ER is an important site for secretory protein folding and various post-translational modifications such as glycosylation and disulfide bond formation. The homeostasis regulation of ER ensures that correctly folded proteins proceed to the next step of modification, while slowly folded or unfolded proteins are retained in the ER for proteasome degradation through ER related protein degradation, which is the unfolded protein response (UPR).

Under physiological conditions, three independent branches regulate the UPR, mediated by ER stress receptor proteins, PERK (RNA-dependent protein kinase (PKR)-like ER kinase), ATF6 (activating transcription factor 6), and IRE1α (Inositol-requiring enzyme-1α). These three individual proteins respectively bind to ER chaperone GRP78 (glucose-regulated protein 78) and remain inactive and serve as sensors and effectors for enhanced ER stress (Oakes and Papa, 2015; Kopp et al., 2019). When the nucleotide-binding domain of GRP78 coordinates with luminal domains of IRE1α and PERK, GRP78 is converted from a molecular chaperone to an ER stress sensor, accelerating further UPR activation (Kopp et al., 2019). These mechanisms can monitor the deviant conditions on the ER lumen, deliver signals to the cytosol, then transfer them the nucleus and activate corresponding downstream responses (Figure 1) (Schwarz and Blower, 2016).

PERK, a crucial ER stress sensor of the UPR, is particularly enriched at the MAMs (mitochondria-associated ER membranes), and capable of preventing mRNA translation under ER stress, thus inhibiting protein synthesis, and folding (Verfaillie et al., 2012). ATF4 (activating transcription factor 4) is a stress-induced transcription factor which is at always upregulated in cells, controls the expression of several adaptive genes that protect cells from stress, such as hypoxia or amino acid limitation. But under sustained stress conditions, ATF4 can initiate the transcription of CHOP (C/EBP homologous protein) to induce cell apoptosis (Wortel et al., 2017). PERK phosphorylates eIF2α (eukaryotic initiation factor 2) to decrease the GTP-bound (guanosine triphosphate, GTP) form and allow translation of ATF4 (Han et al., 2013; Luhr et al., 2019; Vanhoutte et al., 2021). Meanwhile, CHOP can bind to BOK (B-cell lymphoma 2 varian killer) and Caspase to act as an antiapoptotic agent (Carpio et al., 2015).

ATF6 is a type II transmembrane protein that induces ER stress response. As an up-regulating chaperone, it is an important element of the ERAD (endoplasmic reticulum—associated degradation) pathway (Jin et al., 2017). The unfolded proteins in the ER lumen separate ATF6 from GRP78, then ATF6 is transferred from the ER membrane to the Golgi apparatus as vesicles; the lumen domain of ATF6 is cleaved by S1P (serine protease site-1), the n-terminal is cleaved by metalloproteinase S2P (site-2 protease), forming the ATF6f with n-terminal cytoplasmic domain. As a result, several ER stress response element genes such as GRP78, GRP94, CHOP can be activated, and promote the ER associated protein degradation gene XBP1 (X-box binding protein 1) transcription. The ATF6f can bind XBP1 and control the expression of some specific genes (Zhang et al., 2019b; Pachikov et al., 2021).

IRE1α is a transmembrane protein, which is composed of n-terminal ER lumen sensor domain, a single transmembrane domain, and c-terminal cytoplasmic protein kinase effector, responsible for protein kinase and endonuclease activity. When ER stress happens, IRE1α cavity structure domain is dissociative with GRP78, causing cavity structure domain two polymerization to further activate the activity of enzymes, catalyze the transcription of XBP1 to upregulate multiple folding enzymes, including glycosylation, redox enzymes degradation to rectify ER homeostasis. IRE1α also degrades specific mRNA in a tissue-specific manner through RIDD (regulated IRE1-dependent mRNA decay) and activates related kinases through binding of adaptor proteins including JNK (C-Jun amino-terminal kinase) and ASK1 (apoptotic signal-regulated kinase 1) pathways (Lerner et al., 2012; Hwang and Qi, 2018; Huang et al., 2019).

