Liver morphological changes are a common pathological feature of acute and chronic liver injury, as well as numerous liver diseases. For instance, a typical pathological characteristic of acute hepatitis is hepatic congestion. This refers to a disruption in liver circulation and the development of local blood stasis (68,69). Toxicity and immune-induced liver injury can increase the water content of hepatocytes, resulting in a loose cytoplasm and cellular oedema (70). Hepatic steatosis is the pathological phenomenon of lipid droplet accumulation in hepatocytes during hepatic hypoxia, ischemia or infection (71). Research has found that, similar to the consequences of numerous liver injuries, exposure to MPs can also lead to pathological liver changes, including congestion, oedema, lipid droplet formation, steatosis, necrosis and fibrosis (72-75). Furthermore, it can also lead to the expansion and tearing of the wall of the central hepatic vein and accumulation of connective tissue fibers in the hepatic sinusoids (76).

In addition to altering liver tissue morphology, MPs also cause structural changes to hepatocytes. For instance, exposure of fish liver to MPs can cause hepatocyte swelling, irregular nuclear shape and cytoplasmic vacuolization (77). These liver lesions can significantly impair the normal function of hepatocytes. Mammalian liver exposure to MPs causes hepatocyte structural disorganization and necrosis (29,36). In summary, MP exposure compromises hepatic system homeostasis through dual impairment of functional dynamics and cytoarchitectural organization. The manifestation of morphological changes in liver tissue and cells suggests that MPs may have additional effects on the liver.

Oxidative stress is the generation of highly reactive molecules due to external stimuli, disrupting the balance between the oxidative and antioxidant systems (78,79), and constitutes a significant physiological and pathological basis in various liver diseases. In addition, it is the primary manifestation of acute liver injury (80). The key hepatic effect of MPs is triggering the oxidative stress response, and this has been demonstrated consistently in recent studies. Research has shown that short-term exposure to MPs can induce oxidative stress reactions in the liver of freshwater fish, as shown by an increase in the activities of glutathione peroxidase (GPx), catalase (CAT) and malondialdehyde (MDA) levels (81,82). GSH and CAT are important components of the hepatic antioxidant defense matrix and MDA is a key biomarker reflecting the completion of the lipid peroxidation cascade in the mammalian hepatic system (83,84). The aforementioned hepatic effects of MPs indicate that they induce oxidative stress. Of note, several studies have investigated the regulatory effect of MPs on the levels and activity of CAT. Samal et al (85) conducted an experiment with cows and discovered that MPs can bind to bovine liver CAT and alter its conformation, leading to a reduction in its activity. Banaei et al (82) found that the expression of metallothionein 1 (Mt1), carboxylesterase 2 (Ces2) and cytochrome P450 (P450) genes increased in carp hepatocytes when exposed to polyethylene (PE) MPs, while the expression of the Mt2 gene showed a significant decrease. Alterations in the expression of oxidative stress-related detoxification genes in hepatocytes of fish provide additional evidence that MPs can induce oxidative stress responses in animal livers (Fig. 3).

The inflammatory response is a pathological process in which the body defends itself against various external injuries and stimuli (86). This process is characterized by pathological changes, including local tissue proliferation, exudation and deterioration (87). Upon inflammatory stimulation of the liver, the monocyte/macrophage system is activated, resulting in the release of a large number of inflammatory molecules and cytokines (including IFN-γ, TNF-α, IL-6 and IL-1β) (88,89). Thus, increased expression of these cytokines in the liver can be used as an indicator of hepatic inflammation. The pro-inflammatory properties of MPs in the liver have been widely investigated. A growing number of studies have shown elevated expression levels of inflammatory molecules and pro-inflammatory cytokines, including TNF-α, inducible nitric oxide synthase, cyclooxygenase 2, IL-1β and IL-6, in MP-exposed livers, indicating the presence of inflammation in the liver (26,64,65).

The liver is the most robust reticuloendothelial cell phagocytic system observed in mammals and has a powerful immune function. Macrophages are a crucial element of the hepatic phagocytic system, as well as an essential conduit for the innate immunological capabilities of the liver (90-92). MPs have been shown to damage macrophages, which in turn affect liver immune function (90). The mechanisms underlying the effect of MPs on hepatic immune cells have not yet been elucidated. However, researchers have conducted in-depth research on this issue.

