers an adaptive response called the unfolded protein response (UPR), which can either restore cellular homeostasis or induce cell death. Melatonin, a safe and multifunctional compound, shows promise in controlling ER stress and could be a valuable therapeutic agent for managing the UPR. By regulating ER and mitochondrial functions, melatonin helps maintain cellular homeostasis via reduction of oxidative stress, inflammation, and apoptosis. Melatonin can directly or indirectly interfere with ER-associated sensors and downstream targets of the UPR, impacting cell death, autophagy, inflammation, molecular repair, among others. Crucially, this review explores the mechanistic role of melatonin on ER stress in various diseases including liver damage, neurodegeneration, reproductive disorders, pulmonary disease, cardiomyopathy, insulin resistance, renal dysfunction, and cancer. Interestingly, while it alleviates the burden of ER stress in most pathological contexts, it can paradoxically stimulate ER stress in cancer cells, highlighting its intricate involvement in cellular homeostasis. With numerous successful studies using in vivo and in vitro models, the continuation of clinical trials is imperative to fully explore melatonin\'s therapeutic potential in these conditions.

The mitochondria‑associated endoplasmic reticulum (ER) membrane (MAM), serving as a vital link between the mitochondria and ER, holds a pivotal role in maintaining the physiological function of these two organelles. Its specific functions encompass the participation in the biosynthesis and functional regulation of the mitochondria, calcium ion transport, lipid metabolism, oxidative stress and autophagy among numerous other facets. Scientific exploration has revealed that MAMs hold potential as effective therapeutic targets influencing the mitochondria and ER within the context of cancer therapy. The present review focused on elucidating the related pathways of mitochondrial autophagy and ER stress and their practical application in ovarian cancer, aiming to identify commonalities existing between MAMs and these pathways, thereby extending to related applications of MAMs in ovarian cancer treatment. This endeavor aimed at exploring new potential for MAMs in clinically managing ovarian cancer.

The endoplasmic reticulum (ER) is an intracellular organelle that contributes to the folding of proteins and calcium homeostasis. Numerous elements can disrupt its function, leading to the accumulation of proteins that are unfolded or misfolded in the lumen of the ER, a condition that is known as ER stress. This phenomenon can trigger cell death through the activation of apoptosis and inflammation. Glucoraphanin (GRA) is the predominant glucosinolate found in cruciferous vegetables. Various mechanical and biochemical processes activate the enzyme myrosinase, leading to the hydrolysis of glucoraphanin into the bioactive compound sulforaphane. Sulforaphane is an organosulfur compound that belongs to the isothiocyanate group. It possesses a wide range of activities and has shown remarkable potential as an anti-inflammatory, antioxidant, antitumor, and anti-angiogenic substance. Additionally, sulforaphane is resistant to oxidation, has been demonstrated to have low toxicity, and is considered well-tolerable in individuals. These properties make it a valuable natural dietary supplement for research purposes. Sulforaphane has been demonstrated as a potential candidate drug molecule for managing a range of diseases, primarily because of its potent antioxidant, anti-inflammatory, and anti-apoptotic properties, which can be mediated by modulation of ER stress pathways. This review seeks to cover a wealth of data supporting the broad range of protective functions of sulforaphane, improving various diseases, such as cardiovascular, central nervous system, liver, eye, and reproductive diseases, as well as diabetes, cancer, gastroenteritis, and osteoarthritis, through the amelioration of ER stress in both in vivo and in vitro studies.

Glutathione (GSH)‑degrading enzymes are essential for starting the first stages of GSH degradation. These enzymes include extracellular γ‑glutamyl transpeptidase (GGT) and intracellular GSH‑specific γ‑glutamylcyclotransferase 1 (ChaC1) and 2. These enzymes are essential for cellular activities, such as immune response, differentiation, proliferation, homeostasis regulation and programmed cell death. Tumor tissue frequently exhibits abnormal expression of GSH‑degrading enzymes, which has a key impact on the development and spread of malignancies. The present review summarizes gene and protein structure, catalytic activity and regulation of GSH‑degrading enzymes, their vital roles in tumor development (including regulation of oxidative and endoplasmic reticulum stress, control of programmed cell death, promotion of inflammation and tumorigenesis and modulation of drug resistance in tumor cells) and potential role as diagnostic biomarkers and therapeutic targets.

