The potential role of necroptosis in clinical diseases (Review)
- Authors:
- Published online on: March 26, 2021 https://doi.org/10.3892/ijmm.2021.4922
- Article Number: 89
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Copyright: © Dai et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
1. Introduction
Necroptosis, an emerging field closely related to apoptosis, is a non-caspase-dependent cell death that has been implicated in the pathological processes of various diseases. It is regulated by various genes that cause regular and ordered cell death. Through activating specific death signaling pathways, it shares typical characteristics of necrosis, including loss of metabolic function and subcellular changes (1,2). Receptor-interacting protein kinase 1 (RIP1) was the first signaling molecule identified in the necrosome (3). RIP1 and RIP3 interact with the receptor protein, transducing death signals, and further recruiting and phosphorylating mixed lineage kinase domain-like protein (MLKL) (4-7). Necroptosis can be involved in the regulation of several signaling pathways, including the caspase-8-dependent apoptotic pathway, the mitogen-activated protein (MAP) kinase cascade, and activation of the nuclear factor-κB (NF-κB) pathway.
To explore the potential role of necroptosis in human diseases, researchers have developed various methods, such as gene knockdown and knockout, and pharmacological inhibitors. By using these methods, it has been found that necroptosis plays an important role in pathophysiological processes of several clinical diseases, including infections, liver diseases, kidney injury, neurodegenerative diseases, cardiovascular diseases, and human tumors (8). In the current review, we aimed to explore the potential role of necroptosis in various clinical diseases.
2. Overview of the molecular mechanism of necroptosis
Necroptosis can be triggered by a variety of factors, such as tumor necrosis factor receptor (TNFR) and toll-like receptor (TLR) families, intracellular DNA and RNA sensors, and interferon (IFN) (9-11). TNF-dependent TNFR1 stimulation has three consequences that depend on the assembly of regulatory proteins. These different pathways ultimately stimulated NF-κB-dependent inflammation, caspase-8-dependent apoptosis, or selective activation of necroptosis under caspase-8 inhibition (Fig. 1) (12). TNF-dependent necroptosis is regulated by RIP1 and RIP3, which interact through unique RIP homotypic-interacting motifs (RHIMs) (Fig. 2) (13,14).
The interaction of RIP1 and RIP3 results in autophosphorylation, transphosphorylation, and assembly of 'necrosome' complex (5). RIP3 and MLKL are essential for necroptosis, whereas RIP1 is only sometimes involved in this process. RIP3 and MLKL knockout mice do not show deficiency in embryogenesis, homeostasis and development, indicating the role of necroptosis may be not essential in non-challenged conditions (15,16).
3. Difference of the key characteristics between apoptosis and necroptosis
Although necroptosis is characterized by caspase independence, the molecular pathway involved is similar to and shares features of apoptosis. However, the immunological and morphological consequences of necroptosis are vastly different (Fig. 3). Necroptosis shares the major morphological features of necrosis, such as the swelling of organelles, gradually translucent cytoplasm, and rupture of the cellular membrane (12). By contrast, apoptosis is characterized by membrane blebbing, cell shrinkage, nuclear fragmentation, and chromatin concentration (17). The rupture of the cellular membrane results in the release of cellular contents, leading to the exposure of damage-associated molecular patterns (DAMPs), triggering a strong inflammatory response in necroptosis, suggesting necroptotic cells are more immunogenic than apoptotic cells, which is relatively intact, with DAMP restricted to the plasma membrane, or encapsulated in the apoptotic bodies (17). It has also been shown that necroptosis was associated with maintenance of T-cell homeostasis, as it has been found to be able to clear excess and abnormal T cells in the absence of caspase-8 (18), which can prevent abnormal proliferation of lymphocytes (19).
