The complement system plays a critical role in modulating immune responses and tissue homeostasis in peripheral organs which influences various physiological processes, including metabolism, inflammation, and tissue repair. Peripheral organs, such as the liver, adipose tissue, gastrointestinal tract, and kidney express complement components and receptors allowing for local complement activation and modulation of organ function [19]. Complement activation products, such as C3a and C5a, serve as an important mediator of inflammation and tissue injury in peripheral organs contributing to the pathogenesis of various diseases [20]. In the cardiovascular system, complement activation can contribute to the pathogenesis of cardiovascular diseases such as myocardial infarction, atherosclerosis, and heart failure. Complement activation products such as C3a and C5a can promote endothelial dysfunction, leukocyte recruitment, and vascular inflammation thereby exacerbating cardiovascular pathology [21].

Moreover, dysregulation of the complement system has been implicated in the pathogenesis of metabolic disorders including obesity, diabetes, and non-alcoholic fatty liver disease (NAFLD). Complement components and regulators are dysregulated in these conditions, leading to chronic low-grade inflammation, insulin resistance, and tissue damage [22]. Additionally, complement activation has been implicated in the pathogenesis of gastrointestinal disorders, such as inflammatory bowel disease (IBD) and celiac disease, where it contributes to mucosal inflammation and tissue damage [23].

Similarly, in the lungs, complement system components are involved in the regulation of pulmonary inflammation and injury. Dysregulation of the complement system has been implicated in the pathogenesis of inflammatory lung diseases such as acute respiratory distress syndrome (ARDS) and chronic obstructive pulmonary disease (COPD). Complement activation products, particularly C5a, can mediate pulmonary inflammation, neutrophil recruitment, and tissue damage in these conditions [24].

Beyond the peripheral organs, the complement system, plays a multifaceted role in CNS, influencing various physiological processes and contributing to both homeostasis and pathology. Complement proteins such as C1q, C3, and C4 are abundantly expressed in the CNS and are involved in synaptic refinement during development and synaptic plasticity in adulthood [25]. However, dysregulated complement activation in the CNS can lead to excessive neuroinflammation and neuronal damage, contributing to the pathogenesis of neurological disorders [26]. The CP has been implicated in synaptic pruning and neuroinflammation in the CNS [27]. The LP contributes to immune surveillance and inflammation in the CNS, particularly in response to microbial infections [28]. The AP amplifies complement activation and contributes to neuroinflammation and tissue damage in CNS disorders [29]. Excessive complement activation and the generation of complement fragments, including C3a, C4a, and C5a, can contribute to neuroinflammation, synaptic dysfunction, and neuronal damage in AD and PD [30]. Complement activation products, including C3a and C5a, exert neurotoxic effects and promote microglial activation and cytokine release. Moreover, the deposition of complement proteins, such as C3d and C5b-9, has been observed in the brains of patients with neurodegenerative diseases [25].

The complement system interacts with neuroimmune cells to modulate immune responses, synaptic pruning, and neuronal function in the CNS. Neuroimmune cells, including microglia, astrocytes, and neurons, play essential roles in maintaining CNS homeostasis and responding to pathological insults (Figure 1). Microglia, the resident immune cells of the CNS, express complement receptors (CRs) and actively participate in complement-mediated immune responses. Complement activation products, such as C3a and C5a, can modulate microglial activation and migration contributing to neuroinflammation and synaptic remodeling [31]. Dysregulated complement signaling in microglia has been implicated in the pathogenesis of neurodegenerative diseases, including AD and PD [29]. Astrocytes, the most abundant glial cells in the CNS, also express CRs and can respond to complement activation products. Complement-mediated signaling in astrocytes regulates their activation, cytokine secretion, and neuroprotective functions [32]. Dysregulated complement signaling in astrocytes has been implicated in various CNS disorders, including multiple sclerosis (MS) and ALS [33]. Neurons, traditionally viewed as non-immune cells also express complement components and receptors and can respond to complement activation [34]. Complement-mediated signaling in neurons influences synaptic pruning, neuronal survival, and synaptic plasticity [30]. Dysregulated complement signaling in neurons has been linked to synaptic dysfunction and neuronal loss in neurodegenerative diseases [25]. The interactions between complement system pathways and neuroimmune cells are complex and bidirectional. Neuroimmune cells can regulate complement activation through the expression of complement regulators and inhibitors, such as CD46, CD55, and CD59 [35]. Conversely, complement activation in neuroimmune cells can modulate their functions and influence CNS homeostasis and pathology.

