Table 2 Shows various role of GRP78 in various cancer with mechanisms
| Â | Cancer types/diseases | Function of GRP78 | Mechanism of GRP78 involvement | References |
|---|---|---|---|---|
1 | Multiple Myeloma | Involvement in the regulation of ER stress and the UPR | GRP78 is greatly expressed in multiple myeloma. The expression of MALATI results into polyubiquitinated proteins accumulation, which actuate ERS, induce the expression of GRP78, actuate autophagy and triggers cell apoptosis | |
2 | Gastric Cancer | Cell proliferation, inhibition of apoptosis | GRP78 stimulates cell proliferation, inhibits apoptosis, and confers resistance to chemotherapy. it activates pro-survival pathways, such as the PI3K/AKT pathway, to enhance cell survival and inhibit apoptosis in gastric cancer cells. It also modulates drug efflux pumps and anti-apoptotic pathways, leading to chemoresistance | (Chen et al. 2018a, b; Zhang et al. 2022a; Zheng et al. 2017) |
3 | Colorectal Cancer | Unfolded protein response, cell survival | GRP78 helps maintain protein homeostasis by activating the UPR in response to endoplasmic reticulum (ER) stress. The UPR regulates protein folding, degradation, and ER-associated degradation. Overexpression of GRP78 in colorectal cancer cells promotes cell survival by modulating the UPR and inhibiting apoptosis. Additionally, GRP78 has been implicated in promoting colorectal cancer metastasis by regulating the epithelial-mesenchymal transition (EMT) process | (Chern et al. 2019; Huang et al. 2021a, b; Xi et al. 2018; Li et al. 2014) |
4 | Breast Cancer | Cell survival, inhibition of apoptosis | In breast tumor, GRP78 contributes to drug resistance by promoting cancer cells survival. GRP78 activates pro-survival pathways, such as the PI3K/AKT and MAPK/ERK signaling pathways, which promote cell survival and inhibit apoptosis. It also interacts with and stabilizes anti-apoptotic proteins, such as Bcl-2 family members, preventing the activation of apoptotic pathways | (Kuang et al. 2016; Kabakov and Gabai 2021; Dong et al. 2011; Sadeghipour et al. 2023) |
5 | Head and Neck Cancer | Tumor progression, chemoresistance | The progression, survival and chemo-resistance properties of head and neck cancer are attributed to GRP78. GRP78 promotes the survival of head and neck cancer cells by maintaining lysosomal activities through the help of MUL 1, one of E3 ubiquitin-protein ligases (MUL1-GRP78) | |
6 | Prostate Cancer | Androgen receptor signaling, cell survival | GRP78 modulates androgen receptor signaling, promotes cell survival, and contributes to castration resistance in prostate cancer. GRP78 interacts with and stabilizes the androgen receptor, which is crucial for prostate cancer growth and progression. It enhances androgen receptor signaling, leading to increased cell survival and proliferation. Moreover, GRP78 has been implicated in castration-resistant prostate cancer, where it sustains androgen receptor activity even in the absence of androgens, allowing cancer cells to bypass hormone deprivation therapy | (Misra et al. 2004, 2005; Kelber et al. 2009; Luo and Lee 2013) |
7 | Alzheimer’s Diseases | Protein folding | Alzheimer's disease (AD), a neurodegenerative condition marked by cognitive changes, and memory loss has been linked to GRP78. The hippocampus and temporal cortex of AD patients have twice the amounts of GRP78 compared to normal individual. Evidently, Tau hyperphosphorylation is a clear sign of the tauopathies and Liu shows that overexpression of GRP78 strengthened the interaction between tau and GSK-3 and caused tau hyperphosphorylation via activating glycogen synthase kinase-3 (GSK-3), a key tau kinase in AD brain | |
8 | Parkinson’s Diseases | Proteostasis, neuroprotection | Lewy bodies and dopaminergic neurons deficiency in the substantia nigra pars compacta (SNc) are two features of Parkinson's disease, an idiopathic movement illness. It has been observed that MPP + treatment induces the translocation of GRP78 from the endoplasmic reticulum (ER) to the nucleus and cytoplasm. This translocation is found to be associated with a significant reduction in the number of cells positive for tyrosine hydroxylase in the SNc | |
9 | Aging | Proteostasis, cellular aging | ER chaperones are less responsive to ER stress in old tissues and this is proven by decreased levels and activity of ER chaperones in aging cells; hence, aging renders the quality control mechanism of proteins ineffective. Increased oxidation of numerous important ER chaperones has been linked to this condition, and this is consistent with the mitochondrial free radical theory of aging. In particular, a decline in GRP78 levels has been seen in aging and degenerative disorders | (Nuss et al. 2008; Rabek et al. 2003; Paz Gavilán et al. 2006) |
