How microplastics harm multiple organs through cell damage and organ interactions

Plastics have become indispensable in modern industry and daily life due to their lightweight nature, corrosion resistance, and high mechanical stability. Since 1950, global plastic production has experienced exponential growth, reaching 348 million tons in 2017, with projections exceeding 3.3 billion tons by 2050 (14). However, effective end-of-life management of plastic products remains a critical global challenge. Despite service lifetimes spanning 1–50 years, current recycling systems capture merely 9% of plastic waste for energy recovery, with only 12% undergoing material recycling. Alarmingly, 8% contaminates terrestrial ecosystems while the majority (71%) is released uncontrolled into the environment, creating persistent pollution (15). It is estimated that the total amount of plastic released into the environment globally each year exceeds 1.5 million tons, with tire wear (28%), urban dust (24%), and textile washing (15%) being the main contributing sources (16). Environmental plastic pollution is predominantly composed of synthetic polymers such as polypropylene (PP), polyethylene (PE), polyethylene terephthalate (PET), polystyrene (PS), polyurethane (PUR), polyvinyl chloride (PVC), and polycarbonate (PC) (17). These polymeric materials undergo progressive environmental degradation through synergistic effects of ultraviolet radiation, chemical oxidation, and mechanical weathering, ultimately fragmenting into size-fractionated plastic debris categorized as: macroplastics (>25 mm), mesoplastics (5–25 mm), microplastics (0.1 μm-5 mm), and nano-plastics (<0.1 μm) (17). Current scientific consensus on microplastic size classification remains debated: Frias and Nash originally defined them as insoluble synthetic solid particles measuring 1–5 mm (18), while more inclusive classification schemes extend the upper size limit to 5 mm (19). In accordance with prevailing conventions, this review operationally defines MPs as plastic particulates with diameters < 5 mm, encompassing the full spectrum of sub-5 mm synthetic polymer fragments. Based on their origin, MPs are classified into two distinct categories: primary MPs and secondary MPs. Primary MPs are intentionally manufactured industrial precursors, including cosmetic microbeads, textile fibers, and raw resin pellets. Secondary MPs result from the progressive environmental degradation of larger plastic items such as packaging materials, fishing nets, and vehicle tires through weathering processes (18). Notably, secondary MPs form through synergistic environmental interactions (photochemical aging, biofilm colonization, hydrodynamic abrasion), which modify their surface properties, including an increased specific surface area and oxidative functionalization. These changes increase the adsorption capacity of toxic contaminants (heavy metals, persistent organic pollutants), ultimately posing substantial risks to ecosystem health through food chain amplification.

MPs are pollutants widely present in the environment, and their physicochemical properties directly affect their interactions with living organisms. The size, shape, and surface characteristics of MPs determine their biocompatibility and the complexity of their biological interactions. The size of MPs is a key factor in their biological penetration ability. Emerging evidence indicates that nano-plastics (<1 μm) exhibit enhanced cellular membrane penetration and biological barrier translocation due to their ultrafine dimensions, consequently inducing cellular damage and systemic responses (20). Furthermore, the shape of MPs greatly affects their biological interactions. Irregularly shaped MPs demonstrate greater mechanical cytotoxicity than spherical counterparts, likely attributable to edge-induced physical disruption during cellular contact (21). The surface characteristics of MPs, particularly their charge distribution and functional group composition, are critical determinants of their interactions with biological systems. Specifically, negatively charged MPs exhibit preferential binding affinity for cationic biomolecules through electrostatic interactions, which can subsequently affect cellular function and biological reactions (22). In addition, MPs can also serve as carriers of pollutants, and this increases their environmental and biological hazards. Research has found that MPs can effectively absorb persistent organic pollutants (POPs) and heavy metals, forming complexes that may lead to more severe toxic effects upon entering living organisms (20). Additives in MPs, such as plasticizers, may leach into the environment, resulting in synergistic toxicity effects that exacerbate harm to organisms. The surface of MPs may also form biofilms, which can promote the spread of pathogens and make MPs a potential vector for disease transmission, posing a threat to ecosystems and human health.