Understanding the intricate relationship between the complement system, aging, and aging-related diseases is crucial for elucidating the underlying mechanisms of age-related pathologies and identifying potential therapeutic interventions. Aging is a multifaceted biological process characterized by a progressive decline in physiological functions and increased susceptibility to various age-related diseases [36]. As individuals age, they experience alterations in immune function, including dysregulation of the complement system [37, 38]. Age-related changes in the complement system include alterations in complement component expression, activation patterns, and regulation, which can lead to chronic low-grade inflammation, tissue damage, and increased vulnerability to infections [38]. The dysregulation of the complement system in aging has been implicated in the pathogenesis of several aging-related diseases, including cardiovascular diseases, neurodegenerative disorders, and age-related macular degeneration (AMD) [38, 39]. Inflammation, oxidative stress, and complement dysregulation contribute to the development and progression of these age-related diseases [40, 41].

Brain aging is a multifaceted process characterized by structural and functional changes in the CNS, often leading to cognitive decline and increased susceptibility to neurodegenerative diseases. The complement system, a crucial component of innate immunity, has recently emerged as a key player in the pathogenesis of age-related neuroinflammation and neurodegeneration. In the aging brain, dysregulation of complement system components has been implicated in the pathogenesis of neurodegenerative diseases such as AD and PD. Complement proteins such as C1q, C3, and C4 are abundantly expressed in the CNS and play crucial roles in synaptic refinement, neurogenesis, and neuroinflammatory responses [26]. However, aberrant complement activation and the generation of complement fragments, including C3a, C4a, and C5a, can contribute to neuroinflammation, synaptic dysfunction, and neuronal damage in aging and neurodegenerative diseases [31]. The dysregulation of complement system components in brain aging can trigger neuroinflammatory responses through various mechanisms. Complement activation products such as C3a and C5a can promote microglial activation, induce the release of pro-inflammatory cytokines, and exacerbate synaptic loss and neuronal damage [31]. Additionally, complement-mediated neuro-inflammation can lead to the recruitment of peripheral immune cells, further amplifying the inflammatory cascade, and contribute to neurodegeneration [25].

The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway and the complement system are two critical components of the innate immune response that play key roles in regulating immune responses and inflammation. Recent research has revealed intricate interactions between NF-κB signaling and the complement system, influencing immune regulation and disease pathogenesis. NF-κB is a transcription factor that regulates the expression of genes involved in inflammation, immunity, cell survival, and proliferation. In response to various stimuli, such as pro-inflammatory cytokines, pathogens, and cellular stress, NF-κB is activated and translocates to the nucleus, where it induces the expression of target genes [42]. Dysregulated NF-κB signaling has been implicated in the pathogenesis of inflammatory and autoimmune diseases, as well as cancer [43]. The complement system can activate NF-κB signaling through multiple pathways. Complement activation products, such as C5a and C3a, can stimulate NF-κB activation directly by binding to their respective receptors on immune cells [44]. Additionally, complement components, including C3 and C4, can induce NF-κB activation through the engagement of pattern recognition receptors (PRRs) and the formation of signaling complexes [45]. This crosstalk between the complement system and NF-κB signaling amplifies immune responses and promotes inflammation. Additionally, NF-κB can regulate the expression of complement regulatory proteins, such as CD46 and CD55, in order to finely control complement activation and prevent excessive tissue damage [46]. The interaction between NF-κB signaling and the complement system has significant implications for immune modulation and the development of various diseases. The dysregulation of NF-κB signaling and complement activation has been implicated in the pathogenesis of numerous diseases, including IBD, RA, and systemic lupus erythematosus (SLE) [42, 44]. The aberrant activation of NF-κB and the complement system can perpetuate chronic inflammation and contribute to tissue damage and organ dysfunction in these diseases.