Adaptive UPR is the initial defense against ER stress to keep the balance of ER homeostasis. However, persistent UPR activation can transform into maladaptive UPR, leading to drastic cell injuries even cell death. Incorrectly or terminally misfolded proteins are retained and degraded within the ER. As ER stress cells evolve further with the integrated stress response, cells actively mobilize stress response proteins to resist the deleterious effects caused by stress triggers. Meanwhile, cells adjust ER function to adapt to new internal environmental change requirements. On the other hand, some stress protein regulatory genes that may cause cell death, such as CHOP, will decide according to the situation to finally clear those ER stress cells that are simply unable to return to a normal functional state (Shirakawa et al., 2013; Hotamisligil and Davis, 2016; Urra et al., 2016; Hetz and Papa, 2018). In ER stress response, the activation of IRE-1, PERK, and ATF6 induces CHOP, promotes the activation of CHOP, and significantly increases its expression, leading to apoptosis. IRE-1-mediated splicing of XBP1 induced UPR can promote cell survival, but its overexpression can also promote cell apoptosis. Activated IRE-1 can combine with TRAF2 (TNF-receptor-associated factor 2) and ASK1 (apoptotic signal-regulated kinase 1) to form into the IRE-1-TRAF2-ASK1 complex on ER outer membrane, which activates JNK and P38 MAP (mitogen-activated protein kinase) (Matsuzawa et al., 2002). CHOP expression is induced by phosphorylation of ser78/81 in the transcriptional activation domain of P38 MAP kinase. After ER stress induced GRP78 dissociation from ATF6, the cytoplasmic ATF6 n-terminal domain also dissociated from ER membrane and formed a 50 ku active fragment. It was found that the activated ATF6 entered the nucleus and bound to the NF-Y (nuclear transcription factor-Y) and bound to the promoter ER stress element with homologous or heterologous dimer structure. The complex then induces the transcriptional expression of ER stress genes including CHOP (Feng et al., 2019). PERK is also a transmembrane protein. After dissociation from GRP78, PERK is activated by self-dimerization and phosphorylation of the intracellular domain. Activated PERK phosphorylates serine of the eukaryotic translation initiation factor eIF2α. Phosphorylated eIF2α cannot accept the exchange of GTP-GDP by eIFβ, thus slowing or suspending protein synthesis, thereby promoting the activation of CHOP, and thus inducing cell metabolism and apoptosis (Pillai, 2005; Kopp et al., 2019).

ROS can directly attack the free thionyl group, necessary to maintain the protein foldase activity, leading to oxidative modification of proteins in the ER lumen, and then induce abnormal function of ER molecular chaperones, resulting in the accumulation of unfold proteins and retention in the ER lumen, ultimately triggering ER stress. At the same time, the expression of the chaperone protein GRP78 significantly increased and dissociated from the three transmembrane proteins to bind unfolded proteins to enhance ER protein folding ability and reduce protein accumulation in ER. After dissociation of GRP78, ER stress receptor proteins are activated to trigger UPR generation, reduce the load of ER by limiting the synthesis of unfold proteins, and trigger their respective induced pro-survival response. The PERK-activated-pro-survival pathway inhibits protein translation and synthesis by limiting the entry of abnormally folded proteins into ER and reducing ER’s pressure for new protein folding (Borges and Lake, 2014; Hetz et al., 2015; Khanna et al., 2021). PDI (phosphorylation of protein disulfide isomerases), fundamental enzymes involved in ER protein folding, allows these proteins to combine with luminal IRE1α, then moderating excessive IRE1α activity to protect against cell injuries induced by maladaptive UPR (Zhang et al., 2019a). PDI is a kind of oxidoreductase which can catalyze disulfide bonds and it is the correct sequence of cysteine residue pairs with different redox potentials and substrate specificity (Ellgaard and Ruddock, 2005). Cysteine residues within the active site of PDI provide two electrons to assist disulfide bond formation, which results in reduction of the active site of PDI and oxidation of the substrate (Fu et al., 2020). The formation of disulfide bond in the ER is catalyzed by ERO1 (endoplasmic reticulum oxidoreductin 1) family of sulfhydryl oxidases. ERO1 oxidizes PDI and introduces disulfides into ER client proteins. ERO1 can couple disulfide transfer to PDI with reduction of molecular oxygen, forming hydrogen peroxide. Hence, ERO1 activity is a underlying source of ER-derived oxidative stress (Tavender and Bulleid, 2010). Research has found that ROS inhibitor MnTMPyP can inhibit the increase of ROS in ER stress and delay the activation of UPR, suggesting that ROS is the upstream signal molecule that triggers ERS-mediated apoptosis pathway and initiates ER stress-mediated apoptosis (Xu et al., 2018).