4. Identification of necroptosis
As there is currently no specific marker for necroptosis, multiple methods are usually required to identify necroptosis (Fig. 4). In cultured cells, transmission electron microscopy can be used to identify necroptotic cells (20). Detection of key molecular, including RIP1, RIP3 and MLKL activation, necrosome formation, MLKL oligomerization, and membrane translocation can also be used to identify necroptosis (21). Activation of RIP3 and MLKL can be monitored by western blot analysis to assess phosphorylation status (22,23). Phosphorylation of MLKL at Ser358 and Thr357 and RIP3 at S227 indicates the activation of necroptosis (24). In particular, MLKL phosphorylation has been used as a biomarker for certain disease diagnosis and prognosis (25). In addition, several pharmacological inhibitors such as the necrostatin (Nec)-1, GSK872, and necrosulfonamide (NSA) have also been used to detect necroptosis (7,26). In vivo, the activation of necroptosis can be identified by the elevated levels of RIP1, RIP3, or MLKL mRNA or protein. Additionally, previous findings suggested that RIP3 and MLKL are more specific molecular biomarkers than RIP1 for the detection of necroptosis (27).
5. Potential role of necroptosis in clinical diseases
Physiological functions
Over the last decade, researchers have put a lot of effort into the development of effective RIP1, RIP3, and MLKL inhibitors, and created mouse models that lack one or more components of the necroptotic pathway at systemic level or in specific tissues (28). Due to the existence of these models, the physiological function of proteins of necroptosis have been investigated. Conditional deletion of RIP1 in keratinocytes or intestinal epithelial cells suggested RIP1 plays an essential role in maintaining epithelial homeostasis (29,30). It is worth noting that the role of RIP1 in maintaining the intestinal barrier is similar to caspase-8 (31). In addition, mice with Birc2, Birc3, and Xiap codeletion in the myeloid lineage have high levels of circulating inflammatory cytokines, sterile inflammation, and granulocytes, which can be partially corrected by the lack of RIP1 or RIP3 (32). Tamoxifen-induced systemic RIP1 gene knockout in adult mice is fatal due to a surge in cell death and intestinal bone marrow failure, which accumulates and causes fatal systemic inflammation (33,34). Fetal hepatocytes that received tamoxifen-induced RIP1 deletion or RIP1−/− progenitor cells are unable to repopulate irradiated receptors. This defect can be partially corrected by the concomitant lack of RIP3, indicating that RIP1 plays a key role in the survival of hematopoietic stem and progenitor cells (33,34). Furthermore, systemic inflammation caused by RIP1−/− can be restricted in RIP1−/−RIP3−/−Casp8−/− hosts (34,35). These hosts show age-related lymphoproliferative disorders similar to those developed by RIP3−/−Casp8−/− mice (11,34,36). In addition, compared to control animals, RIP1+/− mice, mice treated with intravenous siRNA targeting RIP1, and Nec-1-treated mice showed a higher rate of physiological intestinal epithelial cell regeneration in the small intestine (37). In addition, the negative effects of Nec-1 on the regeneration of intestinal epithelial cells are also present in RIP3−/− mice (37). Findings of those studies suggest that there may be a delicate balance between different cell deaths in maintaining homeostasis in adults.
Infectious diseases
Viral infections
Findings have shown the crucial role of necroptosis in inflammation during viral infection (Table I). The viruses use the host's signaling pathways, such as anti-apoptotic proteins, to enhance infection, thereby increasing its ability to replicate in the host cell. It has been reported that viral encoding protein involving the RHIM domain interacts with RIP1 and RIP3 to inhibit virus-induced cell death (38). Viral inhibitor of RIP activation (vRIA) disrupts the combination of DAI and RIP3, thereby suppressing cytomegalovirus-mediated necroptosis (9). By contrast, human cytomegalovirus differs in protein, which does not disrupt RIP3 binding with DAI; it works via blocking signaling downstream of MLKL (39). Experimental studies in mice lacking RIP3 have shown impaired virus-induced necroptosis and increased susceptibility to viral infections such as vaccinia virus, influenza A virus, and HSV-1 (5,25,38,40) (Fig. 5).