Endoplasmic reticulum (ER) homeostasis is essential for maintaining human health, and once imbalanced, it will trigger endoplasmic reticulum stress (ERS), which participates in the development of digestive system tumors and other diseases. ERS has dual effect on tumor cells, activating adaptive responses to promote survival or inducing apoptotic pathways to accelerate cell death of the tumor. Recent studies have demonstrated that Chinese botanical drug extracts can affect the tumor process of the digestive system by regulating ERS and exert anticancer effects. This article summarizes the dual effect of ERS in the process of digestive system tumors and the intervention of Chinese botanical drug extracts in recent years, as reference for the combined treatment of digestive system tumors with Chinese and modern medicine.

Chronic pain is a severely debilitating condition with enormous socioeconomic costs. Current treatment regimens with nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, or opioids have been largely unsatisfactory with uncertain benefits or severe long-term side effects. This is mainly because chronic pain has a multifactorial aetiology. Although conventional pain medications can alleviate pain by keeping several dysfunctional pathways under control, they can mask other underlying pathological causes, ultimately worsening nerve pathologies and pain outcome. Recent preclinical studies have shown that endoplasmic reticulum (ER) stress could be a central hub for triggering multiple molecular cascades involved in the development of chronic pain. Several ER stress inhibitors and unfolded protein response modulators, which have been tested in randomised clinical trials or apprpoved by the US Food and Drug Administration for other chronic diseases, significantly alleviated hyperalgesia in multiple preclinical pain models. Although the role of ER stress in neurodegenerative disorders, metabolic disorders, and cancer has been well established, research on ER stress and chronic pain is still in its infancy. Here, we critically analyse preclinical studies and explore how ER stress can mechanistically act as a central node to drive development and progression of chronic pain. We also discuss therapeutic prospects, benefits, and pitfalls of using ER stress inhibitors and unfolded protein response modulators for managing intractable chronic pain. In the future, targeting ER stress to impact multiple molecular networks might be an attractive therapeutic strategy against chronic pain refractory to steroids, NSAIDs, or opioids. This novel therapeutic strategy could provide solutions for the opioid crisis and public health challenge.

The development of central nervous system (CNS) can form perceptual, memory, and cognitive functions, while injuries to CNS often lead to severe neurological dysfunction and even death. As one of the prevalent post-translational modifications (PTMs), O-GlcNAcylation has recently attracted great attentions due to its functions in regulating the activity, subcellular localization, and stability of target proteins. It has been indicated that O-GlcNAcylation could interact with phosphorylation, ubiquitination, and methylation to jointly regulate the function and activity of proteins. Furthermore, a growing number of studies have suggested that O-GlcNAcylation played an important role in the CNS. During development, O-GlcNAcylation participated in the neurogenesis, neuronal development, and neuronal function. In addition, O-GlcNAcylation was involved in the progress of CNS injuries including ischemic stroke, subarachnoid hemorrhage (SAH), and intracerebral hemorrhage (ICH) and played a crucial role in the improvement of brain damage such as attenuating cognitive impairment, inhibiting neuroinflammation, suppressing endoplasmic reticulum (ER) stress, and maintaining blood-brain barrier (BBB) integrity. Therefore, O-GlcNAcylation showed great promise as a potential target in CNS development and injuries. In this article, we presented a review highlighting the role of O-GlcNAcylation in CNS development and injuries. Hence, on the basis of these properties and effects, intervention with O-GlcNAcylation may be developed as therapeutic agents for CNS diseases.

