Decoding MPO: New Breakthroughs in Versatile Enzyme Technology from Immune Defense to Clinical Care
In the defense network of the human innate immune system, Myeloperoxidase (MPO) always acts as an “invisible guardian” — it is not only the core force that eliminates pathogenic microorganisms, but also a pivotal hub connecting inflammatory responses and the onset and progression of multiple diseases. As life sciences and clinical detection technologies have become deeply integrated, the mystery of MPO has been gradually unraveled. Its application potential in immune regulation, disease pathogenesis and clinical care has continued to stand out, making it a prominent research focus and key area for technological breakthroughs in biomedicine.
As one of the most abundant proteins in human neutrophils, MPO accounts for about 5% of the dry weight of neutrophils. It is also present in small amounts in monocytes and some macrophages, mainly stored in the azurophilic granules of neutrophils, and is an indispensable effector molecule in the innate immune system.
Under physiological conditions, MPO acts as the "first line of defense" for the body against invading pathogens. Under pathological conditions, however, its abnormal expression and dysregulated activity trigger oxidative stress and inflammatory injury, and participate in the occurrence and progression of various chronic diseases. This makes MPO an important molecular target linking immune defense and disease diagnosis and treatment, providing a new direction for early screening, disease monitoring and targeted therapy of clinical diseases.
First, the mechanism of immune defense:
When the body is invaded by pathogens such as bacteria and fungi, neutrophils are activated and undergo a "respiratory burst", activating NADPH oxidase, which converts oxygen molecules into superoxide radicals, which are further converted into hydrogen peroxide (H₂O₂) by superoxide dismutase.
At this time, MPO is released from azurophilic granules and catalyzes H₂O₂ to produce hypochlorous acid (HOCl) in the presence of chloride ions. As one of the strongest oxidants in the human body, HOCl has a bactericidal effect 50 times higher than that of hydrogen peroxide. It can efficiently destroy the cell membranes, proteins and nucleic acids of pathogens, thereby rapidly eliminating invading microorganisms and completing the innate immune defense function.
In addition, MPO can generate other reactive oxygen species (ROS), including superoxide anions and hydroxyl radicals, which further strengthen the bactericidal effect and participate in the degradation and clearance of pathogens by phagocytes.
Second, the main characteristics:
First, high specificity. MPO is the only enzyme in the human body that can generate hypochlorous acid at physiological chloride concentrations, and its catalytic reaction has high substrate specificity and environmental adaptability.
Second, significant dual effects. At physiological levels, MPO can efficiently exert immune defense functions, while when overexpressed or abnormally activated, the reactive oxidant species (ROS) it produces will cause damage to the host's own tissues and induce inflammatory responses.
Third, concentrated distribution. MPO is mainly enriched in neutrophils and accumulates in large quantities at inflammatory sites, making it a biomarker of inflammatory reactions.
Fourth, regulability. Its expression and activity are regulated by multiple transcription factors, and the MPO gene exhibits genetic polymorphisms. Some polymorphic loci can affect the transcription level and activity of MPO, and thus are associated with disease susceptibility.
3.1 MPO-μ-Calpain Signaling Pathway: This is the key pathway by which MPO induces vascular endothelial dysfunction. Studies have found that MPO can activate μ-calpain (but not the m-calpain isoform) in a time-dependent manner through denitrosylation of the C-terminal domain of μ-calpain. At the same time, by upregulating the expression of protein phosphatase 2A (PP2A), it reduces the phosphorylation levels of AMP-activated protein kinase (AMPK) at Thr¹⁷² and endothelial nitric oxide synthase (eNOS) at Ser¹¹⁷⁷, thereby increasing the expression of vascular cell adhesion molecule 1 (VCAM-1), promoting the adhesion of leukocytes to the aortic endothelium, and causing vascular inflammation and endothelial damage. This is also one of the important mechanisms by which MPO participates in the pathogenesis of cardiovascular diseases.
3.2 MPO-oxidized low-density lipoprotein (oxLDL) signaling pathway: In cardiovascular diseases such as atherosclerosis, MPO can catalyze the oxidation of low-density lipoprotein (LDL) to generate oxLDL. OxLDL cannot bind to native LDL receptors and can only be recognized and phagocytosed by scavenger receptors on endothelial cells and macrophages. Macrophages differentiate into foam cells after phagocytosing oxLDL, and a large accumulation of foam cells forms atherosclerotic plaques, accelerating disease progression. Meanwhile, oxLDL will further induce oxidative stress and inflammatory responses, forming a vicious cycle.