10 | Amyotrophic Lateral Sclerosis (ALS) | Proteostasis, ER stress | A progressive neurodegenerative condition called ALS causes the motoneurons in the cerebral cortex, the majority of the brainstem, and the spinal cord to selectively degenerate. Familial ALS is characterized by a variety of mutations, all of which cause protein misfolding and aggregation. Superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43-KDa, FUS, and other genes are affected by these mutations. SOD1 aggregates have been seen in sporadic ALS cases. In microsomal fractions of spinal cords made from mice models of ALS, mutant SOD1 aggregates, produces high molecular weight species, that interacts with GRP78. In addition, SIL1 and Sig1R are a few of GRP78 co-chaperones that are significant in ALS. The fact that SIL1 is mostly expressed in tough motoneurons suggests that it has a role in neuroprotection. Due to better endoplasmic reticulum proteost axis and decreased SOD1 aggregation, SIL1 overexpression provides considerable neuroprotection, whereas SIL1 deficiency worsens ALS pathogenesis | |
11 | Renal Cancer Carcinoma | Cell survival, drug resistance | It has been scientifically proven that GRP78 is significantly upregulated in Renal Cancer Carcinoma (RCC), promoting cell survival and inhibiting apoptosis. GRP78 overexpression induced sunitinib resistance of RCC cells by triggering the unfolded protein response | |
12 | Primary Sjögren's syndrome (pSS) | Autoimmunity, Inflammatory | Elevated activation of both β-arrestin2 and the GRP78-ATF6-CHOP apoptotic signaling pathway has been observed in patients with primary Sjögren's syndrome (pSS). This suggests that an hyperactivation of the GRP78-ATF6-CHOP pathway plays a role in the development of pSS, and β-arrestin2 promotes apoptosis in epithelial cells triggered by inflammation by acting through the GRP78-ATF6-CHOP pathway | |
13 | Renal tubulointerstitial fibrosis | Promotes fibrosis and inflammation | Jin reported that S100A16 expression is significantly increased in the cytoplasm during renal injury, making path for GRP78 entrance into the cytoplasm. The co-interaction of S100A16 with GRP78 promote the release of IRE1 in the cytoplasm | (Jin et al. 2021) |
14 | Retina degradation | Involved in the degradation of retinal cells | Studies have implicated GRP78 in the deterioration of the retina. Elevated levels of GRP78 is associated with the activation of glial cells and their neuroprotective function through the modulation of the unfolded protein response (UPR) during stressful conditions | (Park et al. 2021) |
15 | Pathogenesis of osteoarthritis (OA) | Contributes to the development and progression of OA | It has been suggested that GRP78 plays a role in the excessive growth of synovial cells in osteoarthritis (OA). Studies show that the presence of IL-1β, a pro-inflammatory cytokine, leads to an upregulation of GRP78, NF-κB (phosphorylation of the p65 subunit), IL-6, and PGE2 in primary synoviocytes. This increase in GRP78 expression is accompanied by enhanced polarization of macrophages towards the M1 phenotype. Moreover, when GRP78 is specifically knocked down, there is a significant reversal in the expression of downstream molecules associated with GRP78 and macrophage polarization induced by IL-1β | (Lee et al. 2021) |
16 | COVID-19 patients | Plays a role in the pathogenesis and severity of COVID-19 | GRP78 is a crucial chaperone within the endoplasmic reticulum (ER) and its regulation is influenced by ATF4, either through direct or indirect mechanisms. In times of cellular stress, GRP78 becomes overexpressed and can be found on the surface of nearly all cells, where it serves as a receptor for the SARS-CoV-2 virus. A different clinical study, involving a significant number of participants, demonstrated that COVID-19 patients exhibited GRP78 levels approximately five times greater than those observed in the healthy control group Recent research has demonstrated that in addition to the receptor ACE2, csGRP78 can function as a co-receptor for the SARS-CoV-2 spike protein. In order to enter target cells more easily, csGRP78 forms a protein complex on the cell surface with the host cell receptor ACE2 and directly interacts with the SARSCoV-2 spike protein | (Shahriari-Felordi et al. 2022; Sabirli et al. 2021; Shin et al. 2021, 2022a; Carlos et al. 2021; Shin et al. 2022a, b) |