Modulating NF-κB signaling and complement activation presents potential therapeutic strategies for immune-related diseases. Inhibitors of NF-κB signaling, such as small molecule inhibitors and biologics targeting NF-κB components, have been developed and tested in preclinical and clinical studies for various inflammatory conditions [43]. Similarly, targeting complement components or receptors has shown efficacy in preclinical models and clinical trials of inflammatory and autoimmune diseases [47]. Combined therapies that target both NF-κB signaling and the complement system may offer synergistic effects and improve therapeutic outcomes in immune-related disorders.

MicroRNAs (miRNAs) are small, non-coding RNA, molecules that play a pivotal role in post-transcriptional gene regulation. They fine-tune gene expression by binding to the 3’ untranslated region (UTR) of target mRNAs, leading to mRNA degradation or translational repression. Recent research has discovered the intricate interactions between miRNAs and the complement system, a crucial component of the innate immune system. Several miRNAs have been identified as regulators of complement components, receptors, and regulators. miR-223 has been implicated in modulating the expression of the complement component C3, influencing the activation of the complement cascade [48]. Additionally, miR-146a has been shown to target complement factor H (CFH), a critical regulator of the alternative complement pathway [49]. These findings emphasized the role of miRNAs in finely tuning the expression of complement-related genes to maintain immune homeostasis. The crosstalk between miRNAs and the complement system holds significant implications in immune modulation. Dysregulation of miRNA-mediated complement regulation may contribute to chronic inflammation, autoimmunity, and other immune-related disorders.

In the CNS, where complement dysregulation is implicated in neuroinflammatory disorders, the interplay with miRNAs is of particular interest. miRNAs have been shown to modulate the expression of complement factors in microglia, astrocytes, and neurons, influencing neuroinflammation and synaptic plasticity [50]. Understanding the complex connections between miRNAs and the complement system in the CNS may offer new avenues for therapeutic interventions in neurodegenerative diseases. The dysregulation of miRNA-complement interactions has been implicated in various diseases. In SLE, aberrant miRNA expression profiles have been linked to complement activation and immune dysregulation [51]. Similarly, in AMD, alterations in miRNA-mediated complement regulations are associated with disease progression [52]. Harnessing the regulatory potential of miRNAs in the complement system opens avenues for therapeutic intervention. miRNA-based therapeutics, such as miRNA mimics or inhibitors, could be designed to modulate complement activity in a targeted manner, providing precision in immune modulation.

Genetic variations in complement genes have been linked to neurodegenerative disorders, as mutations in the CFH gene are associated with an increased risk of AMD and AD [53]. Chronic inflammation plays a significant role in dysregulation of the complement system in neurodegenerative disorders. In conditions like AD, chronic neuroinflammation perpetuates complement activation, exacerbating neuronal damage [25]. Oxidative stress-induced activation of the complement system contributes to neuroinflammation and neurodegeneration. Studies have shown that oxidative stress markers are elevated in neurodegenerative disorders such as PD and AD, correlating with complement dysregulation [54, 55]. Dysfunctional microglia can aberrantly activate the complement system, leading to synaptic loss and neuronal injury. Recent research highlighted the role of microglial complement signaling in neuroinflammation and neuro-degeneration, implicating it in diseases like AD and PD [56, 57]. Impairment of the blood-brain barrier (BBB) allows peripheral immune cells and complement proteins to infiltrate into the CNS, exacerbating neuroinflammation. Studies have demonstrated BBB dysfunction in neurodegenerative disorders such as AD and MS, contributing to complement dysregulation [58, 59]. Environmental factors like air pollution and heavy metal exposure can trigger neuroinflammation and complement activation, contributing to neurodegenerative diseases. Recent studies have highlighted the impact of environmental toxins on complement dysregulation in disorders such as PD and ALS [60, 61]. Metabolic dysregulation, including obesity and insulin resistance, can promote complement activation and neuroinflammation. Studies have shown a link between metabolic syndrome and increased risk of neurodegenerative disorders, partly mediated by complement dysregulation [62, 63]. Emerging evidence suggested a bidirectional communication between the gut microbiota and the brain, influencing neuroinflammation and complement activation. Dysbiosis of gut microbiota has been implicated in neurodegenerative disorders, potentially affecting complement regulation [64, 65]. Epigenetic changes can modulate complement gene expression and contribute to neuroinflammation in neurodegenerative diseases. Studies have identified epigenetic alterations in complement-related genes in AD and PD, highlighting their role in disease pathogenesis [66, 67].

