p-Cresol has effects on various cell types, including renal endothelial cells, monocytes, and renal tubular cells (RTCs). The endothelial cell barrier plays a critical role in regulating the exchange of plasma proteins and circulating cells through endothelial cell-to-cell junctions (Lugano et al., 2023). This barrier function is mediated by the small GTPase Rho protein and Rho kinase, which maintain actin cytoskeleton organization and thereby preserve endothelial barrier integrity (Krogt et al., 2023). p-Cresol significantly increases the endothelial permeability through activating the Rho/Rho kinase pathway. This effect is demonstrated by the fact that the specific Rho kinase inhibitor Y-27632 markedly attenuates p-cresol-induced increases in endothelial permeability (Cerini et al., 2004). The endothelial cell barrier is also involved in adherens junctions (AJs), which are constituted by vascular endothelial (VE)-cadherin, a membrane-bound protein. VE-cadherin is connected to the actin cytoskeleton (Nan et al., 2023), and its proper localization is essential for endothelial barrier function. p-Cresol disrupts the actin cytoskeleton and alters AJs by reducing the dense peripheral band of junctional F-actin, inducing stress fiber formation, and relocalizing VE-cadherin away from cell-to-cell junctions. These changes result in the formation of visible gaps between adjacent endothelial cells, thereby increasing endothelial permeability (Cerini et al., 2004).

Leukocytes have been utilized to investigate the cellular dysfunction caused by uremia (Vanholder et al., 2008). When an infection occurs, leukocytes adhere to endothelium, cross the endothelial barrier, and trigger an immune response (Arts et al., 2021). The process is mediated by endothelial adhesion molecules (EAMs), such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin. Inflammatory cytokines, including tumor necrosis factor (TNF) or interleukin-1ß (IL-1ß), can induce the production of adhesion molecules (Kihara et al., 2021; Versele et al., 2022). p-Cresol, on its own, has no direct impact on the expression of EAMs. However, it has been found to inhibit cytokine-induced stimulation and the mRNA expression of ICAM-1 and VCAM-1, but not E-selectin. TNF or IL-1ß stimulates the adhesion of monocyte (e.g., THP-1) to endothelial cells, Conversely, p-cresol can reduce this THP-1 adhesion. Additionally, p-cresol can induce monocyte migration. Integrin-linked kinase (ILK), a kinase involved in cell migration, is activated at the protein level in THP-1 cells by p-cresol. Subsequently, ILK participates in the transmigration of THP-1 cells by mediating the remodeling of F-actin and podosome formation (Campillo et al., 2022).

Evidence has demonstrated the cytotoxic effects of p-cresol on RTCs in a concentration-dependent manner in patients with CKD (Brocca et al., 2013). p-Cresol elicits a toxic reaction and induces cell death through pathways of apoptosis and necrosis, especially at high concentrations. The apoptosis of RTCs has been morphologically observed during the progression of CKD (Maremonti et al., 2022). The loss of cell membrane permeability caused by p-cresol is likely the primary cause of necrosis (Brocca et al., 2013). In addition to apoptosis and necrosis, autophagy, which can be induced by toxins, also contributes to cell death (Lin et al., 2015). It has been reported that p-cresol can reduce the proliferation of renal proximal tubular cells by significantly increasing cell apoptosis, which is accompanied by the activation of autophagy. The signaling adaptor p62 serves as a signaling hub that determines cell survival and apoptosis, and its interaction with caspase 8 can trigger apoptotic cell death (Lee et al., 2021). p-Cresol leads to the accumulation of p62, followed by the activation of caspase 8-induced cell apoptosis (Lin et al., 2015). Moreover, treatment with p-cresol upregulates autophagy markers such as LC3-II, beclin 1, and Atg 4 (Lin et al., 2015).