3.3 MPO-oxidative stress-apoptosis signaling pathway: The excessive reactive oxidation products produced by MPO (such as HOCl and hydroxyl radicals) will attack lipids, proteins and nucleic acids in cells, leading to protein denaturation and mitochondrial dysfunction, thereby inducing cell apoptosis. In neurodegenerative diseases, MPO can increase the toxicity and aggregation of β-amyloid (Aβ) through oxidative modification, accelerating neuronal apoptosis. In kidney diseases, MPO participates in renal tubulointerstitial fibrosis through this pathway and promotes the progression of renal function impairment. In addition, MPO can further regulate immune-inflammatory responses by modulating the migration, activation, phagocytosis and extracellular trap formation of neutrophils, and participate in the pathogenesis of autoimmune diseases.
4.1 Diagnosis and monitoring of autoimmune diseases: Anti-MPO antibodies are an important subtype of antineutrophil cytoplasmic antibodies (ANCA). Their detection can be used to assist in the diagnosis of autoimmune diseases such as microscopic polyangiitis, granulomatosis with polyangiitis and idiopathic necrotizing crescentic glomerulonephritis, as well as for disease monitoring and therapeutic efficacy evaluation. The serum levels of anti-MPO antibodies in patients with active disease are significantly elevated, and they decrease significantly after treatment-induced remission. At present, anti-MPO antibody detection is mainly performed using ELISA, which is convenient and low-cost, and has been widely used in clinical diagnosis and treatment in the Department of Rheumatology and Immunology.
4.2 Risk prediction and assessment of cardiovascular diseases: MPO is an important risk factor for cardiovascular diseases. Its plasma and serum levels can independently predict endothelial dysfunction of large arteries in cardiovascular patients. People with higher MPO levels have a 15 to 20 times higher probability of abnormal coronary angiography findings than the general population. In clinical practice, MPO detection can be used for early risk screening of diseases such as atherosclerosis, hypertension and myocardial infarction. At the same time, by monitoring changes in MPO levels, plaque stability and treatment prognosis can be evaluated. Persistently elevated MPO levels indicate an increased risk of disease progression, and MPO gene polymorphism detection can also be used to assess individual susceptibility to cardiovascular diseases, providing a basis for precise prevention.
4.3 Auxiliary diagnosis and research of other diseases: In neurodegenerative diseases (such as Alzheimer's disease), MPO levels are positively correlated with disease severity and can be used as an auxiliary monitoring indicator for disease progression. In pulmonary diseases (such as chronic obstructive pulmonary disease and COVID-19), MPO is highly expressed in alveolar macrophages, and its level changes are closely related to the degree of pulmonary inflammation, which can provide a reference for condition assessment. In the field of cancer, MPO has a dual role in the tumor microenvironment. Its expression level can be used for prognostic evaluation of some tumors and provides a new target for tumor immunotherapy. In chronic kidney disease, MPO participates in the process of renal tubulointerstitial fibrosis, and its level detection can assist in assessing the degree of renal function damage.
4.4 Research and application of targeted therapeutic drugs: Based on the core role of MPO in the pathogenesis of diseases, the research and development of drugs targeting MPO have become a hotspot in the field of biomedicine. At present, a variety of MPO inhibitors have entered the clinical research stage, which mainly reduce the production of reactive oxidation products by inhibiting the activity of MPO, thereby alleviating oxidative stress and inflammatory damage, and are suitable for the treatment of cardiovascular diseases, autoimmune diseases and other conditions. In addition, gene therapy and antibody-based drug research targeting MPO are also gradually advancing, which are expected to provide novel treatment options for related diseases and break the limitations of conventional treatments.
In the defense network of the human innate immune system, Myeloperoxidase (MPO) always acts as an “invisible guardian” — it is not only the core force that eliminates pathogenic microorganisms, but also a pivotal hub connecting inflammatory responses and the onset and progression of multiple diseases. As life sciences and clinical detection technologies have become deeply integrated, the mystery of MPO has been gradually unraveled. Its application potential in immune regulation, disease pathogenesis and clinical care has continued to stand out, making it a prominent research focus and key area for technological breakthroughs in biomedicine.
As one of the most abundant proteins in human neutrophils, MPO accounts for about 5% of the dry weight of neutrophils. It is also present in small amounts in monocytes and some macrophages, mainly stored in the azurophilic granules of neutrophils, and is an indispensable effector molecule in the innate immune system.