CRs, including CR1 (CD35), CR2 (CD21), and CR3 (CD11b/CD18), are integral to immune cell function and antigen presentation. Dysregulated CR signaling has been implicated in autoimmune diseases such as SLE and RA [68]. Activation of CRs can initiate inflammatory responses, perpetuating tissue damage in autoimmune pathologies. Targeting CRs presents a promising avenue for therapeutic development [69].

Various regulatory proteins play a crucial role in maintaining a delicate equilibrium between complement activation and regulation. Among these proteins, CD55 (decay-accelerating factor) and CD59 (protectin) act as inhibitors of MAC formation, effectively protecting host cells from complement-mediated lysis [70]. However, deficiencies in these regulatory proteins, as seen in conditions like atypical hemolytic uremic syndrome (aHUS) and paroxysmal nocturnal hemoglobinuria (PNH), increase the susceptibility of individuals to complement-mediated disorders [71]. Therefore, exploring strategies to enhance the function of regulatory proteins holds promising therapeutic potential in mitigating complement-driven pathology.

Genetic polymorphisms in complement components and regulatory proteins influence disease susceptibility and phenotype manifestation. Genome-wide association studies (GWAS) have identified variants in genes encoding CFH and CR3 associated with autoimmune disorders [72]. Unraveling the genetic architecture of complement dysregulation aids in personalized risk assessment and therapeutic targeting in affected individuals.

Advancements in deciphering the molecular intricacies of complement system-related pathophysiology offer promising avenues for therapeutic intervention. Understanding the crosstalk between complement and inflammatory pathways, the role of CRs, the regulation of complement activation by regulatory proteins, and genetic determinants of disease susceptibility provide a comprehensive framework for targeted therapeutic strategies. Harnessing this knowledge may pave the way for precision medicine approaches in managing complement-mediated disorders.

AD is the most common cause of dementia, characterized by progressive cognitive decline and memory impairment. The pathological hallmarks of AD include the accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs), synaptic dysfunction, and neuronal loss. While the exact etiology of AD remains elusive, growing evidence suggests the role of neuroinflammation in disease progression. The complement system, a crucial component of innate immunity, has emerged as a key regulator in AD pathogenesis, contributing to neuroinflammation and neurodegeneration [75]. The complement system comprises a complex network of proteins involved in immune surveillance, host defense, and tissue homeostasis. In the context of AD, dysregulated complement activation leads to the increased deposition of complement proteins and activation products in the brain parenchyma and around Aβ plaques. Studies have shown elevated levels of complement components, including C1q, C3, and C4, in post-mortem AD patient’s brains [77]. Complement activation products, such as C3b and C5b-9, are also detected in AD brain tissues, suggesting ongoing complement-mediated inflammation [78]. Synaptic dysfunction is an early pathological feature of AD, preceding neuronal loss and cognitive decline. The complement system plays a critical role in synaptic pruning and elimination during development and synaptic plasticity in the adult brain [79]. However, dysregulated complement activation in AD leads to excessive synaptic loss and dysfunction. Complement proteins, including C1q and C3, localize to synapses in AD patient’s brains and mediate synapse elimination through microglial phagocytosis [80]. Targeting complement activation has emerged as a potential therapeutic strategy for AD [76]. Preclinical studies using complement inhibitors or genetic deletion of complement components have demonstrated neuroprotective effects in AD mouse models [81]. A recent study showed that genetic deletion of C3 or treatment with complement inhibitors reduces Aβ deposition, neuroinflammation, and synaptic loss in transgenic AD mice [82].