UPR as a protective means at the cellular level reduces the accumulation of unfolded or misfolded proteins on the ER. In the early stage of ER stress, ER mainly restore the normal function of ER for survival through activation of UPR to protect cellular damage caused by ER stress, which is a pro-survival response (Senft and Ronai, 2015; Frakes and Dillin, 2017).

The endoplasmic reticulum is an important calcium reservoir, which regulates ER function, membrane transport and internal homeostasis through maintaining the balance of Ca²⁺ concentration inside and outside the cell. As a messenger molecule, Ca²⁺ participates in cell proliferation, differentiation, movement, muscle contraction, hormone secretion, glycogen metabolism, neuronal excitability, and other physiological activities, and then regulates gene and protein expression, secretion, metabolism, and apoptosis (Frakes and Dillin, 2017). Current studies have shown that disruption of calcium homeostasis in the ER can initiate early apoptosis signals (Rizzuto et al., 2012; Orrenius et al., 2015; Marchi et al., 2018). A study revealed that sodium nitrite (anti-tumor drug) can induce ER stress-mediated apoptosis in human NB4 cells in acute leukemia, certified selenite-induced production of ROS is the upstream of the JNK/ATF2 axis, application of ROS inhibitors partially inhibited the intracellular Ca²⁺ increase caused by sodium nitrite, suggesting that ROS is involved in the sodium nitrite-induced ERS-mediated apoptosis (An et al., 2013). Aoyama elucidated that rotenone, a mitochondrial complex I inhibitor, can cause ER hyperplasia, ER membrane lipid oxidative damage, increase the permeability of ER, cause the increase of cytosol-free Ca²⁺ and then induce ER stress and apoptosis. After using the ER stress inhibitor SUN N8075, mitochondrial ROS production obviously reduced and Ca²⁺ elevation induced by rotenone was significantly weakened, indicating the increase of intracellular free Ca²⁺ induced by rotenone is stimulated by ROS (Aoyama et al., 2021). Although some specific mechanisms are still being studied, ROS production and the increase of ER Ca²⁺ level are both crucial events in ER stress-mediated apoptosis.

At resting state, the concentration of Ca²⁺ in the ER is higher than that in the cytoplasm. There are three channels related with Ca²⁺ uptake and release for maintaining Ca²⁺ homeostasis on the ER: 1. Ca²⁺-release channels: RyRs (ryanodine receptors) and IP3Rs; 2. Ca²⁺ -ATPase or SERCA (sarcoplasmic-endoplasmic-reticulum Ca²⁺-ATPase) in transporting Ca²⁺ from cytoplasm to ER; 3. Ca²⁺-binding protein in ER cavity (such as calnexin and calreticulin) (Ong and Ambudkar, 2020). Studies have confirmed that the IP3R and RyR distributed on the sarcoplasmic reticulum can be regulated by the redox response (Ong and Ambudkar, 2020). ER includes the NOX subtypes of NADPH oxidase and co-exists with calnexin and calreticulin. The NOX subtype contains the main catalytic subunit GP91Phox (NOX2), which produces ROS mainly involved in cell signaling transduction. Recent studies suggest that NOX1 and NOX4 (NADPH Oxidase 4) can act on PDI, that is, ROS outside the mitochondria may also regulate ER function. Moreover, research has demonstrated NOX4 can act as a proximal signaling intermediate to transduce ER stress-related conditions to the UPR, and sulfonate and modify it through interaction with IRE1 to cause ER stress even cell injuries (Kim et al., 2016; Ochoa et al., 2018; Lee et al., 2020).