Under physiological conditions, MPO acts as the "first line of defense" for the body against invading pathogens. Under pathological conditions, however, its abnormal expression and dysregulated activity trigger oxidative stress and inflammatory injury, and participate in the occurrence and progression of various chronic diseases. This makes MPO an important molecular target linking immune defense and disease diagnosis and treatment, providing a new direction for early screening, disease monitoring and targeted therapy of clinical diseases.
First, the mechanism of immune defense:
When the body is invaded by pathogens such as bacteria and fungi, neutrophils are activated and undergo a "respiratory burst", activating NADPH oxidase, which converts oxygen molecules into superoxide radicals, which are further converted into hydrogen peroxide (H₂O₂) by superoxide dismutase.
At this time, MPO is released from azurophilic granules and catalyzes H₂O₂ to produce hypochlorous acid (HOCl) in the presence of chloride ions. As one of the strongest oxidants in the human body, HOCl has a bactericidal effect 50 times higher than that of hydrogen peroxide. It can efficiently destroy the cell membranes, proteins and nucleic acids of pathogens, thereby rapidly eliminating invading microorganisms and completing the innate immune defense function.
In addition, MPO can generate other reactive oxygen species (ROS), including superoxide anions and hydroxyl radicals, which further strengthen the bactericidal effect and participate in the degradation and clearance of pathogens by phagocytes.
Second, the main characteristics:
First, high specificity. MPO is the only enzyme in the human body that can generate hypochlorous acid at physiological chloride concentrations, and its catalytic reaction has high substrate specificity and environmental adaptability.
Second, significant dual effects. At physiological levels, MPO can efficiently exert immune defense functions, while when overexpressed or abnormally activated, the reactive oxidant species (ROS) it produces will cause damage to the host's own tissues and induce inflammatory responses.
Third, concentrated distribution. MPO is mainly enriched in neutrophils and accumulates in large quantities at inflammatory sites, making it a biomarker of inflammatory reactions.
Fourth, regulability. Its expression and activity are regulated by multiple transcription factors, and the MPO gene exhibits genetic polymorphisms. Some polymorphic loci can affect the transcription level and activity of MPO, and thus are associated with disease susceptibility.
3.1 MPO-μ-Calpain Signaling Pathway: This is the key pathway by which MPO induces vascular endothelial dysfunction. Studies have found that MPO can activate μ-calpain (but not the m-calpain isoform) in a time-dependent manner through denitrosylation of the C-terminal domain of μ-calpain. At the same time, by upregulating the expression of protein phosphatase 2A (PP2A), it reduces the phosphorylation levels of AMP-activated protein kinase (AMPK) at Thr¹⁷² and endothelial nitric oxide synthase (eNOS) at Ser¹¹⁷⁷, thereby increasing the expression of vascular cell adhesion molecule 1 (VCAM-1), promoting the adhesion of leukocytes to the aortic endothelium, and causing vascular inflammation and endothelial damage. This is also one of the important mechanisms by which MPO participates in the pathogenesis of cardiovascular diseases.
3.2 MPO-oxidized low-density lipoprotein (oxLDL) signaling pathway: In cardiovascular diseases such as atherosclerosis, MPO can catalyze the oxidation of low-density lipoprotein (LDL) to generate oxLDL. OxLDL cannot bind to native LDL receptors and can only be recognized and phagocytosed by scavenger receptors on endothelial cells and macrophages. Macrophages differentiate into foam cells after phagocytosing oxLDL, and a large accumulation of foam cells forms atherosclerotic plaques, accelerating disease progression. Meanwhile, oxLDL will further induce oxidative stress and inflammatory responses, forming a vicious cycle.
3.3 MPO-oxidative stress-apoptosis signaling pathway: The excessive reactive oxidation products produced by MPO (such as HOCl and hydroxyl radicals) will attack lipids, proteins and nucleic acids in cells, leading to protein denaturation and mitochondrial dysfunction, thereby inducing cell apoptosis. In neurodegenerative diseases, MPO can increase the toxicity and aggregation of β-amyloid (Aβ) through oxidative modification, accelerating neuronal apoptosis. In kidney diseases, MPO participates in renal tubulointerstitial fibrosis through this pathway and promotes the progression of renal function impairment. In addition, MPO can further regulate immune-inflammatory responses by modulating the migration, activation, phagocytosis and extracellular trap formation of neutrophils, and participate in the pathogenesis of autoimmune diseases.