Initially, research predominantly focused on the ecological impacts of MPs. However, recent studies have detected MPs within human tissues and organs, suggesting potential health hazards to humans. Current research identifies dietary intake, water consumption, inhalation, and dermal contact as the primary pathways for human microplastic uptake (23). Specifically, orally ingested MPs traverse the digestive system, eventually reaching the intestines where they may be absorbed by intestinal epithelial cells. This absorption process is not only dependent on the microplastics’ particle size and chemical properties but is also highly contingent upon the host’s physiological state. Studies have demonstrated that fluorescently labeled polystyrene nanoparticles accumulated and aggregated within the digestive systems of mice, disseminating to multiple organs and profoundly impairing cellular function (2). Furthermore, MPs could potentially enter the systemic circulation via intestinal permeability, reaching major target organs such as the liver and inducing systemic biological effect (5). Additionally, MPs can be inhaled through the respiratory system. Ultrafine plastic particles present in the air may enter the lungs during breathing and deposit within lung tissue. Research has shown that such pulmonary deposition can not only cause mechanical obstruction but also trigger localized inflammatory responses and oxidative stress, thereby compromising pulmonary function and overall health (24). Recent studies reveal that nanoscale plastics (<0.1 μm) can penetrate biological barriers – such as the blood–brain barrier and placental barrier – inducing oxidative stress and mitochondrial dysfunction. For instance, experimental evidence demonstrates that polystyrene nanoparticles administered to mice traverse these barriers, accumulating in the brain and placenta where they trigger apoptosis and inflammatory responses (25). Current research has identified that MPs accumulate primarily in vital organs including the circulatory system, liver, kidneys, lungs, heart, and brain (1). Hepatic accumulation of MPs significantly contributes to impaired metabolic functions, while MPs induced renal damage can compromise electrolyte balance and detoxification capabilities. Furthermore, pulmonary deposition of MPs has been demonstrated to induce chronic inflammation and oxidative stress, thereby compromising respiratory health. Within the brain, accumulating MPs show potential links to the pathogenesis of neurodegenerative disorders. These organ-specific accumulation profiles underscore the necessity of investigating particulate distribution patterns and mechanisms of action when evaluating the health impacts of MPs.

MPs accumulate in and induce damage within the livers of fish, mammals, and cirrhotic patients (26, 27). The exposure of mice to 0.1 μm MPs (1 mg/L, 60 days) induces hepatocytic mtDNA lesions and hepatic fibrosis (28). Zou et al. (29) demonstrated that exposure to 5 μm and 0.5 μm MPs (10 mg/L, 3mouths) reduces the liver-to-body weight ratio in mice, concurrently disrupting hepatic architecture and inducing nuclear pyknosis and mitochondrial vacuolization. Similarly, exposure to 5 μm MPs (0.5 mg/100 μL) for four weeks significantly elevated serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in mice, while enhancing intrahepatic natural killer (NK) cell activity and macrophage infiltration (30). These collective findings demonstrate microplastic-induced hepatic injury.