In resting conditions, Ca²⁺ is absorbed by the cytoplasm into the ER cavity through SERCA pump and released into the cytoplasm by RyR and IP3R channels. Most of the Ca²⁺ released into the cytoplasm will be recaptured by the Ca²⁺ pump to maintain the Ca²⁺ concentration in the ER. Therefore, Ca²⁺ accumulation in ER is mainly accomplished through the activity of SERCA pump (Ivanova et al., 2020). Ca²⁺-ATPase, as a known promoter of ER stress, since oxidative damage suppresses Ca²⁺-ATPase activity, ROS can affect Ca²⁺ storage within ER by inhibiting Ca²⁺-ATPase, and hence affecting intracellular Ca²⁺ homeostasis and causing ER stress (Krylatov et al., 2018). Studies have revealed ROS production and ER Ca²⁺ pump were sensitive to oxidative damage in ischemia and hypoxia cell models. ROS can make proteins in ER cavity be oxidized and retained, thus inhibiting protein synthesis, and leading to cell apoptosis. Puteney et al. found that Ca²⁺ releasing from the ER via IP3R causes decreased ER calcium reserves, Ca²⁺ can enter the cell from the extracellular, a process known as SOCE (store-operated Ca²⁺ entry) (Putney, 1986) Ivan demonstrated that exposure to environmental or cell-intrinsic ROS can affect Ca²⁺ homeostasis, modify multiple pathways and cause cell injuries (Bogeski et al., 2012). ROS production can induce Ca²⁺ release within the ER to cause ER stress, whereas Ca²⁺ release within the ER further stimulates Ca²⁺ aggregation on the mitochondria, causing mitochondrial damage and subsequently inducing apoptosis. As illustrated above, calreticulin is the main Ca²⁺ binding chaperone in the ER lumen, which binds to Ca²⁺ through the C-domain in a high capacity and increases the Ca²⁺ storage capacity of the ER lumen (Venkatesan et al., 2021). Leta found that calreticulin acts directly with SERCA2b glycosylated C-terminal tails to regulate Ca²⁺ storage in ER. When ER Ca²⁺ is sufficient, the activity of ATP-ase can be inhibited and intracellular Ca²⁺ transport to ER stops (Johnson et al., 2014).

Elevated ROS levels send feedback signals that stimulate ER stress. ER stress promotes the correct folding of the wrong proteins and degrades the proteins that cannot be folded. Transient ER stress helps to restore cell homeostasis, but long-term and high-intensity ERS can lead to multiple pulmonary diseases.

IPF (idiopathic fibrosis of the lung) is a serious interstitial lung disease that can cause progressive loss of lung function, and its pathological mechanism is constantly being updated. Many cells in the lung parenchyma, including alveolar epithelial cells, macrophages, and fibroblasts, are affected by UPR during the pathological process of IPF. CE (Alveolar epithelial cells) are mainly divided into AEC I (alveolar epithelial cells I), and AEC II (alveolar epithelial cells II). AEC II cells are the progenitor cells required to maintain alveolar integrity. Loss of AEC II function and apoptosis are considered as important processes in the initial stage and development of IPF (Hetz et al., 2020). Researchers took samples of peripheral transplanted lung tissues, analyzed through protein detection, and found that AEC II in IPF can produce much UPR related proteins such as ATF6, ATF4 and CHOP. On the contrary, it does not exist in COPD and normal organ donors, indicating that in IPF patients, UPR activation can lead to the apoptosis of AEC II cells in the inner surface of the fibrotic site and be replaced by fibrous tissue (Korfei et al., 2008; Lawson et al., 2011). Timothy and his colleagues used tunicamycin to induce UPR activation, which enhanced AEC death and pulmonary fibrosis in IPF mice models, demonstrating UPR activation may increase AEC vulnerability, lead to enhanced lung injuries and IPF occurrence. Although UPR cannot directly aggravate the occurrence of IPF, it can improve the incidence probability of IPF in patients (Kropski et al., 2012). In many IPF patients, herpesviruses have been found to be closely associated with the occurrence of IPF. Herpesviruses are frequently found in the IPF lungs and can induce the UPR. Modification and maturation of viral glycosylated envelope proteins during virus replication may induce ER stress, while ER stress play double-acting roles in virus infection. Herpesvirus infection can directly promote UPR activation, causing decreased immune function induced malignant pulmonary fibrosis and IPF (Lee et al., 2009; Tanjore et al., 2012; Liu et al., 2021).