4.1 Diagnosis and monitoring of autoimmune diseases: Anti-MPO antibodies are an important subtype of antineutrophil cytoplasmic antibodies (ANCA). Their detection can be used to assist in the diagnosis of autoimmune diseases such as microscopic polyangiitis, granulomatosis with polyangiitis and idiopathic necrotizing crescentic glomerulonephritis, as well as for disease monitoring and therapeutic efficacy evaluation. The serum levels of anti-MPO antibodies in patients with active disease are significantly elevated, and they decrease significantly after treatment-induced remission. At present, anti-MPO antibody detection is mainly performed using ELISA, which is convenient and low-cost, and has been widely used in clinical diagnosis and treatment in the Department of Rheumatology and Immunology.
4.2 Risk prediction and assessment of cardiovascular diseases: MPO is an important risk factor for cardiovascular diseases. Its plasma and serum levels can independently predict endothelial dysfunction of large arteries in cardiovascular patients. People with higher MPO levels have a 15 to 20 times higher probability of abnormal coronary angiography findings than the general population. In clinical practice, MPO detection can be used for early risk screening of diseases such as atherosclerosis, hypertension and myocardial infarction. At the same time, by monitoring changes in MPO levels, plaque stability and treatment prognosis can be evaluated. Persistently elevated MPO levels indicate an increased risk of disease progression, and MPO gene polymorphism detection can also be used to assess individual susceptibility to cardiovascular diseases, providing a basis for precise prevention.
4.3 Auxiliary diagnosis and research of other diseases: In neurodegenerative diseases (such as Alzheimer's disease), MPO levels are positively correlated with disease severity and can be used as an auxiliary monitoring indicator for disease progression. In pulmonary diseases (such as chronic obstructive pulmonary disease and COVID-19), MPO is highly expressed in alveolar macrophages, and its level changes are closely related to the degree of pulmonary inflammation, which can provide a reference for condition assessment. In the field of cancer, MPO has a dual role in the tumor microenvironment. Its expression level can be used for prognostic evaluation of some tumors and provides a new target for tumor immunotherapy. In chronic kidney disease, MPO participates in the process of renal tubulointerstitial fibrosis, and its level detection can assist in assessing the degree of renal function damage.
4.4 Research and application of targeted therapeutic drugs: Based on the core role of MPO in the pathogenesis of diseases, the research and development of drugs targeting MPO have become a hotspot in the field of biomedicine. At present, a variety of MPO inhibitors have entered the clinical research stage, which mainly reduce the production of reactive oxidation products by inhibiting the activity of MPO, thereby alleviating oxidative stress and inflammatory damage, and are suitable for the treatment of cardiovascular diseases, autoimmune diseases and other conditions. In addition, gene therapy and antibody-based drug research targeting MPO are also gradually advancing, which are expected to provide novel treatment options for related diseases and break the limitations of conventional treatments.
1. A Brief Introduction to MPO: The Core Enzymatic Shield of Innate Immunity
MPO is a heme-containing peroxidase belonging to the heme peroxidase-cyclooxygenase superfamily. It was first isolated and identified in 1941. It is encoded by a gene located on human chromosome 17q23 and has a molecular weight of approximately 150 kDa.As one of the most abundant proteins in human neutrophils, MPO accounts for about 5% of the dry weight of neutrophils. It is also present in small amounts in monocytes and some macrophages, mainly stored in the azurophilic granules of neutrophils, and is an indispensable effector molecule in the innate immune system.
Under physiological conditions, MPO acts as the "first line of defense" for the body against invading pathogens. Under pathological conditions, however, its abnormal expression and dysregulated activity trigger oxidative stress and inflammatory injury, and participate in the occurrence and progression of various chronic diseases. This makes MPO an important molecular target linking immune defense and disease diagnosis and treatment, providing a new direction for early screening, disease monitoring and targeted therapy of clinical diseases.
2. Mechanisms and Characteristics of MPO: Coexistence of Efficient Defense and Dual Effects
The main function of MPO relies on its powerful peroxidase activity. Its mode of action is highly specific and efficient, and at the same time presents dual biological characteristics of "defense and injury", which can be specifically divided into two core dimensions:First, the mechanism of immune defense:
When the body is invaded by pathogens such as bacteria and fungi, neutrophils are activated and undergo a "respiratory burst", activating NADPH oxidase, which converts oxygen molecules into superoxide radicals, which are further converted into hydrogen peroxide (H₂O₂) by superoxide dismutase.