Research has found that MPs have an impact on hepatic immune function, particularly innate immune function. For instance, rainbow trout exhibited impaired innate immune function following exposure to PE-MPs, evidenced by an increase in hepatic mucus cells and a decrease in white blood cells (66). It has been established that intravenous injection of polystyrene (PS)-NPs mediates transcriptional repression of key innate immunity effectors in minnow liver, including macrophage stimulation 1, neutrophil cytoplasmic factor 2, NADPH oxidase 2 and complement component 3 (93,94). Liu et al (64) demonstrated that 10 and 20% polyvinyl chloride-MPs (PVC-MPs; a common material of MPs) induced downregulation of IFNγ and TNFα genes, which regulate the function of immune cells, and upregulation of IL-1β and IL-6 genes, which promote innate immunity. In addition, they observed an increase in the activity of the non-specific immune factor, lysozyme in the liver of the common carp, indicating that PVC-MPs also affected hepatic immune regulation (64). Furthermore, PS-NPs have been demonstrated to specifically induce the biosynthesis pathway of steroid hormones, resulting in the production of related metabolites. Steroid hormones are potent endocrine regulatory hormones, impacting the activity of immune cells. Therefore, MPs may affect liver immune cell activity by promoting the synthesis of steroid hormones (95). In conclusion, research has identified that MPs of various materials can influence the immune function of the liver, with a particular impact on innate immune function. However, at present, the majority of studies regarding the effects of MPs on liver immune function have concentrated on freshwater fish and there are few studies on the effects of MPs on mammalian liver immune function, highlighting the need for further research in this area.

By regulating gene expression and signal transduction, lipids can affect various life processes in organisms, including immune processes, as well as provide energy for survival (96). The liver plays a pivotal role in maintaining lipid homeostasis, is the primary site for cholesterol synthesis and transport, and is the most important organ for lipid metabolism (96). Research has found that exposure to NPs increases the mRNA transcription of several genes involved in the breakdown and oxidation of fatty acids in the liver of eels. These include acyl CoA oxidase 1, carnitine palmitoyltransferase 1a (CPT1A), angiopoietin-like 4 and phosphoenolpyruvate carboxyl kinase (PCK). This indicates that lipid metabolism disorders may be occurring in the liver (97,98).

One study suggested that the adverse effects of MPs disrupting gut microbiota can potentially be transmitted to the liver via the gut-liver axis, which refers to the material flow and functional effects between the two organs; this could be a contributing factor in liver lipid metabolism disorder associated with MPs (99). Further research has revealed that modulating PPAR represents a pivotal mechanism by which MPs induce hepatic lipid metabolic disorders. PPARs are ligand-activated receptors of the nuclear hormone receptor family, which have three subtypes, including α, β and γ. Among them, PPARα is abundantly present in the liver and plays an important regulatory role in liver lipid metabolism processes (100). To date, multiple studies have demonstrated that liver exposure to MPs (particularly PS particles and PVC particles) can significantly activate PPARα and its multiple downstream target genes, thus affecting the expression of various proteins related to hepatocyte lipid metabolism (101,102). By acting on PPAR and altering the expression of hepatocyte lipid metabolism-related proteins, MPs can ultimately trigger the disruption of hepatocyte lipid metabolism (Fig. 3).

In conclusion, MPs are able to disrupt lipid metabolism in the liver through specific mechanisms. Of note, mice administered with MPs showed a dose-dependent increase in the levels of total free fatty acids (FFAs), which are mainly derived from the hydrolysis of neutral fats (a type of lipid prevalent in mammals) and are a key metabolic currency of the lipid cycle in hepatocytes. Of note, the composition of FFAs remained stable, with the mono- and polyunsaturated fatty acid subpopulations balanced across exposure groups (103). By contrast, there is a notable increase in saturated fatty acids (SFAs). It has been postulated that high levels of SFA may be a contributing factor in the disruption of endoplasmic reticulum homeostasis in hepatocytes (30). It can be observed that the disturbance of hepatic lipid metabolism resulting from exposure to MPs may facilitate the generation of additional liver-related effects by MPs.