Pulmonary cystic fibrosis (CPF or CF) is a congenital disease with familial autosomal recessive inheritance. It is most common among white North Americans and rarely seen in other races. As an exocrine gland lesion, the gastrointestinal tract and respiratory tract are often affected (Elborn, 2016). The airway of patients with CF presents a persistent and intense inflammatory response, and AMs (alveolar macrophage) play key roles in the pathogenesis of CF (Hey et al., 2021). Some AMs can secrete many inflammatory mediators such as TNF-α and IL-6 induction (Lambertsen et al., 2012). XBP1 cut by IRE1 pathway mRNA in UPR affects peripheral macrophages and produces inflammatory effects (Lubamba et al., 2015). It was found that the UPR activated the expression of XBP1 in AMs in CF patients, and lipopolysaccharide was associated with the increased level of transcription factor XBP-1 in the UPR. Knockdown of XBP-1 in cultured dTHP-1 (differentiated human acute monocytic leukemia-1) cells reduced the inflammatory response of CF patients. Inflammatory factors in CF patients can be regulated by the expression of XBP-1 in UPR, and AMs in CF patients can promote the occurrence of airway inflammation in CF patients by upregulating xBP-1-mediated cytokines (Zhu et al., 2012; Lubamba et al., 2015). CFTR (cystic fibrosis transmembrane conductance regulator) is a central regulator of chlorine channel and epithelial function. Loss of CFTR function in airway can lead to mucus thickening, reduced mucosal ciliary clearance, chronic infection, and respiratory failure. UPR can induce the binding of ATF6 to the minimum promoter of CFTR, leading to the inhibition of CFTR transcription and reduce expression of CFTR (Trouvé et al., 2021).

There are many causes of the acute pneumonia response, where acute lung injury is the most important cause. In acute pneumonia caused by acute lung injury, the UPR activation plays an important role in cellular autophagy, as well as in apoptosis (Bettigole and Glimcher, 2015). In lipopolysaccharide-induced acute lung injury mice model and human alveolar epithelial cell model, the UPR inhibitor 4-PBA (4-phenylbutyric acid) blocks the activation of NF-κB pathway and reduces the release of pro-inflammatory mediators including TNF-α, IL-1β and IL-6. 4-PBA reduces the activation of inflammation by inhibiting UPR pathway and the mechanism is likely to be related to PERK-eIF2α-mediated translation reduction promoting NF-κB activation, suggesting that UPR is a crucial promoter of lipopolysaccharide-induced inflammation. 4-PBA leads to decreased autophagy, which plays a protective role in acute pneumonia through the classical AKT/mTOR signaling pathway and exacerbates lipopolysaccharide-induced A549 cytotoxicity through the 3-MA (autophagy inhibitor 3-methyladenine). 4-PBA inhibits UPR activation and has protective effects on autophagy in acute pneumonia models. UPR can stimulate the activation of NF-κB pathway, leading to the translocation of free NF-κB into the nucleus, possibly through conformational changes in cytoplasmic regions induced by IRE1α autophosphorylation. The IREα -TRAF2 complex binds to the adaptor protein TNF-α receptor-associated factor 2 to recruit IκB kinase and phosphorylates IκB, resulting in degradation of IκB and nuclear NF-κB translocation (Urano et al., 2000). Jiang et al. investigated whether ER stress during simulated microgravity induced endothelial inflammation and apoptosis in HUVECs (human umbilical vein endothelial cells), and they found that the increase of apoptosis in HUVECs during clinorotation was significantly suppressed by inhibiting ER stress, iNOS activity, NF-κB/IκB, and the NLRP3 inflammasome signaling pathway, indicating ER stress-dependent activation of iNOS/NO-NF-κB signaling and NLRP3 inflammasome contributes to chronic injury endothelial inflammation and apoptosis associated with microgravity (Jiang et al., 2020).