Bacterial infections
Necroptosis also plays an important role in the inflammation caused by bacterial infections. Enteropathogenic E. coli (EPEC) has been shown to synthesize and secrete large amounts of the immunogenic effector protein NleB1 and modify the arginine residues of the Fas-associated death domain (FADD) and RIP1 death domains to prevent apoptosis and necroptosis (41,42). EPEC lacking NleB1 fails to colonize intestinal epithelial cells, indicating that bacterial necroptosis is a protective mechanism of the organism (41,42). Similarly, the absence of RIP3 sensitizes host cells to Yelsonella. Moreover, the simultaneous knockout of FADD or caspase-8 could make cells more sensitive (43,44). In vitro, Salmonella typhimurium is able to escape TNFα, causing RIP1- and RIP3-dependent necroptosis in infected macrophages. In a model of Salmonella typhimurium venous infection, RIP3 knockout significantly reduces splenic macrophage death, thereby reducing bacterial numbers and prolonging mouse survival (45,46). Findings focusing on oral Salmonella typhimurium infection have also shown that outer protein B was downregulated during infection, which resulted in promoting bacterial translocation, increasing macrophage necroptosis, and exacerbating bacterial infection (Table I) (47).
Parasite infections
Parasitic diseases such as malaria and leishmaniasis usually cause hemolysis, anemia, and bleeding. These are due to the release of hemoglobin (Hb) into the circulation by the rupture of red blood cells. When Hb is oxidized, heme is generated, the Fenton reaction starts, and peaks with the generation of reactive oxygen species (ROS). Heme is also involved in the activation of TLR4, causing autocrine secretion of ROS and TNF, and synergistically activating RIP1/3-dependent necroptosis (48). In addition, it has been shown that 10 ng/ml TNFα can induce infected human foreskin fibroblasts egressing Toxoplasma gondii (Table I) (49).
Cancers
Type of cancers
Studies on necroptosis highlight its role in cancer because of its necroptosis-inducing function (Table II) (50). Chen et al suggested that necroptosis is an important cell death mechanism for blocked apoptosis, and has been proposed as an alternative cell death procedure to prevent cancer (20). Previous studies have shown that a decreased expression of RIP3 or MLKL is associated with worse prognosis and poor survival in breast cancer (51,52), colorectal cancer (53-55), acute myeloid leukemia (56,57), melanoma (58,59), head and neck squamous cell carcinoma (60), gastric cancer (61), ovarian cancer (62), and cervical squamous cell carcinoma (63). However, increased RIP3 or RIP1 expression was also correlated with cancer development, including glioblastoma (64), lung cancer (65), and pancreatic cancer (66,67). SN38, the topoisomerase inhibitor, was found to be able to promote necroptosis progression, inhibit cell proliferation, and induce DNA damage accumulation in colon cancer (68). These findings indicate that inhibiting activities of necroptosis components may be a strategy in the treatment of cancers.
Metastasis
Metastasis is the most common cause of cancer-related death. Researchers have found that metastasis involves a complex interaction between cancer cells and the microenvironment. By promoting inflammation, necroptosis may be able to promote metastasis (69). It has been shown that TNFα plays a critical role in cancer progression. However, the exact mechanism of this process has not been fully understood. Increased expression of TNFα in cancer is a key characteristic in numerous malignancies and is usually associated with a poor prognosis and decreased survival (69). Consistent with the pro-inflammatory properties of necroptosis and the cancer-promoting effect of inflammation, Nec-1 was able to reduce inflammation and colitis-related tumor formation (70), indicating that targeting necroptosis may be a strategy for preventing cancer metastasis.
Neurodegenerative diseases
Parkinson's disease
Researchers have shown that necroptosis was activated in Parkinson's disease (PD), and may be associated with mitochondrial defects which led to necroptosis (Table III) (71). Compared with healthy brain, the level of necroptosis components, including RIP1, RIP3 and MLKL, was significantly increased in the substantia nigra of PD brain (72). Moreover, researchers have found Nec-1 could protect PC12 cells from death in PD models (73). This suggests that the activation of RIP1 may be a risk factor for dopaminergic neurons lost in PD patients. In addition, leucine-rich repeat kinase 2, which was identified in a systematic RNAi screen, is encoded by a gene that is frequently mutated in PD and is able to promote activation of RIP1 (74).