It has been demonstrated that PS-MPs can induce an acute toxic response in human hepatocytes in vitro through multiple pathways. For instance, acute and subacute exposure of MPs in vitro activates the mitochondria-dependent apoptotic pathway in HepG2 cells, resulting in the elevation of caspase-9 activity and a significant increase in the ratio of the pro-apoptotic protein Bax to the anti-apoptotic protein Bcl-2, suggesting that apoptotic processes are induced (104). Of note, PS-NP exposure was found to significantly inhibit the expression of tumor-related genes such as polo-like kinase 1 (PLK1) and mitotic checkpoint serine/threonine kinase (BUB) 1 (105). The PLK1 and BUB1 enzymes are involved in the regulation of human hepatocyte apoptosis as well as liver tumorigenesis and progression. These findings suggest that exposure to MPs may affect liver tumor formation and development, while inducing apoptosis in human hepatocytes (Fig. 4).

Acute and subacute exposure to MPs in vitro can also damage hepatocyte organelles. For instance, JC-1 fluorescent probe assay results showed that the intracellular mitochondrial membrane potential (MMP) was decreased when hepatocytes were exposed to 25 µg/ml PS-MPs (105). Reduced MMP impairs the ability of mitochondria to produce ATP, leading to impaired mitochondrial energy production (106). It was also found that mitochondrial ATP levels in hepatocellular carcinoma cells were further reduced with increasing concentrations of PS-NP exposure (101). In conclusion, MPs can affect the energy supply of hepatocyte mitochondria and antioxidants can attenuate this effect. MPs also affect lysosomes, another important organelle within hepatocytes, that degrade cellular metabolites and waste products. Hepatocyte stability and function depend on the efficient operation of lysosomes (107). It has been shown that MPs can interact with hydrolases and other enzymes in lysosomes, and act to reduce lysosomal viability and further inhibit lysosomal phagocytosis (108). A noteworthy study found a correlation between exposure to MPs and enhanced lysosomal perinuclear localization, which was consistent with the effect of inhibiting mammalian target of rapamycin 1 (mTORC1) enzyme activity (109). mTORC1 responds to metabolic regulatory signals both inside and outside of the cell and is primarily recruited to the surface of the lysosome where it functions (110). Given the role of the mTORC1 pathway in regulating hepatic inflammation and interfering with hepatic lipid metabolism within hepatocytes, the effects of MPs on lysosomal function may result in increased inflammatory responses and disruption of lipid metabolism, reminiscent of inhibition of the mTORC1 pathway.

Although animal model studies have systematically revealed the hepatotoxicity of MPs in vivo and in vitro, human toxicological data are still highly dependent on in vitro cellular models. Although in vitro experiments can elucidate the molecular mechanisms, they cannot mimic the complex metabolic clearance, tissue barrier and systemic compensatory mechanisms that occur in the human body. Variability in key regulatory pathways (such as nuclear receptor signaling) between species may influence the severity of the toxic response (101,109). These research gaps make it challenging to translate current findings for public health decision-making. On the one hand, quantitative associations between in vitro markers of toxicity (such as mitochondrial damage and elevated inflammatory factors) and actual health damage in humans are still not established. On the other hand, population exposure heterogeneity (e.g., differences in age and metabolic status) may significantly alter toxicity risk thresholds.