At this time, MPO is released from azurophilic granules and catalyzes H₂O₂ to produce hypochlorous acid (HOCl) in the presence of chloride ions. As one of the strongest oxidants in the human body, HOCl has a bactericidal effect 50 times higher than that of hydrogen peroxide. It can efficiently destroy the cell membranes, proteins and nucleic acids of pathogens, thereby rapidly eliminating invading microorganisms and completing the innate immune defense function.
In addition, MPO can generate other reactive oxygen species (ROS), including superoxide anions and hydroxyl radicals, which further strengthen the bactericidal effect and participate in the degradation and clearance of pathogens by phagocytes.
Second, the main characteristics:
First, high specificity. MPO is the only enzyme in the human body that can generate hypochlorous acid at physiological chloride concentrations, and its catalytic reaction has high substrate specificity and environmental adaptability.
Second, significant dual effects. At physiological levels, MPO can efficiently exert immune defense functions, while when overexpressed or abnormally activated, the reactive oxidant species (ROS) it produces will cause damage to the host's own tissues and induce inflammatory responses.
Third, concentrated distribution. MPO is mainly enriched in neutrophils and accumulates in large quantities at inflammatory sites, making it a biomarker of inflammatory reactions.
Fourth, regulability. Its expression and activity are regulated by multiple transcription factors, and the MPO gene exhibits genetic polymorphisms. Some polymorphic loci can affect the transcription level and activity of MPO, and thus are associated with disease susceptibility.
3. Signaling Pathways and Mechanisms of MPO: A Molecular Bridge Linking Inflammation and Diseases
The biological effects of MPO are mainly achieved by regulating multiple signaling pathways, and its core mechanism revolves around "oxidative stress" and "inflammatory regulation". Among them, the research on signaling pathways related to cardiovascular diseases and autoimmune diseases is the most in-depth, which can be categorized into the following three core pathways:3.1 MPO-μ-Calpain Signaling Pathway: This is the key pathway by which MPO induces vascular endothelial dysfunction. Studies have found that MPO can activate μ-calpain (but not the m-calpain isoform) in a time-dependent manner through denitrosylation of the C-terminal domain of μ-calpain. At the same time, by upregulating the expression of protein phosphatase 2A (PP2A), it reduces the phosphorylation levels of AMP-activated protein kinase (AMPK) at Thr¹⁷² and endothelial nitric oxide synthase (eNOS) at Ser¹¹⁷⁷, thereby increasing the expression of vascular cell adhesion molecule 1 (VCAM-1), promoting the adhesion of leukocytes to the aortic endothelium, and causing vascular inflammation and endothelial damage. This is also one of the important mechanisms by which MPO participates in the pathogenesis of cardiovascular diseases.
3.2 MPO-oxidized low-density lipoprotein (oxLDL) signaling pathway: In cardiovascular diseases such as atherosclerosis, MPO can catalyze the oxidation of low-density lipoprotein (LDL) to generate oxLDL. OxLDL cannot bind to native LDL receptors and can only be recognized and phagocytosed by scavenger receptors on endothelial cells and macrophages. Macrophages differentiate into foam cells after phagocytosing oxLDL, and a large accumulation of foam cells forms atherosclerotic plaques, accelerating disease progression. Meanwhile, oxLDL will further induce oxidative stress and inflammatory responses, forming a vicious cycle.
3.3 MPO-oxidative stress-apoptosis signaling pathway: The excessive reactive oxidation products produced by MPO (such as HOCl and hydroxyl radicals) will attack lipids, proteins and nucleic acids in cells, leading to protein denaturation and mitochondrial dysfunction, thereby inducing cell apoptosis. In neurodegenerative diseases, MPO can increase the toxicity and aggregation of β-amyloid (Aβ) through oxidative modification, accelerating neuronal apoptosis. In kidney diseases, MPO participates in renal tubulointerstitial fibrosis through this pathway and promotes the progression of renal function impairment. In addition, MPO can further regulate immune-inflammatory responses by modulating the migration, activation, phagocytosis and extracellular trap formation of neutrophils, and participate in the pathogenesis of autoimmune diseases.