Alzheimer's disease
Alzheimer's disease (AD) is a degenerative brain disease featured by loss of neurons. Previous studies have found that there were activated necroptosis in both human (75) and mouse (76) AD brain. In the AD brain, the levels of necroptosis components, such as RIP1 and MLKL, were significantly higher than the normal brain (Table III) (75). Treatment of AD in brain of mice with the necroptosis inhibitor can significantly suppress necroptosis and prevent neuronal loss (75). This indicates that targeting necroptosis may be a new therapeutic strategy for AD treatment.
Amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that is characterized by loss of motor neurons. In a previous study, the ALS spinal cord was shown to have a significant increase in necroptosis components including RIP1, RIP3, and MLKL in the ALS mouse model compared to healthy mouse spinal cord (77). In addition, loss of optineurin, an ALS-related gene, resulted in susceptibility to necroptosis. Nec-1 inhibition of RIP1 or knockout of RIP3 could prevent demyelination and reduce axonal pathological hallmarks in ALS mouse models (Table III) (77). Those findings suggested that targeting necroptosis may have potential therapeutic value in ALS patients.
Multiple sclerosis
Multiple sclerosis (MS) is degenerative disease characterized by oligodendrocyte loss and demyelination. Previous findings have shown a significant increase in necroptosis components including RIP1, RIP3, and MLKL in MS patients. In addition, MLKL oligomers were significantly increased in MS pathology samples compared with controls (Table III) (78). This suggests necroptosis is activated in the pathogenesis of MS. In MS mouse model, oral administration of RIP1 inhibitor can suppress oligodendrocyte degeneration and reduce disease severity (78). Moreover, researchers have shown that inhibition of RIP1 reduced demyelination and disease progression in an MS model (79). Notably, MLKL was shown to be involved in the MS process (79).
Liver diseases
Non-alcoholic fatty liver disease (NAFLD), Non-alcoholic fatty liver disease (NAFLD) is a chronic disease characterized by excess triglyceride accumulation in the liver. Several studies have used different models to assess the effects of necroptosis on NAFLD (Table IV). Studies have found necroptosis components, including RIP1, RIP3 and MLKL, were increased in NAFLD models, as well as in RIP3KO mice (80-85). In addition, an increased expression of RIP3 and MLKL in the human NAFLD was identified (83,85). Increased level of RIP3 and p-MLKL was also found in visceral adipose tissue of obese patients. Furthermore, RIP3 expression correlated with p-MLKL and metabolic serum markers including blood insulin levels and Hemoglobin A1c (84).
Alcoholic hepatitis
Similar to the pathologies of NAFLD, alcoholic hepatitis is an inflammatory syndrome in liver, which can result in high morbidity and mortality. Several studies have found that RIP3 was increased following ethanol feeding, and RIP3 deletion could protect the liver from ethanol-mediated injury (Table IV). In addition, p-JNK was regulated by RIP3 in a model of alcoholic hepatitis, and RIP3 deletion reduced ethanol-induced p-JNK expression (86). Another study found pharmacological inhibition of proteasome and liver-specific PSMC1 KO mice could increase RIP3 expression, indicating RIP3 expression was post-translationally regulated in ethanol-mediated liver injury (87). Additionally, when RIP3 was deleted, the steatosis and inflammatory effects of ethanol in hepatocyte could be reduced (86). However, the inflammatory and steatosis effects of high fat diet for hepatocyte were increased when RIP3 was deleted (80).
Fibrosis
Hepatic fibrosis is one of the most common liver diseases, which is closely related to liver failure and hepatocellular cancer. RIP3 deletion reportedly aggravated hepatic fibrosis by increasing insulin resistance (80). Furthermore, inhibition of RIP3 did not result in protective effect in carbon tetrachloride (CCL4)-induced fibrosis (83) (Table IV). Additionally, curcumol suppressed serum inflammatory markers, transaminases, and fibrosis in a dose-dependent manner by inducing necroptosis of hepatic stellate cells in a liver fibrosis model (88). Curcumol-induced increased necroptosis was mediated by increased expression of p-RIP3 and p-JNK (88). Those results indicated that pharmacotherapy which induced increased necroptosis may be a notable strategy for the treatment of hepatic fibrosis in the future.