Aspergillus fumigatus is an opportunistic pathogen that is responsible for a life-threatening fungal infection called as invasive aspergillosis. The sensitization of AF (aspergillus fumigatus) was associated with severe allergic pulmonary inflammation, and allergic bronchopulmonary aspergillosis (ABPA) was the most common disease in allergic mycosis (Krishnan and Askew, 2014). Studies found that in clinical studies, glucoregulatory protein GRP78 was increased in lung tissues of patients with allergic bronchopulmonary aspergillus. Lee found that utilizing of the ER stress inhibitor or a ROS scavenger improved AF-induced allergic inflammation. The PI3K-δ inhibitor reduced AF-induced mitochondrial ROS generation and ER stress accordingly ameliorated. They revealed that PI3K-δ regulates AF-induced steroid-resistant eosinophilic allergic lung inflammation through ER stress (Lee et al., 2016). Wang revealed the effects and mechanisms of resveratrol on fungus-induced allergic airway inflammation, and they demonstrated resveratrol alleviated the AF-exposed allergic inflammation and apoptosis through inhibiting ER stress via Akt/mTOR pathway, exerting therapeutic effects on the fungus-induced allergic lung disorder (Wang et al., 2022). These studies revealed the UPR is a critical step in ABPA production.

The most common type of lung cancer is adenocarcinoma, comprising around 40% of all lung cancer cases, and lung adenocarcinoma is still one of the most aggressive and rapidly fatal tumor types with overall survival less than 5 years (Denisenko et al., 2018). Many studies have shown that adenocarcinoma is often accompanied by activation of the UPR pathway. Lu found that ER stress can induce the high expression of the transcription factor XBP1 in 2D and 3D culture lung adenocarcinoma cells and promote the proliferation of lung adenocarcinoma in 3D culture in vitro. Knockdown the expression of XBP1 can block cell growth induced by Tm/Tg treatment. Meanwhile, LOX gene, as a key downstream sensor of XBP1, can block XBP1-induced cell proliferation by knocking down the expression of LOX, suggesting that XBP1 can regulate the proliferation of lung adenocarcinoma cells through LOX (Yang et al., 2017). It was found that asterosaponin 1 increased ER dilation and cytosolic Ca²⁺ concentration, enhanced the expression of GRP78 and GRP94 in a dose-and-time-dependent manner and increased the expression of CHOP, Caspase-4 and JNK, the three UPR related apoptotic molecules. Finally, the proliferation of A549 cells was inhibited and apoptosis was promoted (Zhao et al., 2011).

Large cell carcinoma is a barely descriptive term indicating a subtype of lung cancer with no specific features of small-cell lung cancer, adenocarcinoma or squamous cell carcinoma (Weissferdt, 2014). Azam et al. have found that GRP78 is closely related to the regulation of large cell carcinoma. The expression of GRP78 in tumor of patients with large cell carcinoma is more than three times that of the negative control. Both miR-495 and miR-199a-5p can promote the malignant transformation of tumor cells. Increased GRP78 in cells can downregulate Mir-495 and Mir-199a-5p in NSCLC, and overexpression or inhibition of miR-495 and miR-199a-5p can also significantly change the expression of GRP78 and XBP1 level. UPR and microRNA interact to promote the occurrence of cancer (Ahmadi et al., 2017). Pau and his colleagues found that the anti-cancer molecule ABTL0812 increases cellular long-chain dihydroceramides by impairing DEGS1 (delta 4-desaturase, sphingolipid 1) activity, which resulted in persistent ER stress and activated UPR via ATF4-DDIT3-TRIB3 that ultimately promotes cytotoxic autophagy in cancer cells (Muñoz-Guardiola et al., 2021). Studies have proved that in large-cell lung carcinoma H460 treated with cisplatin, the cell viability is distinctly reduced after adding ERS inhibitor 4-PBA (4-phenylbutyric acid). Intracellular caspase-3 gene and cytochrome C were significantly upregulated and promoted cell apoptosis, confirming that chemotherapy drugs can activate UPR and enhance drug resistance of tumor cells (Shi et al., 2016). Blocking the adaptive pathway of ER stress or promoting the apoptotic pathway could be a promising anti-cancer strategy.