Hepatic fibrosis represents the pathological endpoint of recurrent liver injury and repair processes. Studies demonstrate that small particle size MPs (0.1 μm) activate the hepatic cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) signaling pathway in mice, driving nuclear factor kappa B (NF-κB) nuclear translocation, upregulating pro-inflammatory cytokines [interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α)], and ultimately promoting fibrogenesis (28). Additionally, MPs induce macrophage extracellular trap macrophage extracellular trap (MET) formation, subsequently activating the reactive oxygen species (ROS)/transforming growth factor-β (TGF-β)/Mothers against decapentaplegic homolog 2/3 (Smad2/3) axis to drive inflammatory responses and hepatocyte epithelial-mesenchymal transition (EMT), thereby accelerating fibrosis progression (31). Three-dimensional liver organoid (LO) models reveal that microplastic exposure (1 μm, 25 μg/mL, 2.5 μg/mL and 0.25 μg/mL,48 h) downregulates fatty acid oxidation genes (carnitine palmitoyltransferase-1α, CPT-1α) while upregulating lipogenesis genes (acetyl-CoA carboxylase 1, ACC1), causing abnormal lipid accumulation and suggesting potential induction of hepatic steatosis and fibrosis (32). Furthermore, MPs instigate oxidative stress by suppressing sirtuin 3 (SIRT3) and superoxide dismutase 2 (SOD2) expression. This oxidative cascade disrupts mitochondrial membrane potential and suppresses respiratory chain activity, culminating in hepatocyte damage (33). These findings establish oxidative stress and mitochondrial dysfunction as key mechanisms of microplastic-induced hepatocyte injury. Critically, MPs exposure triggers hepatic Ca²⁺ overload, activating AMP-activated protein kinase-peroxisome proliferator-activated receptor gamma coactivator 1-alpha (AMPK-PGC-1α) signaling and enhancing glycolytic flux to induce hepatocyte apoptosis (34). Particle size dictates distinct cell death pathways: smaller MPs (1-10 μm, 10 mg/L, 30 days) induce necroptosis via the phosphatase and tensin homolog/phosphoinositide 3-kinase/protein kinase B (PTEN/PI3K/AKT)/autophagy axis, while larger MPs (50-100 μm, 10 mg/L, 30 days) promote apoptosis through the same pathway, with autophagy inhibition partially rescuing these phenotypes (35). Collectively, MPs drive hepatotoxicity through concerted pathways involving oxidative damage, metabolic disruption, and dysregulated cell death programs (Table 1).

MPs particles translocating through the gastrointestinal and respiratory tracts can cross the blood–brain barrier into the central nervous system, eliciting neurotoxic effects (36, 37). MPs (5 μm, 0.01, 0.1 and 1 mg/day for 4 weeks) exposure compromises learning and memory in mice, characterized by disorganized hippocampal neurons, reduced Nissl bodies, elevated ROS and malondialdehyde (MDA) levels, decreased glutathione and acetylcholine, and significant suppression of the cAMP response element-binding protein/brain-derived neurotrophic factor (CREB/BDNF) signaling pathway (38). Furthermore, MPs (100 nm) exposure induces neuronal apoptosis while downregulating synapse-associated protein markers (39). Exposure to MPs triggers reactive astrogliosis and significantly elevates the expression of lipocalin-2 (LCN2), a secreted neurotoxic protein, in activated astrocytes, thereby driving paracrine neuronal degeneration (40). Thus, MP-induced neurotoxicity may arise either from direct cellular stress in MP-internalizing neurons, or from the release of neurotoxin (e.g., LCN2) by adjacent reactive astrocytes. Furthermore, MPs exhibit strong iron-binding capacity. Co-exposure to MPs and iron induces cerebral iron overload and cognitive deficits in aged mice, significantly promoting ferroptosis—an iron-dependent cell death pathway driven by lipid peroxidation and neuroinflammation (9). This indicates that iron-microplastic synergism may exacerbate cognitive impairment by disrupting cerebral iron homeostasis and inducing ferroptosis in cognition-related brain regions. This synergy highlights a specific and potent mechanism through which MPs can amplify the toxicity of environmental pollutants.

Beyond acute neurotoxicity, MPs exposure may also exacerbate molecular hallmarks associated with neurodegenerative diseases. Reduced acetylcholinesterase (AChE) activity is a feature observed in pathologies neurodegenerative such as Alzheimer’s and Parkinson’s diseases (41). Similarly, MPs exposure has been shown to suppresses AChE activity across multiple species (3), suggesting a potential for MP to modulate cholinergic neurotransmission in a manner reminiscent of neurodegenerative pathogenesis. Consistent with this, Liang et al. demonstrated that MPs induce Parkinson’s disease-like neurodegeneration in mice, characterized by disrupted energy metabolism in the substantia nigra pars compacta (SNC) and striatum—evidenced by diminished adenosine triphosphate (ATP) levels and downregulation of ATP-associated genes/proteins (42), This indicates MPs may drive neurodegeneration via impaired.