Pulmonary diseases
Chronic obstructive pulmonary disease
Chronic obstructive pulmonary disease (COPD) is characterized by persistent and progressive airway inflammation and narrowing, and is a major source of the high healthcare expenditure in the elderly (89). An increasing number of studies have shown that necroptosis is associated with the etiology of COPD (Table V). In addition, necroptosis of epithelial cell is associated with COPD (90). Cigarette smoking (CS)-related necroptosis and DAMP release could cause neutrophil inflammation in mice, and Nec-1 could reduce the inflammation (91). In addition, researchers have found that in airway epithelial cells, endoplasmic reticulum chaperone protein GRP78 could promote CS-induced inflammation. This may be due to the upregulation of necroptosis and subsequent activation of the NF-κB pathway (92).
Acute lung injury
Acute lung injury (ALI) is one of the most common complications in critically ill patients (93). Recent findings have shown the involvement of RIP3-mediated necroptosis in neonatal mice with hypoxia-induced lung injury, which can be attenuated by gene deletions in RIP3 (94). In additional, inhibition of RIP3 could significantly reduce inflammatory activation and lipopolysaccharide-induced necroptosis (95). Researchers have also found that mice lacking RIP3 were protected from ventilator-induced lung injury (96). Additionally, inhibition of RIP1 can reduce systemic and pulmonary inflammation and increase survival rate of septic neonatal mice (Table V) (97).
Idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic lung disease characterized by the usual interstitial pneumonia pattern at histopathologic examination (98). In a previous study using alveolar epithelial cells, RIP3-mediated necroptosis was associated with IPF development by releasing DAMP (99). Additionally, RIP3 and p-MLKL levels in the lungs of IPF patients are significantly higher than those in healthy lungs (99). Mice with RIP3 knockout showed a reduced cell death, with a decrease of p-MLKL level in alveolar epithelial cells (99). RIP3 knockout could effectively suppress the DAMP releasing, cell death, and pulmonary fibrosis without reducing the expression of cleaved caspase-3 (Table V) (99). These indicate that inhibiting activities of necroptosis components may be a strategy in the treatment of IPF.
Bronchial asthma
Bronchial asthma is the most common chronic respiratory disease characterized by bronchial hyper-responsiveness and airway obstruction (100). Viral-induced bronchial asthma exacerbation mimicked by IFN-β knockout mice treated with house dust mite is associated with increased necroptosis components, including p-MLKL and LDH in the bronchoalveolar lavage fluid (101). As a major inflammatory cytokine in bronchial asthma, IL-33 is released in response to necroptosis and causes eosinophil and basophil activation (102). Moreover, in a mouse model of asthma induced by Aspergillus fumigatus extract, the necroptosis inhibitor GW806742X can eliminate necroptosis and IL-33 response, and attenuates eosinophilia (102). Additionally, The TNFα-induced necroptosis enhanced by mucin 1 can be reduced by Nec-1 in human bronchial epithelial cells (103) (Table V).
Renal diseases Acute kidney injury
Acute kidney injury (AKI) is a common and severe clinical disease that often requires renal replacement therapy (Table VI). Signs of an ongoing necroptotic response have been found in AKI caused by ischemia-reperfusion injury (IRI) (104-106), urolithiasis (107), cisplatin-based chemotherapy or radiocontrast (104,108-111). Previous findings have shown that compared with wild-type counterparts, RIP3−/− and MLKL−/− mice are less sensitive to oxalate crystal-induced AKI, and are associated with reduced plasma creatinine levels, neutrophil infiltration, and limited tubular injury (107,110). Moreover, the RIP3−/− mice confer protection from mild IRI, and the protection can be extended to severe IRIs with the deletion of Ppif (104). Similar results are also found when Nec-1, SfA, and 16-86 are employed alone or in combination (104,109). The abovementioned results suggest that inhibition of necroptosis may be a therapeutic option for AKI treatment.