4-PBA. 4-phenyl butyric acid, a low-molecular-weight aromatic fatty acid, affect the activation of LPS-induced inflammation human alveolar epithelial cell in acute lung injury models. It further prevents the activation of the NF-κB pathway, decreases the release of the inflammatory mediators through regulating ER stress (Zeng et al., 2017).

TUDCA. TUDCA (Tauroursodeoxycholic) is a hydrophilic bile acid with chaperone properties that is produced endogenously in humans at very low levels. Tong found that the TUDCA can moderate pulmonary ER stress and epithelial-mesenchymal transition in bleomycin-induced lung fibrosis (Tong et al., 2021). TUDCA can inhibit CHOP expression and the bleomycin -induced pulmonary fibrosis and inflammation, suggesting TUDCA may be a promising strategy for preventing pulmonary fibrosis (Tanaka et al., 2015).

EIF2A phosphorylation levels are controlled by two phosphatase complexes, hydrophobic the protein Phosphatase 1 (PP1) catalytic subunit complexed with either constitutively expressed PPP1R15B (PP1 regulatory subunit 15B) or the ER Stress-inducible isoform PPP1R15A, which is an ATF4 -- CHOP Target (PP1). Salubrinal is a cell-permeable, small-molecule inhibitor of the PP1 complex (Liu et al., 2014). Wang found that Salubrinal attenuated A549 cells from Paraquat-induced damages through upregulating the PERK-eIF2α signaling (Wang et al., 2018b). Salubrinal may be a promising therapeutic strategy to suppress ER stress in pulmonary dysfunctions.

Metformin is an antidiabetic drug that has been proved to be beneficial to other diseases independent of its glycaemia effects. Francesca found that metformin may ameliorate cigarette smoke-induced pathologies of emphysematous COPD through the AMPK (AMP-activated protein kinase) pathway (Polverino et al., 2021).

Qin demonstrated ER stress-induced cell death was mediated by autophagy which was partly attributed to the inactivation of the mTOR (mammalian target of rapamycin) (Qin et al., 2010). Tian found that ginkgo biloba leaf extract attenuates atherosclerosis in streptozotocin-induced diabetic ApoE^−/− mice by Inhibiting ER stress via restoration of autophagy through the mTOR Signaling Pathway (Tian et al., 2019), which inspired us that the mTOR pathway is expected to become a promising target of ER stress-induced lung diseases.

AβM acid can resolve the inflammatory and UPR in inflammatory diseases (Vander Zanden et al., 2019). Emily proved that AβM acid-based therapy can inhibit the allergen-induced UPR and allergic airway disease in mice via preferential binding of ATF6α, suggesting a novel avenue to treat allergic asthma using AβM (Nakada et al., 2019).

Pharmacologic arm selective UPR signaling pathway activation is emerging as a promising strategy to improve imbalances in ER proteostasis implicated in diverse diseases. The compound 147 was considered to activate ATF6-regulated signaling associated with localized metabolic activation and selective covalent modification of ER stress (Paxman et al., 2018). Therefore, the compound 147 is a promising strategy in preventing ER stress-induced pulmonary disease.

Melatonin is an anti-inflammatory molecule, which has been effective in acute lung injury induced by many conditions (Tordjman et al., 2017). Zhao revealed that melatonin obviously inhibited the activation of NLRP3 inflammation, ER stress and epithelial-mesenchymal transition during bleomycin-mediated pulmonary fibrosis in mice models (Paxman et al., 2018).

Li found that ursolic acid derivative has preventive effects on particulate matter 2.5-induced COPD, causes obvious suppression in PM2.5-induced increase in oxidative stress markers and inflammatory cytokines, suggesting ursolic acid derivative can be a promising therapeutic treatment for PM2.5-induced COPD (Li et al., 2020).

Resveratrol, a natural polyphenol, is beneficial in supporting its numerous biological properties including antioxidant, anti-inflammatory, ant obesity, antidiabetic, and ant-ischemic activities. The compound also has beneficial effects on cognitive function and lung health (Ahmadi et al., 2021). Wang demonstrated that resveratrol attenuates inflammation and apoptosis through alleviating ER stress via Akt/mTOR pathway in fungus-induced allergic airways inflammation, providing therapeutic strategies for fungus-induced allergic lung disease (Wang et al., 2022).