Interleukins (ILs), predominantly secreted by macrophages, exhibit regulatory activity on immunocompetent cells (Mansurov et al., 2022). In patients with CKD, immune dysregulation is often a concomitant condition, leading to elevated levels of ILs (Glorieux et al., 2020). Existing evidence has indicated that p-cresol can inhibit the production of IL-12 in a dose-dependent manner (Kawakami et al., 2009). Moreover, p-cresol has been demonstrated to suppress cytokine-induced endothelial adhesion (Flynn et al., 2025). IL-12 plays a crucial role in immune responses (Wang et al., 2025), and endothelial adhesion is an essential step in the inflammatory process (Varinder et al., 2023). By inhibiting the production of IL-12 and cytokine-induced endothelial adhesion, p-cresol disrupts normal immune signaling and the recruitment of immune cells. These findings suggest that p-cresol contributes to the immunodeficiency observed in CKD patients by impeding the responses of endothelial cells to inflammatory cytokines.

Mitochondria are crucial intracellular organelles responsible for energy production and maintenance of cell homeostasis. They are highly enriched in the proximal tubules, serving as a vital source of adenosine triphosphate (ATP) (Galvan et al., 2017). However, mitochondria are susceptible to a variety of intrinsic and environmental stressors, which can render them vulnerable and dysregulated (Tang et al., 2021). A growing body of evidence has shown the connection between mitochondrial dysfunction and CKD progression (Huang et al., 2024). In CKD patients, the uremic toxin p-cresol accumulates. Research has reported that p-cresol suppresses mitochondrial respiration and mitophagy. Specifically, it reduces the activity of mitochondrial complexes I and IV, which are essential for the electron transport chain that drives ATP production (Yoon et al., 2018). Moreover, p-cresol disrupts mitochondrial dynamics. It promotes mitochondrial mitofusion, leading to the formation of enlarged, interconnected mitochondrial networks. This process is accompanied by an elevation in the level of cytochrome c oxidase subunit 4 (COX4) (Chiao-Yin et al., 2017). The changes in mitochondrial structure and the upregulation of COX4 further interfere with normal mitochondrial function, exacerbating mitochondrial dysfunction in the context of CKD (Yoon et al., 2018).

CKD patients frequently experience complications like uremic pruritus. Protease-activated receptor 2 (PAR-2) plays a key role in mediating itching. In addition to being highly expressed in epidermal keratinocytes of patients with atopic dermatitis (Zhao et al., 2020). PAR-2 is also significantly upregulated in CKD patients with pruritus. These patients exhibit higher protease activity and greater expression level of PAR-2 compared to healthy controls (Moon et al., 2014). Reports have indicated that p-cresol is involved in the development of uremic pruritus in CKD patients. When normal human epidermal keratinocytes are exposed to p-cresol, both the mRNA and protein expression of PAR-2 are significantly upregulated, and protease activity increases (Kim et al., 2021). Nevertheless, the exact pathogenesis underlying uremic pruritus induced by p-cresol still requires further investigation.

Diabetes mellitus is another prevalent complication among CKD patients. Approximately 40% of diabetes mellitus patients progress to diabetic nephropathy (Oladi-Ghadikolaei et al., 2023). In these patients, the uremic toxin p-cresol accumulates significantly. Evidence suggests that p-cresol may contribute to the development of nephropathy in diabetic individuals (Oladi-Ghadikolaei et al., 2023; Zhu et al., 2023). Emerging evidence suggests that the level of p-cresol can potentially serve as a predictive marker for the progression of kidney failure in patients with diabetic nephropathy. This underlines the importance of understanding the role of p-cresol in the context of diabetic nephropathy, a prevalent comorbidity among CKD patients.

p-Cresol is generated in the colon and exerts genotoxicity on colonocytes (Andriamihaja et al., 2015). When acting on colonocytes, p-cresol can induce diverse outcomes, such as reduced cell proliferation and mitochondrial function, as well as increased DNA damage. Exposure to p-cresol causes colonocytes to accumulate in the S-phase of cell cycle, indicating a disruption in cell cycle progression. Concurrently, an elevation in oxygen consumption is observed. The detrimental effect of p-cresol on mitochondrial function is manifested by the increased oxidation of mitochondrial NADPH/NADH and decreased ATP content (Andriamihaja et al., 2015; Wong et al., 2016). p-Cresol also induces the phosphorylation of the H2AX histone in a dose-dependent manner, indicating its effect on DNA damage (Andriamihaja et al., 2015).