17 | Ovarian Cancer | Cell survival, angiogenesis, chemoresistance | GRP78 enhances cell survival, promotes angiogenesis, and contributes to resistance to chemotherapy in ovarian cancer. GRP78 enhances cell survival by activating pro-survival signaling pathways, such as the PI3K/AKT pathway. It also interacts with pro-apoptotic proteins to inhibit death | |
18 | Myeloid leukemia (AML) | Implicated in the pathogenesis and progression of AML | In a recent study, a T cell that produces a chimeric antigen receptor (CAR) targeting GRP78, was developed. This approach demonstrated several advantages, including minimal T cell self-destruction after activation and genetic modification, as well as T cell differentiation dependent on the presence of the target antigen. The GRP78-CAR T cells effectively identified and eliminated AML (acute myeloid leukemia) cells that expressed GRP78, without harming healthy hematopoietic progenitor cells (HPCs). In vivo experiments also revealed significant effectiveness of GRP78-CAR T cells in combating AML. Furthermore, the study revealed high levels of GRP78 expression on the cell surface of AML patients' peripheral blood cells, and its overexpression in chronic lymphocytic leukemia patients' cells compared to normal B cells. Surface-expressed GRP78 was discovered to boost the generation of diverse cytokines with anti-tumor properties, including interferon (IFN)-γ, interleukin (IL)-2, tumor necrosis factor α (TNFα), and granulocyte–macrophage colony-stimulating factor (GM-CSF). Moreover, it exhibited a moderate elevation in the levels of interleukins -4, -5, -6, -10, and -13 | (Hebbar et al. 2022) |
19 | Astrocytoma and Glioblastomas | Involved in tumor growth and progression | In astrocytoma’s and glioblastomas, the protein that is activated by GRP78 is called Akt (also known as protein kinase B). Akt is a key player in cell survival and growth pathways. The mechanism by which GRP78 activates Akt involves a process called phosphorylation. When GRP78 is overexpressed in cancer cells, it can bind to and activate a protein called PI3K (phosphoinositide 3-kinase). Activated PI3K then phosphorylates Akt, leading to its activation. The activation of Akt through GRP78 leads to an increase in the phosphorylation of procaspase-9. This phosphorylation event subsequently leads to a decrease in the levels of cleaved caspase 7, a protein involved in apoptosis. On the other hand, GRP78 can also interact with the proapoptotic protein BIK, as well as caspases 7 and 12, forming a complex. This complex formation serves to inhibit the release of cytochrome c from mitochondria and effectively limits the process of apoptosis | (Zhang et al. 2011) |
20 | ZIKV virus | Impacts ZIKV virus replication and pathogenesis | ZIKV viral domain III, which is involved in receptor binding, is capable of interacting with GRP78. Therefore, ZIKV binding, internalization, and replication in cells can be mediated by GRP78 to fulfill its function. Once ZIKV binds to GRP78, it triggers a series of events that facilitate viral entry into the cell. The virus is internalized through a process called endocytosis, where it is engulfed by the cell membrane and enclosed in a vesicle. This allows ZIKV to enter the cell's interior while remaining protected from the immune system. Once inside the cell, ZIKV can release its genetic material and start replicating. GRP78 may also play a role in facilitating viral replication by creating a favorable environment for viral protein synthesis and assembly | (Khongwichit et al. 2021; Elfiky and Ibrahim 2021; Turpin et al. 2020; Royle et al. 2020; Mufrrih et al. 2021) |
21 | Hepatitis B virus infectivity and antigen secretion | Regulates HBV infectivity and antigen secretion | In human hepatocellular cell line, the presence of GRP78 was confirmed in human hepatocellular cell line; interestingly, it is associated with preS2, a specific component of the hepatitis B virus (HBV). The study revealed that preS2 and GRP78 co-localize, indicating their proximity within the cells. Notably, preS2 selectively binds to the ATPase domain of GRP78, establishing a specific interaction between the two. This interaction has significant implications for both HBV infectivity and the secretion of HBV antigens. Moreover, the study demonstrated that GRP78's interaction with preS2 plays a role in promoting HBV replication. It achieves this by suppressing the expression of CHOP, a protein involved in the cellular stress response. By inhibiting CHOP, GRP78 enhances the survival of hepatocytes during persistent HBV infection. This finding shed light on the mechanism by which GRP78 influences HBV replication and suggests its importance in facilitating HBV-related cellular processes | (Suwanmanee et al. 2021) |