UNASSIGNED: Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver condition with significant clinical implications. Emerging research indicates endoplasmic reticulum (ER) stress as a critical pathogenic factor governing inflammatory responses, lipid metabolism and insulin signal transduction in patients with NAFLD. ER stress-associated activation of multiple signal transduction pathways, including the unfolded protein response, disrupts lipid homeostasis and substantially contributes to NAFLD development and progression. Targeting ER stress for liver function enhancement presents an innovative therapeutic strategy. Notably, the natural bioactive compounds of plant extracts have shown potential for treating NAFLD by reducing the level of ER stress marker proteins and mitigating inflammation, stress responses, and de novo lipogenesis. However, owing to limited comprehensive reviews, the effectiveness and pharmacology of these bioactive compounds remain uncertain.
UNASSIGNED: To address the abovementioned challenges, the current review categorizes the bioactive compounds of plant extracts by chemical structures and properties into flavonoids, phenols, terpenoids, glycosides, lipids and quinones and examines their ameliorative potential for NAFLD under ER stress.
UNASSIGNED: This review systematically analyses the literature on the interactions of bioactive compounds from plant extracts with molecular targets under ER stress, providing a holistic view of NAFLD therapy.
UNASSIGNED: Bioactive compounds from plant extracts may improve NAFLD by alleviating ER stress; reducing lipid synthesis, inflammation, oxidative stress and apoptosis and enhancing fatty acid metabolism. This provides a multifaceted approach for treating NAFLD.
UNASSIGNED: This review underscores the role of ER stress in NAFLD and the potential of plant bioactive compounds in treating this condition. The molecular mechanisms by which plant bioactive compounds interact with their ER stress targets provide a basis for further exploration in NAFLD management.

Cadmium (Cd) is an important environmental pollutant that poses a threat to human health and represents a critical component of air pollutants, food sources, and cigarette smoke. Cd is a known carcinogen and has toxic effects on the environment and various organs in humans. Heavy metals within an organism are difficult to biodegrade, and those that enter the respiratory tract are difficult to remove. Autophagy is a key mechanism for counteracting extracellular (microorganisms and foreign bodies) or intracellular (damaged organelles and proteins that cannot be degraded by the proteasome) stress and represents a self-protective mechanism for eukaryotes against heavy metal toxicity. Autophagy maintains cellular homeostasis by isolating and gathering information about foreign chemicals associated with other molecular events. However, autophagy may trigger cell death under certain pathological conditions, including cancer. Autophagy dysfunction is one of the main mechanisms underlying Cd-induced cytotoxicity. In this review, the toxic effects of Cd-induced autophagy on different human organ systems were evaluated, with a focus on hepatotoxicity, nephrotoxicity, respiratory toxicity, and neurotoxicity. This review also highlighted the classical molecular pathways of Cd-induced autophagy, including the ROS-dependent signaling pathways, endoplasmic reticulum (ER) stress pathway, Mammalian target of rapamycin (mTOR) pathway, Beclin-1 and Bcl-2 family, and recently identified molecules associated with Cd. Moreover, research directions for Cd toxicity regarding autophagic function were proposed. This review presents the latest theories to comprehensively reveal autophagy behavior in response to Cd toxicity and proposes novel potential autophagy-targeted prevention and treatment strategies for Cd toxicity and Cd-associated diseases in humans.

Silicosis is a chronic lung inflammatory disease induced by long-term inhalation of high concentrations of silicon dioxide (SiO2), characterized by pulmonary fibrosis. Inhalation of silica invades alveolar macrophages (AMs) and changes the micro-environment of the cell, resulting in abnormal morphology and dysfunction of the endoplasmic reticulum (ER). Once beyond the range of cell regulation, the endoplasmic reticulum stress (ERS) will occur, which will lead to cell damage, necrosis, and apoptosis, eventually causing silicosis fibrosis through various mechanisms. This is a complex and delicate process accompanied by various macrophage-derived cytokines. Unfortunately, the details have not been systematically summarized yet. In this review, we systematically introduce the basic two processes: the process of inducing ERS by inhaling SiO2 and the process of inducing pulmonary fibrosis by ERS. Moreover, the underlying mechanism of the above two sequential events is also be discussed. We conclude that the ERS of alveolar macrophages caused by silica dust are involved deeply in the pathogenesis of silicosis. Therefore, changing the states of SiO2-induced ERS of macrophage may be an attractive therapeutic target for silicosis fibrosis.