PD is the second most common neurodegenerative disorder, characterized by motor symptoms such as bradykinesia, rigidity, and tremor as well as non-motor symptoms including cognitive impairment and autonomic dysfunction. The complement system, a crucial part of innate immunity, has emerged as a key player in PD pathogenesis, contributing to neuroinflammation and neurodegeneration. Dysregulated complement activation occurs in PD, leading to increased deposition of complement proteins and their activation products in the brain parenchyma and around Lewy bodies [83]. Studies have shown elevated levels of complement components, including C1q, C3, and C5b-9 in post-mortem PD patient’s brains [54]. Complement activation products, such as C3b and C5b-9 are also detected in PD brain tissues, suggesting ongoing complement-mediated inflammation [54]. Activated complement proteins contribute to neuroinflammation in PD through various mechanisms. Complement activation promotes microglial activation and recruitment of peripheral immune cells, leading to the release of pro-inflammatory cytokines and chemokines, such as interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), and IL-6 [84]. Additionally, complement-mediated synaptic dysfunction and neuronal damage exacerbate neuro-inflammatory responses, further contributing to disease progression [13].

Targeting the astrocyte-neuron C3/C3ar (C3a receptor) pathway could be a promising therapeutic strategy for PD [85]. Preclinical studies using complement inhibitors or genetic deletion of complement components have demonstrated neuroprotective effects in PD animal models [86–88]. For instance, genetic deletion of C3 or treatment with complement inhibitors reduces neuroinflammation, synaptic loss, and motor deficits in PD mice [89]. Translating complement-targeted therapies to clinical applications holds promise for slowing disease progression and preserving motor function in PD patients.

Huntington’s disease (HD) is a progressive neurodegenerative disorder characterized by motor dysfunction, cognitive impairment, and psychiatric symptoms. Emerging evidence suggests that dysregulated complement system activation contributes to the pathogenesis of HD [90]. Complement proteins and their activation products are found in HD patients’ brain tissues, where they promote neuroinflammation, synaptic dysfunction, and neuronal damage [90]. Histopathological studies have revealed the presence of complement proteins and activation products in the brains of HD patients [91]. Complement components such as C1q, C3, and C5b-9 are detected in HD brain tissues, where they colocalize with areas of neuronal loss and gliosis [92]. Complement activation products, including C3b and C5b-9, contribute to neuroinflammatory responses and exacerbate neuronal damage in HD. Activated complement proteins promote neuroinflammation in HD by activating microglia and astrocytes, leading to the release of pro-inflammatory cytokines and chemokines [90]. Complement-mediated inflammation further exacerbates neuronal damage and synaptic dysfunction, contributing to disease progression [90]. Additionally, dysregulated complement activation disrupts the BBB, allowing peripheral immune cells to infiltrate the CNS and exacerbate neuroinflammatory responses [91]. Targeting complement system has emerged as a potential therapeutic strategy for HD [29, 93]. Preclinical studies using complement inhibitors or genetic deletion of complement components have demonstrated neuroprotective effects in HD animal models, showing that genetic deletion of C3 or treatment with complement inhibitors reduces neuroinflammation, synaptic dysfunction, and motor deficits in HD mice [94].