22 | Tongue cancer | Contributes to tumor growth and metastasis | In a study conducted by Lin et al., it was observed that the overexpression of GRP78/BiP is a strong indicator of a worse outcome in both precancerous and cancerous lesions, indicating a significant association with increased malignant potential in oral lesions. Another study by Kaira et al. analyzed 85 tongue cancer patients and found that elevated expression of GRP78/BiP independently predicts a poor prognosis in these patients. Moreover, GRP78/BiP exhibited significant associations with PERK expression, vascular invasion, glucose metabolism, and cell proliferation. Importantly, the expression of GRP78/BiP was markedly elevated in metastatic sites when compared to the primary sites | |
23 | Lung Cancer | Cell proliferation, inhibition of apoptosis | GRP78 in lung cancer enhances cellular proliferation, inhibits apoptosis, and imparts resistance to chemotherapy. It achieves these effects through various mechanisms. GRP78 stimulates cell proliferation by activating signaling pathways responsible for cell growth and survival, such as PI3K/AKT and MAPK/ERK pathways. It also suppresses apoptosis by interacting with proteins that promote cell death and inhibiting their function. Moreover, GRP78 facilitates the metastasis of lung cancer cells by promoting their invasiveness, migration, and invasion into surrounding tissues. This is accomplished through its interaction with proteins involved in epithelial-mesenchymal transition (EMT), a process enabling cancer cells to acquire characteristics associated with invasiveness and metastasis | (Du et al. 2019; Xia et al. 2021; Ning et al. 2022a, b; Tsai et al. 2007) |
24 | Pancreatic Cancer | ER stress, cell survival | Pancreatic cancer cells often face harsh microenvironments with limited nutrient and oxygen supply, leading to ER stress. GRP78 helps pancreatic cancer cells adapt to these conditions by activating the UPR and promoting cell survival. It also contributes to chemoresistance by regulating drug efflux transporters and modulating the activity of apoptosis-related proteins | |
25 | Obesity & type 2 diabetes patients | Implicated in insulin resistance and metabolic dysfunction | GRP78 plays diverse roles in the development of obesity and type 2 diabetes by influencing ER stress, insulin signaling, inflammation, and lipid metabolism. It interacts with inflammatory signaling pathways, such as NF-κB and JNK, regulating the production of pro-inflammatory cytokines like TNF-α and IL-6, which contribute to chronic inflammation and insulin resistance. Additionally, GRP78 modulates lipid metabolism by interacting with transcription factors like SREBP-1c and PPARγ, affecting processes such as lipogenesis, adipocyte differentiation, and fatty acid handling. These mechanisms collectively contribute to insulin resistance and β-cell dysfunction observed in obesity and type 2 diabetes | (Pan et al. 2022; Han et al. 2015; Luo et al. 2022; Nourbakhsh et al. 2022) |
26 | Sperm Function | Essential for sperm maturation and fertilization | Inhibition of GRP78 has detrimental effects on the signaling of the PI3K/PDK1/AKT pathway in spermatozoa during capacitation. Additionally, suppressing GRP78 leads to adverse effects on sperm motility, kinematic parameters, capacitation state, cell viability, and abnormal tyrosine phosphorylation. These findings collectively suggest that the disruption of PI3K/PDK1/AKT signaling and tyrosine phosphorylation resulting from GRP78 suppression can have a negative impact on sperm function | (Lee et al. 2022b) |
27 | Osteosarcoma | Promote tumor growth, invasion and drug resistance | Osteosarcoma cells have elevated GRP78 expression andAKT activity is activated due to this. P-glycoprotein (P-gp), an important contributor to acquired multidrug resistance (MDR) in osteosarcoma, is consequentially produced in high levels as a result of AKT activation | |
28 | Squamous cell carcinoma (SCC) | Contributes to tumor growth, invasion and metastasis | Overexpression of GRP78 in squamous cell carcinoma (SCC) contributes to its aggressive nature and unfavorable prognosis. It promotes cell survival, activates pro-survival pathways, induces chronic ER stress, stimulates angiogenesis, and enhances tumor invasion and metastasis. These mechanisms collectively drive the aggressive behavior of SCC. Targeting GRP78 and its associated pathways holds promise as a potential therapeutic strategy for managing this type of skin cancer. A recent study demonstrated that TMTC3 disrupts the interaction between PERK and GRP78, resulting in the activation of the PERK pathway. This activation facilitates the translocation of ATF4 to the nucleus, leading to increased transcriptional activity of ILEI. These findings suggest that TMTC3 promotes the GRP78/PERK signaling pathway during ER stress-induced epithelial-mesenchymal transition (EMT) in SCC. Targeting this pathway involving TMTC3 could offer new therapeutic opportunities for treating SCC | (Yuan et al. 2022) |