4. Clinical Applications of MPO: Full-Spectrum Coverage from Diagnostic Biomarkers to Therapeutic Targets
With the in-depth research on the mechanisms of action of MPO, its clinical applications have gradually expanded from traditional blood testing to multiple fields such as disease diagnosis, disease monitoring, prognosis evaluation and targeted therapy, establishing itself as a versatile tool in clinical diagnosis and treatment. Its core clinical applications are mainly divided into the following four aspects:4.1 Diagnosis and monitoring of autoimmune diseases: Anti-MPO antibodies are an important subtype of antineutrophil cytoplasmic antibodies (ANCA). Their detection can be used to assist in the diagnosis of autoimmune diseases such as microscopic polyangiitis, granulomatosis with polyangiitis and idiopathic necrotizing crescentic glomerulonephritis, as well as for disease monitoring and therapeutic efficacy evaluation. The serum levels of anti-MPO antibodies in patients with active disease are significantly elevated, and they decrease significantly after treatment-induced remission. At present, anti-MPO antibody detection is mainly performed using ELISA, which is convenient and low-cost, and has been widely used in clinical diagnosis and treatment in the Department of Rheumatology and Immunology.
4.2 Risk prediction and assessment of cardiovascular diseases: MPO is an important risk factor for cardiovascular diseases. Its plasma and serum levels can independently predict endothelial dysfunction of large arteries in cardiovascular patients. People with higher MPO levels have a 15 to 20 times higher probability of abnormal coronary angiography findings than the general population. In clinical practice, MPO detection can be used for early risk screening of diseases such as atherosclerosis, hypertension and myocardial infarction. At the same time, by monitoring changes in MPO levels, plaque stability and treatment prognosis can be evaluated. Persistently elevated MPO levels indicate an increased risk of disease progression, and MPO gene polymorphism detection can also be used to assess individual susceptibility to cardiovascular diseases, providing a basis for precise prevention.
4.3 Auxiliary diagnosis and research of other diseases: In neurodegenerative diseases (such as Alzheimer's disease), MPO levels are positively correlated with disease severity and can be used as an auxiliary monitoring indicator for disease progression. In pulmonary diseases (such as chronic obstructive pulmonary disease and COVID-19), MPO is highly expressed in alveolar macrophages, and its level changes are closely related to the degree of pulmonary inflammation, which can provide a reference for condition assessment. In the field of cancer, MPO has a dual role in the tumor microenvironment. Its expression level can be used for prognostic evaluation of some tumors and provides a new target for tumor immunotherapy. In chronic kidney disease, MPO participates in the process of renal tubulointerstitial fibrosis, and its level detection can assist in assessing the degree of renal function damage.
4.4 Research and application of targeted therapeutic drugs: Based on the core role of MPO in the pathogenesis of diseases, the research and development of drugs targeting MPO have become a hotspot in the field of biomedicine. At present, a variety of MPO inhibitors have entered the clinical research stage, which mainly reduce the production of reactive oxidation products by inhibiting the activity of MPO, thereby alleviating oxidative stress and inflammatory damage, and are suitable for the treatment of cardiovascular diseases, autoimmune diseases and other conditions. In addition, gene therapy and antibody-based drug research targeting MPO are also gradually advancing, which are expected to provide novel treatment options for related diseases and break the limitations of conventional treatments.
Conclusion: MPO Technology Empowers a New Future of Precision Medicine
From the "defense guardian" of innate immunity to the "molecular target" of disease diagnosis and treatment, the research and application of MPO have always revolved around human health needs. Its unique mode of action, clear signaling pathway mechanisms and extensive clinical application scenarios make it an important link connecting basic research and clinical diagnosis and treatment. With the continuous upgrading of detection technologies and ongoing breakthroughs in drug research and development, MPO will play a more important role in early screening, precise diagnosis and targeted therapy of diseases, safeguard human health and promote the field of biomedicine into a new stage of precision medicine. In the future, with further exploration of the molecular mechanisms of MPO, more innovative technologies and treatment solutions based on MPO will continue to emerge, bringing new hope for the treatment of various chronic diseases.In the defense network of the human innate immune system, Myeloperoxidase (MPO) always acts as an “invisible guardian” — it is not only the core force that eliminates pathogenic microorganisms, but also a pivotal hub connecting inflammatory responses and the onset and progression of multiple diseases. As life sciences and clinical detection technologies have become deeply integrated, the mystery of MPO has been gradually unraveled. Its application potential in immune regulation, disease pathogenesis and clinical care has continued to stand out, making it a prominent research focus and key area for technological breakthroughs in biomedicine.