Chronic kidney disease
Similar to the AKI, necroptosis was also found in chronic kidney disease (CKD) after unilateral nephrectomy (Table VI) (112). Researchers have shown that necroptosis and the highest levels of RIP1 and RIP3 occurred 8 weeks after subtotal nephrectomy (112). Notably, the renal pathological changes and renal function could be significantly improved after Nec-1 treatment, and the overexpression of RIP1, RIP3, MLKL could be significantly reduced (112). These results suggest that necroptosis contributes to the loss of renal cells in subtotal nephrectomized rats. Furthermore, during the AKI to CKD process, upregulation of expression and inter-action between RIP3 and MLKL can induce necroptosis in proximal renal tubular cells and promote inflammasome activation under IRI conditions (113). RIP3 or MLKL knockout could protect the renal tubular cells from necroptosis and inflammasome activation, which prevent kidney from interstitial fibrogenesis after IRI (113).
Cardiovascular diseases
Myocardial infarction
Myocardial infarction, characterized by regional myocardial ischemia and hypoxia, is one of the leading causes of death worldwide (114). Previous findings have shown that compared to wild-type mice, the levels of RIP1 and RIP3 were significantly higher in hearts of ischemic mice (22,115). In an acute IRI mouse model, RIP3 deficiency was able to protect heart from IRI-induced necroptosis and reduce the infarct size (116). Notably, researchers have found that Nec-1 could protect heart against short-term and long-term effects of myocardial ischemia, including reduced necrotic cell death and size of myocardial infarction, which helped to maintain long-term cardiac function (22) (Table VII).
Atherosclerosis, Atherosclerosis, a chronic inflammatory disease, is frequently observed in middle-aged individuals and the elderly, and is a major cause of cardiovascular death (117). It has been demonstrated that necroptosis may promote the inflammatory response and atherosclerosis development. Oxidized low-density lipoprotein (LDL) is able to upregulate RIP3 and oxidized LDL-related gene expression in macrophages, leading to macrophage necroptosis (118). It triggers an inflammatory response, which leads to atherosclerosis. During the progression of the disease, some cytokines are released and monocytes accumulate in the lesion, exacerbating the accumulation of inflammation. Additionally, necroptosis can lead to the death of foam cells, which in turn aggravates the progression of the disease (Table VII) (118). These results suggest that inhibition of necroptosis may be a therapeutic option for atherosclerosis treatment.
Joint diseases
Rheumatoid arthritis
Rheumatoid arthritis (RA), characterized by synovial membrane inflammation, is a chronic systemic inflammatory autoimmune disease that affects 0.5-1% of the population worldwide (119). Previous findings have shown a significant increase in necroptosis components including RIP1, RIP3, and MLKL in the synovium of an arthritis mouse model (120). Additionally, researchers have also found in an arthritis mouse model, Nec-1 could significantly reduce these key components of necroptosis and IL-17, IL-1β, IL-6, and TNFα (Table VIII) (121). These results suggested that inhibiting activities of necroptosis components may be a strategy in the treatment of RA.
Osteoarthritis
Osteoarthritis (OA) is the leading cause of pain and disability among chronic disease, which affects about 10% of men and 18% of women older than 60 years (122). A significant increase in necroptosis components including RIP3, and MLKL was found in highly degenerated cartilage tissue (123). Moreover, it has been shown that Nec-1 could significantly reduce cell death and subsequent release proinflammatory mediators in the OA model (Table VIII) (123).
6. Drugs and agents that regulate necroptosis
As necroptosis not only participate in the maintenance of organismal homeostasis, but also constitute etiological determinants of diverse human pathologies (124), at least two therapeutic paradigms can be envisioned: i) the activation of necroptosis, as a means to bypass the accrued resistance of most tumors to apoptosis (125); ii) the inhibition of necroptosis, as a strategy to limit the loss of post-mitotic cells in pathologies such as inflammatory, ischemic, and toxic syndromes (126). Therefore, drugs affecting either the expression or the activity of necroptosis mediators may have therapeutic potential (Table IX).