The colonic barrier function is highly sensitive to p-cresol. The transepithelial electrical resistance (TEER) level and the flux of fluorescein isothiocyanate-dextran (FD-4) across the monolayer from the apical to the serosal side serve as important indicators, reflecting the integrity and permeability of the epithelial paracellular pathway, respectively (Wong et al., 2016). When the intestinal cell monolayer is exposed to p-cresol, the TEER value decreases, while the transport of FD-4 across the epithelial monolayer correspondingly increases. These changes clearly indicate that p-cresol can disrupt the gut barrier function.

p-Cresol has been reported to have a positive association with colon cancer (Diether and Willing, 2019). In the feces of colorectal cancer patients, p-cresol is present at a significantly high level compared to healthy individuals (Alustiza et al., 2023). Multiple factors contribute to the development of colon cancer. The upregulated expression of proinflammatory cytokine IL-6 and the disturbance of lipid metabolism may underlie the mechanism of intestinal tumorigenesis (F. Li et al., 2015). It is likely that p-cresol, being present at high levels in colorectal cancer patients, may contribute to this process, potentially by influencing cytokine expression and lipid metabolism. Additionally, due to its significantly elevated levels in the feces of colorectal cancer patients, the level of p-cresol has been proposed as a biomarker for the detection of colorectal cancer and pre-malignant lesion (Alustiza et al., 2023).

The microbe-gut-brain axis is pivotal in shaping central nervous system function (Xia et al., 2025), and nowhere is this more evident than in autism spectrum disorder (ASD)—a prevalent neuropsychiatric condition defined by profound social-communicative deficits (Zhuang et al., 2024). Because the gut microbiome is the predominant source of p-cresol, sustained overproduction of this metabolite becomes especially deleterious to individuals with ASD (Figure 5). Elevated urinary and fecal p-cresol has been consistently documented in ASD patients (Zheng et al., 2022), and mechanistic studies now reveal a bidirectional toxicity: p-cresol not only accumulates as a microbial by-product but also re-sculpts the microbial community itself, precipitating autistic-like behaviors (Bermudez-Martin et al., 2021). Consequently, targeted modulation of the gut microbiota is emerging as a promising therapeutic strategy to mitigate ASD symptomatology (Turriziani et al., 2022).

In an open-field environment, p-cresol also triggers anxiety-like behaviors and affects the locomotor activity of mice with ASD (Pascucci et al., 2020). Studies have indicated elevated neurotransmitter levels in ASD patients, for instance, dopamine (Gevi et al., 2020). However, p-cresol attenuates the excitability of central dopamine neurons. This is evidenced by a reduction in the number of evoked action potentials, as well as reduced amplitudes and frequencies of miniature spontaneous excitatory post-synaptic currents (sEPSC) (Bermudez-Martin et al., 2021). p-Cresol further inhibits dopamine β-hydroxylase activity (Shaw, 2024) and disrupts dopamine metabolism, altering the levels of dopamine, homovanillic acid, and 3,4-dihydroxyphenylacetic acid (Pascucci et al., 2020). Ultimately, these disruptions to the dopamine system lead to biochemical damage to brain cells (Shaw, 2024).

Beyond its impact on the dopamine system, p-cresol impairs the function of hippocampal neurons. It does so by decreasing dendritic arborization, decreasing the number of Piccolo and Shank2 proteins, and blunting the intracellular calcium response in hippocampal neurons (Guzman-Salas et al., 2022). The underlying mechanisms through which p-cresol contributes to the development of ASD remain to be further explored.