1. A Brief Introduction to MPO: The Core Enzymatic Shield of Innate Immunity
MPO is a heme-containing peroxidase belonging to the heme peroxidase-cyclooxygenase superfamily. It was first isolated and identified in 1941. It is encoded by a gene located on human chromosome 17q23 and has a molecular weight of approximately 150 kDa.As one of the most abundant proteins in human neutrophils, MPO accounts for about 5% of the dry weight of neutrophils. It is also present in small amounts in monocytes and some macrophages, mainly stored in the azurophilic granules of neutrophils, and is an indispensable effector molecule in the innate immune system.
Under physiological conditions, MPO acts as the "first line of defense" for the body against invading pathogens. Under pathological conditions, however, its abnormal expression and dysregulated activity trigger oxidative stress and inflammatory injury, and participate in the occurrence and progression of various chronic diseases. This makes MPO an important molecular target linking immune defense and disease diagnosis and treatment, providing a new direction for early screening, disease monitoring and targeted therapy of clinical diseases.
2. Mechanisms and Characteristics of MPO: Coexistence of Efficient Defense and Dual Effects
The main function of MPO relies on its powerful peroxidase activity. Its mode of action is highly specific and efficient, and at the same time presents dual biological characteristics of "defense and injury", which can be specifically divided into two core dimensions:First, the mechanism of immune defense:
When the body is invaded by pathogens such as bacteria and fungi, neutrophils are activated and undergo a "respiratory burst", activating NADPH oxidase, which converts oxygen molecules into superoxide radicals, which are further converted into hydrogen peroxide (H₂O₂) by superoxide dismutase.
At this time, MPO is released from azurophilic granules and catalyzes H₂O₂ to produce hypochlorous acid (HOCl) in the presence of chloride ions. As one of the strongest oxidants in the human body, HOCl has a bactericidal effect 50 times higher than that of hydrogen peroxide. It can efficiently destroy the cell membranes, proteins and nucleic acids of pathogens, thereby rapidly eliminating invading microorganisms and completing the innate immune defense function.
In addition, MPO can generate other reactive oxygen species (ROS), including superoxide anions and hydroxyl radicals, which further strengthen the bactericidal effect and participate in the degradation and clearance of pathogens by phagocytes.
Second, the main characteristics:
First, high specificity. MPO is the only enzyme in the human body that can generate hypochlorous acid at physiological chloride concentrations, and its catalytic reaction has high substrate specificity and environmental adaptability.
Second, significant dual effects. At physiological levels, MPO can efficiently exert immune defense functions, while when overexpressed or abnormally activated, the reactive oxidant species (ROS) it produces will cause damage to the host's own tissues and induce inflammatory responses.
Third, concentrated distribution. MPO is mainly enriched in neutrophils and accumulates in large quantities at inflammatory sites, making it a biomarker of inflammatory reactions.
Fourth, regulability. Its expression and activity are regulated by multiple transcription factors, and the MPO gene exhibits genetic polymorphisms. Some polymorphic loci can affect the transcription level and activity of MPO, and thus are associated with disease susceptibility.
3. Signaling Pathways and Mechanisms of MPO: A Molecular Bridge Linking Inflammation and Diseases
The biological effects of MPO are mainly achieved by regulating multiple signaling pathways, and its core mechanism revolves around "oxidative stress" and "inflammatory regulation". Among them, the research on signaling pathways related to cardiovascular diseases and autoimmune diseases is the most in-depth, which can be categorized into the following three core pathways:3.1 MPO-μ-Calpain Signaling Pathway: This is the key pathway by which MPO induces vascular endothelial dysfunction. Studies have found that MPO can activate μ-calpain (but not the m-calpain isoform) in a time-dependent manner through denitrosylation of the C-terminal domain of μ-calpain. At the same time, by upregulating the expression of protein phosphatase 2A (PP2A), it reduces the phosphorylation levels of AMP-activated protein kinase (AMPK) at Thr¹⁷² and endothelial nitric oxide synthase (eNOS) at Ser¹¹⁷⁷, thereby increasing the expression of vascular cell adhesion molecule 1 (VCAM-1), promoting the adhesion of leukocytes to the aortic endothelium, and causing vascular inflammation and endothelial damage. This is also one of the important mechanisms by which MPO participates in the pathogenesis of cardiovascular diseases.