Several drugs have been found to upregulate the expression of the key molecules of necroptosis, including interferons (127), histone deacetylase inhibitor valproic acid (128), and hypomethylating agents such as decitabine and 5-azacytidine (51). Additionally, several traditional Chinese medicine drugs such as shikonin (129), emodin (130), bufalin (131), and resibufogenin (132) were also found to upregulate RIP1 and RIP3, which finally induced necroptosis. By contrast, various drugs have been documented to downregulate necroptosis, including immunosuppressive drug Cyclosporine A (133) and Rapamycin (134), inhibitors of the HSP90 [(G-TPP) (135), Kongensin A (136), 17-demethoxy-reblastatin (137), DHQ3 (137), gamitrinib (18), and geldanamycin (138)], as well as traditional Chinese medicine such as patchouli alcohol (139).
Promising specific inhibitors are also being developed for the central molecules of necroptosis. Currently, several drugs with anti-necroptotic activity have been used for the treatment of different types of cancer [Pazopanib (140), Ponatinib (140), GSK3145095 (141), Dabrafenib (26), Carfilzomib (142), and Sorafenib (143)]. Moreover, a clinically used anti-convulsant, Phenytoin (144) as well as components found in different plants [aucubin (145) and wogonin (146)] could inhibit RIPK1 activity. By contrast, radiotherapy (147), chemotherapeutic agents such as 5-fluorouracil (148), cisplatin (149), oxaliplatin (150), and anthracyclines (150), pan-BCL-2 inhibitor Obatoclax (151), or traditional Chinese medicines such as neoalbaconol (152) and tanshinone (153) have been documented to upregulate necroptosis. Although these drugs did not affect the expression of necroptotic component, these medicines may increase the effect of the drugs affecting the expression of the necroptotic molecules in combination therapy in cancer cells.
7. Conclusions and perspectives
During the last decade, necroptosis has been recognized as an alternative to apoptosis when cells are exposed to various stimuli under specific conditions (154). The necrosome components, RIP1, RIP3, and MLKL, are critical regulators of necroptotic cell death. RIP1 functions as a traffic cop for mechanisms of cell death. MLKL acts as the executioner of necroptosis, based on the phosphorylation, oligomerization and membrane translocation (155). Current understandings demonstrated a pathway in which RIP3 activation, possibly mediated by RIP1, induces MLKL activation, and finally results in permeabilization of the plasma membrane and cell death.
Recent studies have revealed a complex role for necroptosis in diverse clinical diseases, such as ischemia-reperfusion injury, neurological and inflammatory diseases, retinal disorders, acute kidney injury or bacterial infections. On the one hand, it functioned as a cell-death mechanism activated by various signal transduction cascades in the same cell or the same tissue; on the other hand, it acted as an inflammation inducer through the release of DAMPs. Cross-regulation between necroptosis and other modes of cell death increase the complexity of these pathways. The major necroptosis-regulating proteins exert pleiotropic signaling functions that culminate in necroptotic cell death and have cell death-independent functions, such as regulation of inflammasome activation, mitochondrial function and integrity, and cellular metabolic activities (96).
As necroptosis constitutes etiological determinants of multiple human pathologies, targeting the necroptotic pathway is a potential therapeutic approach for multiple diseases, and several activators or inhibitors of the necroptosis pathway have been developed, such as dabrafenib, pazopanib, and ponatinib. These small-molecule activators or inhibitors of necroptosis may be useful as therapeutics in a specific clinical disease. However, most studies investigating the therapeutics targeting necroptosis are based on in vitro experiments or animal models, thus the feasibility of the clinical use of these compounds and agents remains to be assessed in vivo and clinical trials. Additionally, the off-target effects of the necroptosis-targeting therapeutics should be scrutinized, and novel approaches that conjugate necroptosis inducers and disease-guiding agents should be developed to enhance selectivity and safety.
Availability of data and materials
Not applicable.
Authors' contributions
YFA and WLD conceived the study; JC and XQH were involved in data curation; XL, WLD and JC were involved in collection of references as well as writing and editing; YFA, XQH and JC supervised the study. All authors have read and agreed to the published version of the manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Acknowledgments
The authors are grateful to Dr He Xiao for his valuable advice and English editing.
Funding
This work was supported by grants from the National Natural Science Foundation of China (nos. 81672212, 81802153 and 81902205), the Beijing Natural Science Foundation (nos. 7171014, 7174361 and 7182175), and the Beijing Municipal Science and Technology Commission (no. Z171100001017085).
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