Autoimmune encephalitis (AE) is a group of disorders characterized by inflammation of the brain mediated by autoantibodies against neuronal surfaces or synaptic proteins. Emerging evidence suggests that dysregulated complement system activation contributes to the pathogenesis of AE [95]. Histopathological studies have revealed the presence of complement proteins and activation products in AE brain tissues [96]. Complement components such as C1q, C3, and C5b-9 are detected in AE brain lesions, particularly in areas of neuroinflammation and neuronal injury [97]. Complement activation products, including C3b and C5b-9, contribute to neuroinflammatory responses and exacerbate neuronal damage in AE. Synaptic dysfunction is a prominent feature of AE, associated with cognitive deficits and psychiatric symptoms [75, 98]. Dysregulated complement activation contributes to synaptic dysfunction by promoting the elimination of synapses through microglial phagocytosis. Complement-mediated synaptic pruning disrupts neural circuits and impairs neuronal communication, further exacerbating cognitive impairments in AE [99]. Targeting complement activation has emerged as a potential therapeutic strategy for AE [100]. Preclinical studies using complement inhibitors or genetic deletion of complement components have demonstrated neuroprotective effects in AE animal models [101]. Treatment with complement inhibitors reduces neuroinflammation, synaptic dysfunction, and behavioral abnormalities in AE-like rodents [102].

MS is an autoimmune disorder characterized by demyelination, neuroinflammation, and axonal damage in the CNS. Emerging evidence implicates dysregulated complement system activation in the pathogenesis of MS [103]. Complement proteins and activation products are found in MS lesions and cerebrospinal fluid, contributing to myelin destruction and oligodendrocyte injury [104–107]. Recent research has implicated dysregulated complement system activation in the pathogenesis of MS, suggesting a key role for innate immunity in driving disease progression [108]. Evidence from histopathological studies demonstrated the presence of complement proteins and activation products in MS lesions, particularly in active demye-linating lesions [109, 110]. Complement components such as C1q, C3, and C5b-9 are detected in MS plaques, where they colocalize with areas of myelin destruction and axonal injury [111]. The deposition of complement proteins in MS lesions contributes to the recruitment of immune cells, activation of microglia and astrocytes, and promotion of pro-inflammatory cytokine production, exacerbating neuroinflammation and tissue damage [112, 113]. Oligodendrocytes, the myelin-producing cells of the CNS, are targets of complement-mediated injury in MS [114]. Complement activation products, such as C3b and C5b-9, directly damage oligodendrocytes and disrupt myelin integrity [115]. Additionally, complement-mediated inflammation leads to the recruitment of immune cells, including macrophages and microglia, which further contribute to oligodendrocyte death and demyelination [116]. Dysregulated complement activation in MS contributes to BBB dysfunction, facilitating the entry of immune cells and inflammatory mediators into the CNS [117]. Complement components, particularly C5a and C5b-9, disrupt tight junction proteins and endothelial cell integrity, leading to increased BBB permeability and leukocyte infiltration into the CNS [118]. Given the central role of complement dysregulation in MS pathogenesis, targeting complement components or inhibiting complement activation has emerged as a promising therapeutic strategy for disease intervention [119]. Several complement inhibitors and modulators are currently under investigation in preclinical and clinical studies for their efficacy in attenuating neuroinflammation, preserving myelin integrity, and slowing disease progression in MS patients [70].

CIDP is an autoimmune disorder characterized by chronic inflammation and progressive demyelination of peripheral nerves, leading to motor and sensory dysfunction [120]. Despite extensive research, the underlying mechanisms driving CIDP pathogenesis remain elusive. However, growing evidence suggests a role for the complement system in mediating immune-mediated nerve damage in CIDP [121].

The complement system, a crucial component of the innate immune response, has been implicated in driving inflammation and tissue injury in CIDP [122]. Dysregulated complement activation leads to the generation of complement components and activation products, which contribute to immune cell recruitment, demyelination and axonal damage in peripheral nerves [123]. Genetic studies have identified associations between complement gene polymorphisms and susceptibility to CIDP, highlighting the genetic predisposition to complement dysregulation in CIDP [124].

Complement dysregulation contributes to the diverse clinical manifestations of CIDP, including weakness, sensory deficits, and gait disturbances [124]. Deposition of complement components and complement activation products at sites of nerve injury exacerbates inflammation and amplifies tissue damage in CIDP patients [75, 125]. Moreover, complement-mediated mechanisms may underlie treatment-resistant forms of CIDP, suggesting a potential role for complement-targeted therapies in disease management [126].