3.2 MPO-oxidized low-density lipoprotein (oxLDL) signaling pathway: In cardiovascular diseases such as atherosclerosis, MPO can catalyze the oxidation of low-density lipoprotein (LDL) to generate oxLDL. OxLDL cannot bind to native LDL receptors and can only be recognized and phagocytosed by scavenger receptors on endothelial cells and macrophages. Macrophages differentiate into foam cells after phagocytosing oxLDL, and a large accumulation of foam cells forms atherosclerotic plaques, accelerating disease progression. Meanwhile, oxLDL will further induce oxidative stress and inflammatory responses, forming a vicious cycle.
3.3 MPO-oxidative stress-apoptosis signaling pathway: The excessive reactive oxidation products produced by MPO (such as HOCl and hydroxyl radicals) will attack lipids, proteins and nucleic acids in cells, leading to protein denaturation and mitochondrial dysfunction, thereby inducing cell apoptosis. In neurodegenerative diseases, MPO can increase the toxicity and aggregation of β-amyloid (Aβ) through oxidative modification, accelerating neuronal apoptosis. In kidney diseases, MPO participates in renal tubulointerstitial fibrosis through this pathway and promotes the progression of renal function impairment. In addition, MPO can further regulate immune-inflammatory responses by modulating the migration, activation, phagocytosis and extracellular trap formation of neutrophils, and participate in the pathogenesis of autoimmune diseases.
4. Clinical Applications of MPO: Full-Spectrum Coverage from Diagnostic Biomarkers to Therapeutic Targets
With the in-depth research on the mechanisms of action of MPO, its clinical applications have gradually expanded from traditional blood testing to multiple fields such as disease diagnosis, disease monitoring, prognosis evaluation and targeted therapy, establishing itself as a versatile tool in clinical diagnosis and treatment. Its core clinical applications are mainly divided into the following four aspects:4.1 Diagnosis and monitoring of autoimmune diseases: Anti-MPO antibodies are an important subtype of antineutrophil cytoplasmic antibodies (ANCA). Their detection can be used to assist in the diagnosis of autoimmune diseases such as microscopic polyangiitis, granulomatosis with polyangiitis and idiopathic necrotizing crescentic glomerulonephritis, as well as for disease monitoring and therapeutic efficacy evaluation. The serum levels of anti-MPO antibodies in patients with active disease are significantly elevated, and they decrease significantly after treatment-induced remission. At present, anti-MPO antibody detection is mainly performed using ELISA, which is convenient and low-cost, and has been widely used in clinical diagnosis and treatment in the Department of Rheumatology and Immunology.
4.2 Risk prediction and assessment of cardiovascular diseases: MPO is an important risk factor for cardiovascular diseases. Its plasma and serum levels can independently predict endothelial dysfunction of large arteries in cardiovascular patients. People with higher MPO levels have a 15 to 20 times higher probability of abnormal coronary angiography findings than the general population. In clinical practice, MPO detection can be used for early risk screening of diseases such as atherosclerosis, hypertension and myocardial infarction. At the same time, by monitoring changes in MPO levels, plaque stability and treatment prognosis can be evaluated. Persistently elevated MPO levels indicate an increased risk of disease progression, and MPO gene polymorphism detection can also be used to assess individual susceptibility to cardiovascular diseases, providing a basis for precise prevention.
4.3 Auxiliary diagnosis and research of other diseases: In neurodegenerative diseases (such as Alzheimer's disease), MPO levels are positively correlated with disease severity and can be used as an auxiliary monitoring indicator for disease progression. In pulmonary diseases (such as chronic obstructive pulmonary disease and COVID-19), MPO is highly expressed in alveolar macrophages, and its level changes are closely related to the degree of pulmonary inflammation, which can provide a reference for condition assessment. In the field of cancer, MPO has a dual role in the tumor microenvironment. Its expression level can be used for prognostic evaluation of some tumors and provides a new target for tumor immunotherapy. In chronic kidney disease, MPO participates in the process of renal tubulointerstitial fibrosis, and its level detection can assist in assessing the degree of renal function damage.
4.4 Research and application of targeted therapeutic drugs: Based on the core role of MPO in the pathogenesis of diseases, the research and development of drugs targeting MPO have become a hotspot in the field of biomedicine. At present, a variety of MPO inhibitors have entered the clinical research stage, which mainly reduce the production of reactive oxidation products by inhibiting the activity of MPO, thereby alleviating oxidative stress and inflammatory damage, and are suitable for the treatment of cardiovascular diseases, autoimmune diseases and other conditions. In addition, gene therapy and antibody-based drug research targeting MPO are also gradually advancing, which are expected to provide novel treatment options for related diseases and break the limitations of conventional treatments.