The neurotoxic potential of MPs is further modulated by their physical properties and exposure routes, highlighting a critical dimension of risk assessment. Studies reveal enhanced cellular uptake of smaller MPs (80 nm) compared to their larger counterparts (100 or 200 nm) (37). Moreover, the exposure route significantly impacts outcomes; for instance, aerosol-inhaled MPs (80 nm for 7 days) cause greater locomotor deficits in mice than exposure via drinking water (37). These findings suggest inhaled MPs, particularly in the nanoscale range, may pose a heightened neurotoxic risks due to more efficient pulmonary translocation and systemic distribution.

Collectively, these findings demonstrate that MPs induce neurotoxicity through multifaceted mechanisms involving oxidative stress, suppression of neurotrophic signaling (e.g., CREB/BDNF), induction of specific cell death pathways (e.g., ferroptosis), and potential exacerbation of neurodegenerative phenotypes. They also act as vectors for other neurotoxicants like iron. Furthermore, their toxicity is influenced by particle size and exposure route. Despite the established neurotoxicity in experimental models, critical gaps persist regarding the precise mechanisms of MPs translocation to the brain, their capacity to breach the blood–brain barrier under chronic, low-dose scenarios, and their role in initiating or accelerating human neurodegenerative disorders (Table 2).

MPs accumulate in the respiratory system via inhalation, exhibiting significant size-dependent pulmonary toxicity. Clinical evidence confirms MPs in human upper and lower respiratory tracts—including alveoli, lung tissues, and sputum from patients with respiratory diseases—with inhaled MPs constituting the primary source of pulmonary deposition (43–45). Animal studies demonstrate that chronic exposure to both small (1–5 μm,20 μL, 3 weeks) and large (10-20 μm, 20 μL, 3 weeks) MPs induces severe lung injury, characterized by robust inflammatory responses, elevated cellular apoptosis, and pathological collagen deposition (46). Notably, smaller MPs provoke significantly more severe parenchymal damage (46). This indicates that the toxic effects of MPs are closely related to the exposed particle size. Small particle size MPs, due to their larger specific surface area and penetration ability, are more likely to trigger oxidative stress and inflammatory cascade reactions (46, 47).

MPs drive pulmonary injury through multi-pathway disruption of cellular homeostasis. Microplastics activate the NOD-like receptor protein 3 (NLRP3) /caspase-1/IL-1β and Toll-like receptor 3(TLR3) /NF-κB signaling axes, driving the release of pro-inflammatory factors (IL-6, TNF-α, IL-1β), leading to alveolar destruction, disordered arrangement of bronchial epithelium, and lung tissue damage (46, 48). In vitro evidence using murine alveolar epithelial cells (MLE-12) confirms MPs (100 nm, 5 mg/kg, three times/week for a week) exposure activates inflammasomes, elevating pyroptosis, ROS and pro-inflammatory mediators (TNF-α, IL-6, IL-1β), suggesting that MPs-induced lung injury by inflammasome activation, oxidative stress, and inflammation (48). Furthermore, MPs promote cellular senescence in human pulmonary epithelial cells and murine lungs via ROS-dependent pathways (24). Exposure to MPs induces pulmonary dysfunction in Sprague–Dawley (SD) rats, accompanied by infiltration of inflammatory cells and upregulation of aging related markers (p21, p16, p27), resulting in a decline in lung tissue repair function, suggesting that cellular aging may be a key phenotype of MPs induced lung injury (49). Emerging evidence suggests MPs may disrupt respiratory microbiome homeostasis and dysregulate non-coding RNAs (e.g., abnormal expression of 269 circular RNAs (circRNAs) and 109 long non-coding RNAs (lncRNAs)) during lung injury progression (50, 51). However, the epigenetic regulatory mechanisms underlying these effects require further elucidation. In summary, MPs compromise pulmonary integrity through interconnected pathways involving inflammatory activation, oxidative damage, and accelerated cellular senescence (Table 3).