The complement system interacts with other immune mediators implicated in CIDP pathogenesis, including autoantibodies and pro-inflammatory cytokines [127]. Dysregulated complement activation may amplify autoimmune responses and promote tissue inflammation, contributing to nerve damage and clinical symptoms in CIDP [124].

Targeting the complement system represents a promising therapeutic strategy for CIDP management [126]. Several complement inhibitors, including monoclonal antibodies and small molecule inhibitors, are under investigation as potential treatments for CIDP [122]. These novel therapies aim to attenuate complement-mediated nerve damage and inflammation, offering potential benefits for CIDP patients refractory to conventional immunosuppressive agents.

Complement-targeted therapies have emerged as promising treatment modalities for neurodegenerative and neuroimmune disorders, offering targeted approaches to modulate dysregulated immune responses and preserve neuronal integrity. However, the clinical translation of complement-targeted therapies faces several challenges, including issues related to drug specificity, treatment efficacy, safety profiles, and translational barriers. Understanding the limitations of current complement-targeted therapies is crucial for overcoming these challenges and improving treatment outcomes in neurologic disorders.

Lack of target specificity: Many current complement-targeted therapies lack specificity for the desired complement component or pathway, leading to off-target effects and potential adverse events [136].

Future research should focus on developing more specific and efficacious complement inhibitors, optimizing treatment regimens, and identifying novel drug delivery strategies to enhance BBB penetration. Furthermore, the discovery of reliable biomarkers for patient stratification and treatment response monitoring will facilitate the personalized implementation of complement-targeted therapies in neurologic disorders.

Recent progress in the field of neurodegenerative and neuroimmune disorders has led to a growing interest in the potential therapeutic benefits of plant-derived bioactives. These natural compounds have shown promise as complement-targeted therapies, with their molecular interactions with the complement system being a key focus of research [130, 139, 144]. In particular, their effectiveness in preclinical models of neurodegenerative diseases like AD, PD, and MS has been highlighted [132]. The plant-derived bioactives that are enriched with a variety of phytochemicals have been found to possess complement-modulating properties, making them attractive candidates for the development of novel therapies for neurological conditions [75].

Numerous plant-derived bioactives have been identified for their ability to modulate complement activation and regulation (Table 1). Flavonoids such as quercetin, kaempferol rosmarinic acid, and apigenin exhibit potent inhibitory effects on the complement cascade by targeting key components of the CP and AP [145]. Targeting complement-mediated neuroinflammation and neuronal damage through plant-derived bioactives offers promising avenues for disease modification and symptom management in affected patients. Furthermore, standardization of herbal extracts, quality control measures, and regulatory considerations pose additional challenges to their clinical development and commercialization as complement-targeted therapies.

This section provided an in-depth review of the mechanisms of action by which plant-derived compounds modulate the complement system. We discussed how these compounds influence complement activation, regulation, and effector functions through diverse molecular pathways. Furthermore, we highlighted recent advancements in understanding the therapeutic implications of plant-derived compounds in complement-related disorders, offering insights into the development of novel therapeutic strategies.

Inhibition of complement activation pathways: Many plant-derived compounds inhibit the activation of complement pathways, including the CP, LP, and AP [173]. Recent studies showed that kaempferol, quercetin, rosmarinic acid, and piperlactam can directly inhibit complementary pathways thereby preventing the activation of downstream complement components [142, 147, 156].

Overall, plant-derived compounds exert their effects on the complement system through multifaceted mechanisms, offering potential therapeutic benefits for neurodegenerative and neuroimmune disorders (Figure 2). Further elucidation of these mechanisms will facilitate the development of novel complement-targeted therapies from natural sources.

Understanding the mechanisms of action of plant-derived compounds on the complement system has important therapeutic implications for various diseases, including autoimmune disorders, inflammatory conditions, and neurodegenerative diseases. By targeting complement-mediated inflammation, tissue damage, and immune dysregulation, these compounds offer potential benefits for disease management and symptom relief.