Cardiovascular disease (CVD) is particularly common among CKD patients. In these patients, the accumulation of uremic toxins, such as p-cresol, exacerbates the risk of developing CVD. Arterial media calcification is a major life-threatening factor contributing to cardiovascular mortality in CKD patients (Opdebeeck et al., 2020). Inflammation and coagulation within the arterial wall are closely associated with the calcification induced by urinary toxins (Opdebeeck et al., 2019). Both free p-cresol and its circulating form, p-cresyl sulfate (Figures 1A,B), are urinary toxins. They are related to a higher incidence of cardiovascular events and functions as risk predictors of CVD in hemodialysis patients (Lin et al., 2010; Meijers et al., 2010). Exposure to p-cresol, either in the free state or as p-cresyl sulfate, initiates calcification in the aorta and peripheral arteries by activating inflammation, coagulation and lipid metabolism pathways (Opdebeeck et al., 2020; Opdebeeck et al., 2019).

The vascular endothelium plays a crucial role in maintaining the homeostasis of the cardiovascular system. p-Cresol has been demonstrated to have a negative effect on the endothelial cell, contributing to endothelial dysfunction (Guerrero et al., 2020). Endothelial dysfunction is considered a key factor triggering the onset and progression of CVD (Opdebeeck et al., 2020). When endothelial cells are exposed to p-cresol over an extended period, vascular permeability and leakage increase, and endothelial cell viability declines (Mankhong et al., 2024). This damage to the endothelial cells further enables p-cresol to promote monocyte adhesion to the vessel endothelium. As a result, it induces IL-6 production, thereby eliciting endothelial inflammatory responses (Mankhong et al., 2024).

Impaired endothelial regeneration is another factor contributing to the incidence of CVD. A decreased number of endothelial progenitor cells (EPCs) has been repeatedly shown to be involved in the pathogenesis of cardiovascular events (Heinisch et al., 2022). p-Cresol inhibits the proliferation of EPCs in a concentration-dependent manner by restricting vessel formation and cell migration (Zhu et al., 2012). Specifically, treatment with p-cresol results in an extended cell cycle at the G2/M phase of EPCs, as evidenced by decreased levels of G2/M-specific cyclin B1 and phosphorylated CDK1 (Zhu et al., 2012). The reduction in EPCs proliferation further impairs the endothelium’s ability to repair itself, exacerbating endothelial dysfunction and increasing the risk of CVD.

Regarding the underlying toxicological mechanism, p-cresol might disrupt the normal redox balance within endothelial cells. Evidently, p-cresol could induce oxidative stress, which in turn leads to the various detrimental effects on the endothelium (Pan et al., 2017).

Mounting data indicate the association between p-cresol and cardiomyocyte dysfunction. Cardiomyocytes are interconnected through intercalated discs (ICDs), which consist of desmosomes, AJs, and gap junctions (Nielsen et al., 2023). AJs are essential for maintaining the integrity of discs, while gap junctions are responsible for the passage of ions and electric currents between cardiomyocytes (Merkel et al., 2019). The protein kinase Cα (PKCα) signaling pathway is involved in gap junctions, and its activation leads to reduced myocardial contractility and heart failure. p-Cresol causes low contraction rates in cardiomyocytes, together with irregular cardiomyocyte beating. This is because p-cresol activates PKCα (Velasquez et al., 2018). The activation of PKCα disrupts the normal function of AJs, leading to the formation of functional gaps between cardiomyocytes. As a result, the mechanical and electrical coupling between cardiomyocytes is impaired. Also, the activation of PKCα may be the underlying mechanism through which p-cresol exerts its negative effect of on cardiomyocytes (Peng et al., 2012; Peng et al., 2013).