As the central organ regulating hydroelectrolyte balance and metabolic waste excretion, the kidney represents a critical target for MPs toxicity. Studies confirm MPs accumulation in mammalian kidneys, where exposure (100 nm, 25 mg/kg/d for 6 weeks) disrupts serum biomarkers (urea nitrogen [BUN], creatinine [CRE]) and pro-inflammatory mediators, inducing renal injury in juvenile rats (52). MPs exposure compromises renal antioxidant defenses by suppressing superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) activities, while elevating MDA and ROS—thus disrupting redox homeostasis (52, 53). Oxidative stress activates the NF-κB/NLRP3 inflammasome axis, amplifying pro-inflammatory cytokines (interleukin-18 (IL-18), IL-1β) that drive renal inflammatory infiltration and tissue damage (54).

Moreover, MPs dysregulate autophagy via the ROS/AMPK/Unc-51-like autophagy activating kinase 1 (ULK1) pathway (55), while synergizing with endoplasmic reticulum (ER) stress to exacerbate mitochondrial dysfunction (e.g., elevated Bad protein, membrane potential depolarization) and autophagosome accumulation to induce renal damage (56, 57). Concurrently, MPs exposure promotes renal apoptosis, as evidenced by an increased proportion of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells and upregulation of apoptosis-related genes (B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), Caspase-3, Caspase-9, Caspase-12) (58). Chronic MPs exposure promotes ferritinophagy-dependent iron accumulation, suppresses glutathione metabolism, and elevates lipid peroxidation markers (4-hydroxynonenal (4-HNE), 8-hydroxy-2′-deoxyguanosine (8-OHdG)), which synergize with transforming growth factor-β (TGF-β) secretion to induce renal fibrosis (57, 59). Critically, MPs act as contaminant vectors, co-amplifying cadmium-induced oxidative damage through Parkin/autophagy-related 5 (Parkin/ATG5)-dependent mitophagy (57). In short, MPs-induced nephrotoxicity involves interconnected networks of oxidative stress, inflammation, cell death, and autophagic dysregulation. Future research must establish chronic exposure thresholds and elucidate co-contaminant synergism mechanisms (Table 4).

The intestinal toxicity of MPs is closely related to their size dependent absorption: particles >150 μm adhere to the intestinal mucus layer or directly interact with epithelial cells, triggering intestinal inflammation, whereas particles <150 μm penetrate the mucus barrier for subsequent intestinal absorption (60). Clinical evidence reveals significantly elevated fecal MPs loads in inflammatory bowel disease (IBD) patients compared to healthy individuals (up to 1.5-fold higher), with concentrations positively correlated with symptom severity including diarrhea and rectal bleeding (61). MPs enrichment was observed in both colon resection samples (62) and colitis model mice, accompanied by shortened colon length, increased permeability and inflammation, and reduced mucus secretion, suggesting that it may promote disease progression by exacerbating intestinal barrier damage (62, 63).

MPs induce intestinal toxicity through multiple pathways. Studies demonstrate that MPs exposure suppresses the expression of mucus secretion-related genes (Mucin 1(Muc1), Krüppel-like factor 4 (Klf4)) and ion transporters (cystic fibrosis transmembrane conductance regulator (CFTR), Na⁺-K⁺-2Cl⁻ cotransporter 1 (NKCC1), Na⁺/H⁺ exchanger 3 (NHE3)), thereby compromising the mucus barrier and inducing electrolyte imbalances (64, 65). In parallel, MPs exposure elevates (ROS) production. Excessive ROS further mediates intestinal epithelial cell apoptosis (66) and, by inhibiting methyltransferase-like 3 (METTL3) expression, reduces the mRNA stability of pro-angiogenic factors, impeding intestinal angiogenesis (67). Furthermore, as the gut microbiota serves as a pivotal mediator of metabolic and immune regulation, MPs disrupt intestinal homeostasis by altering microbial composition (e.g., causing an imbalance in the Firmicutes/Bacteroidetes ratio) and modulating microbial metabolite secretion (68, 69). Notably, exposure to high-dose (200 μg/g), large-size MPs (10–150 μm) for 5 weeks upregulates Toll-like receptor 4 (TLR4), activator protein 1(AP-1), and interferon regulatory factor 5 (IRF5) expression, driving immune cell infiltration in the colon and duodenum (70). Conversely, short-term (4 weeks) exposure to low-dose (≤ 34 mg/kg), small-size MPs (1–10 μm) did not elicit significant inflammatory responses in the duodenum or colon (71). This suggests that the toxicological effects of MPs are dynamically regulated by particle size, dose, and exposure duration. Moreover, pre-existing pathological conditions (e.g., susceptibility to colitis) may amplify injury risks. These contrasting findings highlight the imperative need to establish standardized exposure models and integrate multi-omics analyses (Table 5).