Unlike acute/subacute exposures, chronic exposure to MPs can cause multidimensional toxic effects on the liver, which dynamically evolve with differences in exposure duration. At exposure durations of 40-60 days, the effects of MPs on the liver were more consistent with acute/subacute exposures. At this exposure duration, MPs were able to significantly increase hepatic cholesterol and triglyceride levels and promote hepatic steatosis by upregulating the expression of fatty acid uptake genes [such as CD36 and fatty acid-binding protein 1 (FABP1)] and synthesis genes [such as acetyl-coenzyme A carboxylase α and peroxisome proliferator-activated receptor γ (PPARγ)] (111). In addition, MP exposure at this duration induced cellular release of pro-inflammatory factors (such as TNF and IL-6), as well as hepatic stellate cell activation, exacerbating liver inflammation and fibrosis (112). When the duration of exposure was 60-90 days, the primary effect of MPs on the liver included the induction of fibrosis and metabolic disorders. At this exposure, MPs promoted hepatic stellate cell activation and collagen deposition through mitochondrial DNA leakage, activating the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/ STING) pathway and driving NF-κB nuclear translocation, ultimately exacerbating liver fibrosis (113). After 90 days of exposure, hepatocyte AMP-activated protein kinase (AMPK) phosphorylation was inhibited and gluconeogenic gene (such as glucose-6-phosphatase catalytic subunit and phosphoenolpyruvate carboxykinase) expression was enhanced. Meanwhile, the expression of the hepatocyte lipid synthesis gene FABP4 was upregulated, demonstrating that 90 days of MP exposure caused a dual disorder of hepatic glucose-lipid metabolism (114).

The hepatic mechanism of action of MPs becomes more complex under ultra-long-term exposure (120-180 days). At an exposure duration of 180 days, MPs activated cellular autophagosome formation via ERK/mTOR signaling, while inhibiting lysosomal function, leading to the disruption of cellular autophagy and lipid droplet accumulation (115). Xia et al (78) conducted a study in which they exposed carp larvae to PVC for 30 and 60 days on a chronic diet. They observed that after 30 days, with an increase in the PVC concentration, the activity of GPx changed from an increasing trend to a decreasing trend. After 30 days of exposure to high concentrations of MPs, the transcription of antioxidant-related genes cytochrome P450 1A and glutathione s-transferase (GST) α in carp liver also changed from increasing to decreasing (78). Therefore, providing animals with a purification period after long-term exposure to MPs may alleviate hepatic oxidative stress. Furthermore, Solomando et al (86) demonstrated that following 90 days of exposure to low-density PE-MPs, a 30-day purification period in herring was sufficient to facilitate the gradual return of elevated oxidative stress biomarkers (including MDA and GSH) to normal levels. This suggests that chronic exposure to MPs can reverse the stress state of fish livers during acute/subacute MP exposure. Furthermore, it indicates that a recovery period after prolonged exposure can have a restorative effect on the oxidative stress caused by MPs.

MPs have the capacity to trigger the onset and progression of MAFLD by exacerbating lipid accumulation, promoting inflammatory responses and inducing oxidative stress. One study revealed that MPs induce activation of the PPARγ pathway, leading to the upregulation of the expression of key lipid synthesizing genes, including sterol regulatory element-binding protein 1c and fatty acid synthase (FASN). In addition, MPs inhibit the activity of enzymes, such as carnitine palmitoyltransferase 1A, involved in fatty acid β-oxidation (116). These observations suggest that the accumulation of lipids within hepatocytes is augmented by the actions of MPs. MPs also indirectly exacerbate hepatic lipid deposition by inducing intestinal flora dysbiosis (117), and stimulate the release of pro-inflammatory factors such as TNF-α and IL-6 from hepatocytes through the engagement of the NF-κB signaling pathway, thus promoting hepatic inflammatory responses (118). Furthermore, acute exposure to MPs induced a significant increase in hepatocyte ROS levels, which markedly promoted hepatic lipid peroxidation and aggravated hepatic steatosis (119).

The interaction between MPs and liver fibrosis is a noteworthy recent finding. MPs were shown to promote hepatic fibrosis in both direct and indirect ways. Firstly, MPs activate hepatic stellate cells through the TGF-β/Smad and Wnt/β-catenin pathways and upregulate fibrosis markers such as α-smooth muscle actin and collagen 1a1 (120). In addition, it was found that MPs induce mitochondrial DNA leakage, and the leaked mitochondrial DNA activated the cGAS/STING pathway, which increased fibronectin deposition in hepatocytes and indirectly contributed to the process of liver fibrosis (121).

The interaction between MPs and liver disease further illustrates the evolution of MP pollution from an environmental concern to a global health threat. Therefore, it is imperative that further research is conducted to establish whether MPs have a potential hepatotoxic effect in order to address the pressing threats to liver health in this era of plastic pollution.