29 | Liver Cancer | Unfolded protein response, cell survival | GRP78 is implicated in liver cancer. It aids cell survival by activating pro-survival pathways, such as the PI3K/AKT and MAPK/ERK pathways. It also regulates the UPR to maintain protein homeostasis and cell survival. Additionally, GRP78 is associated with chemoresistance in liver cancer by modulating drug efflux pumps and anti-apoptotic pathways | (Su et al. 2010) |
30 | Melanoma | Unfolded protein response, cell survival | GRP78 promotes cell survival by activating pro-survival pathways and inhibiting apoptosis in melanoma cells. It interacts with and stabilizes anti-apoptotic proteins, such as Bcl-2 family members, which prevents the activation of apoptotic pathways. This leads to increased survival of melanoma cells | (Martin et al. 2010; Papalas et al. 2010; Lizardo et al. 2016; Sykes et al. 2016) |
31 | Brain Tumors | Tumor angiogenesis, cell survival, tumor invasion | GRP78 promotes tumor angiogenesis in brain tumors by regulating the expression of angiogenic factors. It also stimulates the production and secretion of vascular endothelial growth factor, a potent inducer of blood vessel formation. Increased GRP78 expression leads to elevated VEGF levels, which promote the growth of new blood vessels, providing nutrients and oxygen to tumor cells. Summarily, GRP78 aids tumor angiogenesis, promotes cell survival, and regulates invasion of brain tumors | |
32 | Bladder Cancer | Cell survival, chemotherapy resistance | GRP78 promotes tumor growth and proliferation in bladder cancer through multiple mechanisms. It interacts with cell surface receptors, such as integrins, promoting cell adhesion, migration, and invasion. GRP78 also activates key signaling pathways, including the PI3K/AKT and MAPK/ERK pathways, which enhance cell survival, proliferation, and angiogenesis. GRP78 is involved in the induction of EMT, a process where cancer cells acquire a mesenchymal phenotype with increased invasive properties. It regulates the expression of EMT-related markers, such as E-cadherin, N-cadherin, and vimentin, leading to enhanced migration and invasion of bladder cancer cells | (Udagawa et al. 2008) |
33 | Thyroid Cancer | Cell proliferation, inhibition of apoptosis | GRP78 activates pro-survival signaling pathways, such as the PI3K/AKT and MAPK/ERK pathways, in thyroid cancer cells. These pathways promote cell survival, proliferation, and resistance to apoptosis, leading to enhanced tumor growth and survival. It also influences the tumor microenvironment in thyroid cancer by promoting angiogenesis and inflammation. It interacts with vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs), contributing to the formation of new blood vessels and facilitating tumor growth and metastasis | |
34 | Kidney Cancer | Unfolded protein response, cell survival | GRP78 plays a role in maintaining protein homeostasis by activating the UPR, which helps kidney cancer cells adapt to cellular stress. It promotes cell survival and supports tumor progression by inhibiting apoptosis and promoting cell proliferation in the presence of UPR activation | |
35 | Esophageal Cancer | Cell survival, chemotherapy resistance | GRP78 is active in modulating cell migration, invasion, and metastasis in esophageal cancer. It influences the expression and activity of matrix metalloproteinases (MMPs), enzymes involved in extracellular matrix remodeling and tumor cell invasion. Additionally, GRP78 can interact with cell adhesion molecules and components of the cytoskeleton, affecting cell adhesion, migration, and invasion processes | (Zhang et al. 2020) |
36 | Skin Disease | Regulation of osteoblast and osteoclast | GRP78 regulates the activation of immune cells, such as macrophages and dendritic cells, leading to the production of pro-inflammatory cytokines. GRP78 contributes to the proliferation and migration of skin cells during wound healing. However, GRP78 can heighten cell survival and proliferation, which can result into development and growth of skin cancer. Pro-survival signaling pathways, such as the PI3K/AKT and MAPK/ERK pathways, that enhance cell survival and stimulate cell division is also activated by GRP78 | (Park et al. 2019) |