Clinical studies have detected nine MPs polymer types within pericardial, myocardial, and left atrial tissues of cardiac surgery patients, indicating MPs can breach multiple physiological barriers to invade enclosed organs (72). Notably, plastic medical instruments used during procedures may introduce exogenous MPs via the circulatory system, suggesting iatrogenic exposure as a distinct contamination source (72). Animal studies reveal that acute maternal inhalation of MPs (20 nm, 1% concentration, 300 μL) leads to cardiac deposition in both dams and offspring (73), whereas oral MP intake (50 mg/mL, 60 nm) showed no significant cardiac accumulation (74). This evidence implies: (i) Inhalation poses higher translocation risks than oral exposure, (ii) Cardiac accumulation exhibits dose-dependent thresholds, and (iii) Particle size governs tissue infiltration selectivity.

Troponin-I and creatine kinase-MB (CK-MB) serve as critical biomarkers of myocardial injury. Studies demonstrate that high-dose MPs (50 mg/L) significantly elevate serum CK-MB and troponin-I levels in rats, inducing cardiomyocyte apoptosis and abnormal collagen deposition (75), confirming MPs-induced cardiac damage. Similarly, when exposed to MPs, 3D cardiac organoids (COs) exhibit elevated oxidative stress, inflammatory responses, apoptosis, collagen accumulation, and myocardial hypertrophy (evidenced by upregulated myosin heavy chain 7B (MYH7B), atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and collagen type I alpha 1 chain (COL1A1) expression) (76). Mechanistically, MPs trigger pyroptosis in Wistar rat cardiomyocytes via the NLRP3/Caspase-1 signaling pathway and oxidative stress, thereby exacerbating cardiac injury (77). Furthermore, MPs provoke cardiac fibrosis through Wnt/β-catenin pathway activation and apoptosis driven by oxidative stress, culminating in cardiovascular toxicity (75). Neonatal rat cardiomyocytes exposed to MPs display reduced mitochondrial membrane potential (ΔΨm) and impaired glycolytic homeostasis, ultimately causing contractile dysfunction and electrophysiological abnormalities (78). Thus, MPs induce cardiac functional decline and electrophysiological disturbances by promoting oxidative stress, mitochondrial dysfunction, and fibrosis (Table 6).

The reproductive toxicity of MPs and NPs represents a critical nexus linking systemic multi-organ toxicity with population-level and long-term health risks. Given the extensive evidence that MPs/NPs affect multiple organs—including the gut, liver, immune system, and nervous system—the reproductive system is uniquely important because it serves as both a direct target of toxicity and a conduit for intergenerational transmission. This section therefore integrates evidence across scales, beginning with direct toxic effects on male and female reproductive organs, and extending to developmental and intergenerational outcomes in offspring. In particular, we contextualize nervous system and metabolic impairments in progeny as part of a broader multi-organ developmental toxicity framework, rather than isolated neurodevelopmental endpoints. By doing so, this section aims to clarify how parental exposure—predominantly via oral routes—can translate into systemic and heritable effects mediated by particle translocation, oxidative stress, endocrine disruption, and epigenetic reprogramming.