A significant body of evidence indicates that exposure to MPs may be hazardous to human health. Current methodological limitations in monitoring the bioaccumulation of human MPs, coupled with the lack of translatable in vivo exposure models, fundamentally restrict mechanistic characterization of the pathogenic cascade and prevent quantitative characterization of the dose-response relationship, which is essential for evidence-based risk assessment. The establishment of specific biomarkers for human exposure to MPs is necessary to address the real-world barriers to human toxicity studies of MPs. With specific biomarkers, the level of exposure to MPs in the livers of an individual or group can be precisely quantified, providing an objective basis for risk assessment. Without reliable biomarkers, it is challenging to establish a causal relationship between MP liver exposure dose and disease. In conclusion, the establishment of biomarkers for the exposure of humans to MPs will be key in revealing health risks and guiding public health interventions.

According to the results of animal experiments, the biomarkers of MPs are mainly associated with key mechanisms such as oxidative stress, as well as lysosomal and immune damage. Oxidative stress is the key mechanism by which MPs elicit adverse liver effects, with superoxide dismutase (SOD), CAT, GPx and glutathione S-transferase (GST) being the antioxidant enzymes most affected by MP exposure. Alterations in the activity of these enzymes can directly reflect the capacity of the liver to scavenge ROS, and they are significant biomarkers of MP-induced hepatic oxidative stress (122). The lipid peroxidation product MDA is a key indicator for assessing the extent of oxidative damage to hepatocyte membranes caused by MPs and can be quantified by the thiobarbituric acid reaction (123). The labeling of lysosomal and immune damage is centered on lysosomal membrane stability, whilst blood cell parameters such as total hematocrit and alterations in the granulocyte ratio serve as biomarkers of the hepatic immunosuppressive effects of MPs (124). Together, these markers reconfirm the role of MPs in interfering with hepatic oxidative homeostasis, disrupting hepatic organelle function and inhibiting hepatic detoxification capacity.

Existing studies have shown that specific MP polymers (such as polyurethane and polyester) detected in human sputum can be used as potential exposure markers and their concentrations are significantly correlated with smoking (125). However, human exposure testing samples are mainly sputum or feces, limiting the establishment of direct biomarkers. In addition, MPs often coexist with contaminants, such as plasticizers. This can lead to compound exposure interferences, making it difficult to distinguish between single effects (126). Future population cohort studies incorporating nanoscale detection technologies are required to validate the accuracy of these biomarkers. In conclusion, the establishment of biomarkers for human MPs requires expanding the range of human samples, breaking through technical bottlenecks and enhancing the integration of data from multiple exposure pathways.

MAPK can be activated by different extracellular signaling molecules and plays an important role in transmitting cell surface signals into the nucleus. It can regulate various pathological and physiological processes, such as cell growth, differentiation, the stress response and inflammatory response (127), and the MAPK signaling pathway is implicated in the pathogenesis of hepatocellular carcinoma, fibrosis and hepatic injury (128-130). The main branching pathways of the MAPK pathway include JNK, ERK, ERK5 and p38 MAPK (121). Research has revealed that high concentrations of NPs can activate MAPK kinase 6 (MAP2K6) (131). Phosphorylation of MAP2K6 can lead to p38 MAPK signaling in response to inflammatory cytokine stimulation or environmental stress. In addition, NPs activate MAP2K6 to initiate the phosphorylation cascade MAP2K6-p38 MAPK-mitogen- and stress-activated protein kinase 1/2-cAMP response element-binding protein (a cascade reaction of the p38/MAPK signaling pathway in the cell). This cascade affects the transcription of anti-apoptotic genes in hepatocytes and triggers liver inflammation. In addition to activating the p38 MAPK branch pathway in the MAPK signaling pathway, NP treatment can also induce activation of the ERK branch pathway by promoting excessive ROS in hepatocytes and ultimately promoting lipid accumulation in hepatocytes (Fig. 5) (132,133). In summary, MPs can induce hepatocyte apoptosis, disrupt hepatocyte lipid homeostasis and lead to liver inflammation by activating the MAPK signaling pathway, initiating phosphorylation and multiple cascade reactions.