37 | Eye Diseases | Participation in retinal degeneration | GRP78 plays a role in modulating endoplasmic reticulum (ER) stress and apoptotic pathways in retinal cells. It helps maintain ER homeostasis and prevents the accumulation of misfolded proteins, which can trigger cellular stress and apoptosis in the retina. In eye diseases such as diabetic retinopathy and retinal ischemia, dysregulation of apoptosis can contribute to retinal cell damage and vision loss. GRP78 interacts with pro-apoptotic factors and inhibits apoptotic signaling, promoting cell survival | (Kroeger et al. 2019) |
38 | Reproductive Disorders | Regulation of fertility, hormone secretion, and development in the reproductive system | GRP78 is involved in the regulation of reproductive processes, including follicular development, ovulation, and hormone secretion. It plays a role in maintaining proper ER function and protein folding in the reproductive tissues. Disruption of GRP78 function can lead to reproductive system dysfunction, affecting fertility and hormone balance | |
39 | Blood Disorders | Involvement in hematological malignancies, particularly promoting leukemic cell survival and drug resistance | GRP78 contributes to the survival and proliferation of leukemic cells by regulating ER stress response, promoting anti-apoptotic pathways, and modulating drug resistance mechanisms. Its overexpression can confer a survival advantage to leukemic cells and limit the effectiveness of anti-cancer treatments | |
40 | Autoinflammatory | Modulation of inflammatory responses and cytokine production in autoinflammatory disorders | GRP78 is involved in the regulation of immune signaling pathways and inflammatory responses. It can modulate the production of pro-inflammatory cytokines and influence the activation of immune cells. Dysregulation of GRP78 expression or function may contribute to excessive inflammation and the pathogenesis of autoinflammatory disorders | |
41 | Neuroblastoma | Cell survival, chemoresistance | GRP78 exhibits anti-apoptotic properties by suppressing apoptosis, or programmed cell death. It interacts with and regulates the activity of several pro-apoptotic proteins, such as caspases, BAX, and PERK (protein kinase R-like endoplasmic reticulum kinase). Through these interactions, GRP78 prevents the activation of apoptotic pathways, thereby promoting cell survival and contributing to neuroblastoma progression | |
42 | Wilms Tumor | Cell survival, chemotherapy resistance | Facilitates cell survival and confers resistance to chemotherapy. GRP78 has anti-apoptotic properties by preventing apoptosis, a programmed cell death process. It interacts with and modulates the activity of pro-apoptotic proteins such as caspases, BAX, and PERK (protein kinase R-like endoplasmic reticulum kinase). By inhibiting the activation of apoptotic pathways, GRP78 can promote cell survival and potentially contribute to Wilms tumor progression | |
43 | Cardiovascular disease | Endothelial dysfunction, oxidative stress, inflammation, apoptosis | Cardiovascular disease refers to a group of disorders affecting the heart and blood vessels, including conditions like coronary artery disease, heart failure, and stroke. It is a leading cause of death worldwide. Cell surface GRP78 is involved in multiple mechanisms contributing to cardiovascular disease. It can promote inflammation, angiogenesis, and platelet aggregation. It can also interact with various receptors, such as toll-like receptors (TLRs), integrins, and vascular endothelial growth factor receptor 2 (VEGFR2), leading to downstream signaling pathways that influence cell survival, proliferation, and migration In the context of myocardial infarction (MI), commonly known as a heart attack, cell surface GRP78 has also emerged as a relevant factor. Increased expression of GRP78 on the cell surface has been observed in ischemic myocardium. In MI, cell surface GRP78 contributes to cardiac injury through various mechanisms. It promotes myocardial apoptosis, inflammation, and fibrosis, thereby exacerbating tissue damage and impairing cardiac function. Moreover, GRP78 interacts with integrins and activates downstream signaling pathways, leading to increased fibrotic tissue formation. These combined effects of cell surface GRP78 contribute to the adverse remodeling processes seen in MI | (Wang et al. 2018; Bhattacharjee et al. 2005; Sato et al. 2010b; Girona et al. 2019; Liu et al. 2003; Lee 2007; Sha and Jiang 2023; Hardy and Raiter 2010) |