This section systematically reviews the direct adverse effects of MPs/NPs on the reproductive system and their transgenerational consequences. We first detail toxicity and underlying mechanisms in male and female reproductive systems, focusing on gametogenesis, steroidogenesis, and gonadal integrity. Given the prevalence of maternal exposure, its potential intergenerational health effects are of particular significance. Therefore, we further discuss how parental exposure influences offspring development across multiple organ systems, including the nervous, metabolic, hepatic, and reproductive systems, thereby extending the scope of MPs toxicity from an individual lifespan to a transgenerational scale.

Although microplastics-induced toxicity manifests in an organ-specific manner, converging evidence indicates that several shared cellular and molecular mechanisms underlie these diverse pathological outcomes. Across multiple organ systems, oxidative stress emerges as a central initiating event, characterized by excessive ROS generation, mitochondrial dysfunction, and impaired antioxidant defenses. This oxidative imbalance subsequently activates inflammatory signaling pathways, particularly NF-κB and NLRP3 inflammasome signaling, resulting in sustained cytokine release and chronic tissue inflammation.

In parallel, microplastics disrupt intracellular homeostasis by dysregulating programmed cell death pathways, including apoptosis, autophagy, pyroptosis, and ferroptosis, depending on particle size, exposure route, and tissue context. Emerging evidence further highlights endocrine disruption, metabolic reprogramming, and epigenetic alterations as critical contributors to both systemic and transgenerational toxicity. Importantly, these mechanisms do not operate in isolation but are amplified through inter-organ communication axes such as the gut–liver–brain axis, ultimately driving systemic toxicity. As illustrated in the Figure 1, oxidative stress, mitochondrial dysfunction, inflammatory activation, and dysregulated cell death represent convergent mechanisms across multiple organs.

The preceding sections have described the organ-specific injuries induced by MPs in the gut, liver, brain, lung, and other tissues. However, these toxic effects do not occur in isolation. Instead, accumulating evidence indicates that MP-induced toxicity frequently manifests through coordinated multi-organ communication, in which localized tissue injury is amplified and transmitted via defined physiological axes. Recognizing these cross-organ interactions is therefore essential for understanding how MP exposure leads to systemic pathologies that extend well beyond single-organ dysfunction.

Among these axes, the gut–liver axis represents a primary conduit through which intestinal injury propagates systemic toxicity. As discussed earlier, MPs disrupt intestinal barrier integrity and induce microbial dysbiosis. These local intestinal alterations are accompanied by activation of the Wnt/β-catenin pathway, resulting in increased epithelial permeability and enhanced translocation of lipopolysaccharide (LPS) and microbial metabolites (e.g., secondary bile acids) into the portal circulation. The subsequent delivery of these signals to the liver triggers hepatic inflammation and oxidative stress (5, 6). In parallel, MPs disturb the bile acid-short-chain fatty acid metabolism axis, leading to suppression of farnesoid X receptor (FXR) signaling and thereby promoting hepatic lipid accumulation and insulin resistance (106, 107). Consistent with these findings, further studies demonstrate that MPs activate hepatic Kupffer cells via the TLR2/NF-κB/NLRP3 signaling pathway, stimulating the release of proinflammatory cytokines, including IL-1β and TNF-α, which further exacerbate liver injury (64). Notably, airborne particulate MPs may also induce hepatotoxicity by disrupting the "airway microbiota-lung-liver” axis (108), suggesting that hepatic injury can arise from both intestinal and pulmonary sources of MP exposure.

Importantly, the gut–liver axis does not operate in isolation but can further extend its influence to the central nervous system. Integrating the neurological and hepatic effects described in previous sections, recent evidence supports the existence of a gut–liver–brain axis through which MPs-induced intestinal and hepatic dysfunction converge to impact brain function. Specifically, circulating microbial and metabolic intermediates, including tryptophan-derived metabolites, have been implicated in mediating MP-triggered neurobehavioral abnormalities (6). Preclinical studies demonstrate that activation of this axis induces anxiety-like behaviors in experimental animals while simultaneously aggravating hepatic metabolic dysregulation (6), highlighting a shared mechanistic basis underlying liver–brain comorbidity following MP exposure.