The Nrf2-Keap1-ARE signaling pathway is a central defense mechanism against oxidative stress and exerts protective effects in the liver. This system comprises three core components: The transcription factor Nrf2, the sensor protein Keap1 and the ARE. By coordinately regulating downstream genes, this pathway controls the expression of key enzymes that counteract oxidative and toxic damage. Specifically, it enhances antioxidant capacity through rate-limiting enzymes in GSH synthesis (glutamate-cysteine ligase catalytic subunit/glutamate-cysteine ligase modifier subunit) and SOD, while promoting detoxification by modulating NAD(P)H quinone oxidoreductase 1 and GST. The pathway mediates anti-inflammatory repair via expression of heme oxygenase-1 and thioredoxin, and maintains proteostasis through autophagy-associated proteins p62 and heat shock protein 70. These coordinated responses preserve redox homeostasis, playing protective roles in neurodegenerative diseases and liver fibrosis (134-136). Notably, Keap1 mutations or Nrf2 hyperactivation in cancer contribute to chemotherapy resistance via drug efflux pumps such as multidrug resistance-associated protein and metabolic reprogramming. While moderate pathway activation alleviates chronic tissue injury, prolonged overactivation may exacerbate pathologies (134). These dynamic regulatory properties highlight its therapeutic potential in oxidative stress-related diseases. In the resting state, Keap1 binds to Nrf2 in the cytoplasm. Upon oxidant stimulation, Nrf2 first dissociates from Keap1 and relocates to the nucleus, where it then links to nuclear AREs to initiate the transcription of downstream antioxidant enzymes and detoxification proteins to protect against oxidative damage (135,136). It has been demonstrated that exposure to MPs causes overproduction of ROS within hepatocytes, which in turn activates the Nrf2-Keap1-ARE pathway, contributes to the dissociation of Nrf2 from the Keap1 complex and promotes Nrf2 phosphorylation. Phosphorylated Nrf2 subsequently forms a dimer with small maf proteins, binds ARE and upregulates antioxidant gene expression (137-139). Although this pathway initially mitigates oxidative stress, sustained or high-dose exposure to MPs may exceed its compensatory capacity, ultimately leading to lipid peroxidation and liver injury (Fig. 5). Thus, the Nrf2-Keap1-ARE pathway not only serves as a detoxification mechanism for hepatocytes to withstand oxidative damage from MPs, but also reveals a critical threshold for its protective effect.

In addition to the aforementioned mechanisms, there is a small body of literature that suggests other mechanisms by which MPs exert their effects on the liver. First, it has been hypothesized that MP-induced liver injury may be related to cell death. MPs were found to induce hepatocyte pyroptosis by inducing ROS accumulation and activating NLRP3 inflammatory vesicles. Hepatocyte pyrolysis promotes the release of IL-1β and IL-18, thereby exacerbating cellular inflammation. MPs were also able to reduce the expression of the iron storage protein ferritin heavy chain 1, while upregulating the expression of the iron uptake receptor transferrin receptor protein 1, which in turn triggered cellular iron death (29). Second, it has been demonstrated that MPs can increase the translation of fatty acid synthesis genes (such as FASN) through activation of the protein kinase r-like endoplasmic reticulum kinase-activating transcription factor 4 pathway, leading to the accumulation of hepatic lipid droplets (140). Of note, Fan et al (141) suggested that exposure to MPs can trigger the AMPK/unc-51 like autophagy activating kinase 1 pathway in hepatocytes, driving hepatocytes to produce autophagosomes to encapsulate intracellular lipid droplets. In addition, MP exposure damaged hepatocyte lysosomes. This dual action results in improper degradation of intracellular lipid droplets (141) and has prompted researchers to focus on the impact of multiple pathway interactions on the hepatic effects of MPs.