Uremic patients commonly suffer from platelet dysfunction, which in turn contributes to cardiovascular complications in CKD patients. p-Cresol is considered to suppress arachidonic acid (AA)-induced platelet aggregation by decreasing reactive oxygen species (ROS) production. The extracellular signal-regulated kinase (ERK) and p38 MAPKs have been reported to regulate platelet aggregation (Chang et al., 2011). p-Cresol can inhibit thromboxane A2 production through the ERK/p38 signaling pathway (Chang et al., 2011). In vitro experiments have also confirmed the antiplatelet effect of p-cresol, as it inhibits the aggregation of rabbit platelet-rich plasma and mice platelet (Chang et al., 2011). Moreover, due to its antiplatelet property, p-cresol may potentially suppress blood clot formation and give rise to hemorrhagic disorders, an area that warrants further investigation (Chang et al., 2011).

Given the crucial role of platelets in maintaining cardiovascular health, other factors associated with cardiovascular function also deserve attention. Platelet activating factor (PAF) can be synthesized by cardiomyocytes when they are appropriately stimulated. However, PAF has been demonstrated to have negative inotropic and arrhythmogenic effects on cardiomyocytes (Ajiro et al., 2011). p-Cresol, which affects platelet function, also inhibits PAF production (Dou et al., 2002). By doing so, it may disrupt the normal regulatory mechanisms in the cardiovascular system. Specifically, the inhibitory effect of p-cresol on PAF production may lead to abnormal cardiac function, thus contributing to the development of CVD (Chawla et al., 2023).

p-Cresol exerts hepatotoxic effects in a dose-dependent manner: studies have shown it inhibits liver mitochondrial respiration and increases mitochondrial permeability, thereby identifying mitochondria as a key hepatotoxic target of p-cresol (Kitagawa, 2001).

Notably, liver cancer is disproportionately prevalent in hemodialysis patients, a population with impaired p-cresol clearance and chronic systemic accumulation of p-cresol (Chen et al., 2023). Given that the liver is the primary organ for p-cresol metabolism, the potential tumor-promoting effect of p-cresol on the liver warrants in-depth investigation. Accumulated p-cresol can facilitate the migration and invasion of liver cancer cells (Chen et al., 2023). In this process, p-cresol is oxidized into reactive quinone methide intermediates and 4-methyl-ortho-hydroquinone by cytochrome P450 (Burkina et al., 2018). These reactive biotransformation products of p-cresol may damage cellular DNA, proteins, and lipids, leading to hepatic toxicity. Thus, the biotransformation of p-cresol might be the underlying toxic mechanism (Yan et al., 2005).

p-Cresol has been reported to promote the progression of bladder cancer (Chen et al., 2023). Matrix Metalloproteinases (MMPs) play crucial roles in cancer cell proliferation, migration, and metastasis. p-Cresol promotes the motility and migration of bladder cancer cells by upregulating the expression of MMP2 and MMP-9 (Hsu et al., 2019). Additionally, the Ras and mTOR signaling pathways are implicated in the invasion and migration of bladder carcinoma cells induced by p-cresol (Hsu et al., 2019).

Bone dysfunction represents a newly identified risk factor for CKD patients and may contribute to the incidence of CVD (Fujii et al., 2018). p-Cresol is involved in the progression of bone disorders. Bone marrow-derived mesenchymal stem cells (MSCs) circulate into ischemia sites for tissue repair and revascularization. In vitro and in vivo experiments have demonstrated the functional incompetence of MSCs under uremic conditions, with p-cresol being a major uremic toxin (Noh et al., 2014; Noh et al., 2012). p-Cresol can induce Akt-pathway-selective insulin resistance, a common occurrence in CKD patients. This, in turn, leads to MSC dysfunction (Noh et al., 2014). MSC dysfunction can disrupt the normal process of bone repair and renewal. Moreover, p-cresol is also strongly correlated with bone cellular senescence. Specifically, p-cresol increases cell size, stimulates inflammatory responses within cells, disrupts the cell cycle, and concomitantly decreases the cell proliferation capacity (Zayed and Iohara, 2020).