In parallel, direct gut–brain communication represents another critical pathway linking intestinal injury to neurotoxicity. MPs exposure significantly reduces colonic mucin secretion in mice, leading to compromised gut barrier function and a pronounced reduction in gut microbiota α-diversity, characterized by the abnormal proliferation of opportunistic pathogens such as Mesorhizobium and Lwoffii. Concurrently, MPs upregulate interleukin-17C (IL-17C) expression in intestinal epithelium. This cytokine is capable of penetrating the blood–brain barrier, where it promotes parenchymal inflammation, neuronal damage, and significant impairments in social behavior (109, 110). In addition, NPs induce lysosomal damage in intestinal macrophages, triggering aberrant interleukin-1 (IL-1) secretion that activates microglia and drives T helper 17 (Th17) cell differentiation, ultimately compromising cognitive function and short-term memory (60). MPs have also been shown to activate the macrophage very late antigen 4-vascular cell adhesion molecule 1 (VLA4-VCAM1) signaling axis while concurrently altering intestinal bile acid and carbohydrate metabolic profiles. Together, these effects impair intestinal motility, reduce water absorption, and induce depressive-like phenotypes in experimental models (111). Additional neurotoxic mechanisms associated with gut–brain axis dysfunction include MP-induced disruption of hippocampal circadian rhythms and altered neurotransmitter metabolism (112, 113).

Collectively, the studies summarized above demonstrate that the adverse health effects of MPs are not simply the cumulative outcome of isolated organ injuries. Rather, they emerge from dynamic, networked interactions along defined physiological axes, such as the gut–liver and gut–liver–brain axes. Within this axis-centered framework, MPs initiate localized damage—often in barrier or metabolically active organs such as the gut and lung—which is subsequently propagated to distant organs through circulating immune mediators, microbial metabolites, and neural signaling pathways. This integrative perspective provides a mechanistic bridge between organ-specific toxicity and systemic pathology and underscores the potential risk of environmental MPs exposure to liver and nervous system function in social mammals, including humans (Table 8).

A growing body of preclinical evidence has demonstrated that microplastics can accumulate in multiple organs—including the liver, nervous system, lungs, kidneys, intestines, heart, and reproductive system—and induce multi-organ toxicity, indicating their broad organ targeting potential. Commonly used exposure routes primarily include the respiratory system (e.g., inhalation, intratracheal instillation, and intranasal administration) and the digestive system (e.g., drinking water and oral ingestion). Respiratory exposure tends to cause localized lung injury, whereas digestive exposure may facilitate the transport of microplastics to distant organs via systemic circulation, leading to toxic effects in the liver, nervous system, kidneys, intestines, heart, and reproductive system. However, current research still exhibits several important limitations. First, most studies lack specific and quantitative methods for detecting microplastics within organs; conventional techniques likely underestimate their actual accumulation levels. Therefore, there is an urgent need to develop ultrasensitive, cost-effective, and efficient detection technologies suitable for complex biological matrices to advance the field. Second, substantial variations in exposure doses, durations, and particle sizes across studies have led to low comparability and even inconsistent conclusions. For instance, one study showed that high-dose (200 μg/g), larger-sized (10–150 μm) microplastic exposure for five weeks significantly upregulates the expression of TLR4, activator protein 1(AP-1), and interferon regulatory factor 5 (IRF5), and induces immune cell infiltration in the colon and duodenum (70). In contrast, another study found that short-term (4 weeks) exposure to low-dose (≤34 mg/kg), smaller-sized (1–10 μm) microplastics did not elicit significant inflammatory responses in the same intestinal segments (71). Such heterogeneity underscores the urgency of standardizing experimental parameters. Moreover, many toxicological studies employ high doses of microplastics to accelerate the manifestation of toxicity, but these exposure levels often far exceed realistic environmental concentrations, thereby limiting the physiological and ecological relevance of the findings. Future research should focus more on low-dose exposures that reflect actual environmental pollution levels and further explore the combined effects of microplastics with varying properties to more accurately assess their risks to human health and ecosystems.