The impact of MPs on liver function has been proven to be contingent upon their size and concentration (142-144). In 2021, Zhang et al (75) found that fish exposed to 200 µm PS-MPs resulted in alterations to hepatic adipocyte size and an increase in hepatic lipid content, which subsequently affected the function of hepatic lipid metabolism. However, exposure to 2 and 10 µM PS-MPs primarily caused liver inflammation and excessive deposition of extracellular collagen (liver fibrosis) in the liver. Furthermore, Li et al (104) discovered that PS-MPs with larger diameters could downregulate the translation of mitochondrial division-related genes (such as mitochondrial fission factor and dynamin-related protein 1). In addition, medium to high concentrations of PS-MPs inhibited mitochondrial outer membrane fusion, thereby affecting normal mitochondrial proliferation and material exchange processes. However, the environmental concentration of PS-MPs has the opposite effect (104,145). This suggests that the mitochondrial function of MPs may be reversed with alterations in their exposure concentration. In summary, various hepatic effects induced by MPs have been confirmed to be related to the size and concentration of MPs. Of note, the effects produced by MPs on livers also appears to change with different materials and chemical structures (146-149) (Table I).

While the liver is exposed to MPs, it is also exposed to additives and contaminants carried on the surface of MPs. Several studies have shown that simultaneous exposure to plastic additives and environmental pollutants can exacerbate the hepatic effects of MPs (150-153). For instance, the co-exposure of MPs and the plasticizer di(2-ethylhexyl) phthalate exacerbated histopathological damage to the liver (154). Simultaneous exposure of the liver to MPs and common industrial pollutants, such as polybrominated diphenyl ethers (PBDEs), has been observed to induce liver atrophy and oxidative system dysfunction in zebrafish larvae (155). Concomitant exposure to perfluorooctanoic acid and MPs can disrupt immunoregulation within hepatocytes (156), suggesting that hepatocytes are undergoing immune and inflammatory responses. Of note, Mohsen et al (157) detected 20 heavy metals on the surface of six different types of plastics from various aquaculture areas in the Yellow and Bohai Seas of China. This hypothesis suggests that the human body may accumulate heavy metals attached to the surface of MPs through the ingestion of farmed fish. Of note, the influence of heavy metals on the hepatic effects of MPs is complex. Taking the metal cadmium as an example, studies have shown that exposure to MPs increases the accumulation of low-concentration cadmium in fish and enhances their liver toxicity, while reducing the accumulation of high-concentration cadmium and alleviating its toxicity (158). These and several other studies suggest that the co-exposure of MPs and heavy metals may have a more complex effect on the liver than previously considered (159-163).

Mechanisms by which MPs interact with organic pollutants and heavy metals to exacerbate liver effects include carrier effects, oxidative stress synergy and inflammatory activation. It was found that after the oxidation of MPs, the pores on the surface were enlarged and could adsorb a variety of pollutants, including cadmium and PBDEs (160). These contaminants can attach to MPs and enter the organism through ingestion or gills, thus significantly exacerbating the hepatotoxicity of MPs, and is termed the carrier effect. For instance, binding of NPs to tetrabromodiphenyl ether solutions increased their hepatic accumulation and exacerbated liver atrophy (155,160). In addition, combined exposure of MPs and pollutants can further amplify the role of MPs in inducing excessive ROS generation in the liver and inhibiting antioxidant enzyme activities (such as GSH, CAT and SOD), and ultimately exacerbates hepatic lipid peroxidation and DNA damage (154). For instance, exposure to NPs combined with arsenic markedly increased ROS levels and exacerbated lipid peroxidation in the liver compared with exposure to NPs alone (162). Combined exposure to MPs and pollutants also activates pathways such as NF-κB, upregulates TNF-α, IL-6 and other inflammatory factors, and triggers inflammatory infiltration in liver tissue (156,157). Of note, MPs are also capable of impairing liver detoxification of heavy metals to amplify their toxicity to the liver. For instance, MPs, when co-exposed with cadmium, inhibit the chelation of cadmium by metallothionein, a detoxifying protein in the liver, and promote heavy metal-induced hepatic steatosis (160). In conclusion, MPs can act as pollutant carriers and toxicity amplifiers, and their long-term compound exposure risk requires further exploration. Studies into the interaction between environmental pollutants and MPs have provided a new perspective on the hepatic effects of MPs.