Search Results (111)

Background: In patients with atrial fibrillation receiving long-term anticoagulation therapy with dabigatran etexilate (DABE), moxifloxacin (MFLX) is frequently coadministered to treat concurrent infections; however, the potential drug–drug interaction (DDI) between these agents remains unclear. Herein, we examined the underlying mechanism by which MFLX attenuates DABE pharmacokinetics in rats; subsequently, we elucidated the DDI in humans by establishing a physiologically based pharmacokinetic (PBPK) model based on these animal data. Methods: The 3- and 14-day effects of 40 mg/kg MFLX once daily and secondary bile acid (SBA)-containing dietary intervention on the pharmacokinetic profile of DABE and its active form, dabigatran (DAB), were examined in a rat model. Ileum tissues were harvested to measure the expression of P-glycoprotein (P-gp), pregnane X receptor (PXR), and peroxisome proliferator-activated receptor alpha (PPARα). In addition, we examined the effects of secondary bile acids (SBAs) on P-gp expression and quantified P-gp-mediated DABE efflux transport activity in Caco-2 cells. A PBPK model was used to predict the risk of DAB exposure under this DDI scenario and under combined high-risk conditions, including renal impairment and advanced age. Results: Treatment with MFLX for 3 and 14 days inhibited SBA-producing gut microbiota, thereby suppressing the conversion of primary bile acids to SBAs. Concurrently, a marked reduction in intestinal P-gp expression was observed, along with a significant enhancement of the oral bioavailability of DABE. These effects were reversed by SBA-containing diets. In vitro experiments using Caco-2 cells revealed that physiologically relevant concentrations of SBA significantly upregulated P-gp expression and function, whereas MFLX incubation alone showed no direct modulatory effect on these transporters or regulators. PBPK simulation results showed that in vivo exposure of DAB would increase by 41.7%, 104%, 251%, and 115% when coadministered with MFLX alone, with coexisting mild renal impairment, moderate renal impairment, and aging, respectively. Conclusions: MFLX increases DAB exposure by reducing SBA-regulated intestinal P-gp function. PBPK simulations suggest a low risk of DDI from MFLX coadministration alone; however, caution is warranted in patients with aging or renal impairment. Full article

Impaired amyloid-β (Aβ) clearance across the blood–brain barrier (BBB) is a major contributor to Aβ accumulation in Alzheimer’s disease (AD). P-glycoprotein (P-gp) has been identified as a key BBB efflux transporter involved in Aβ clearance, whereas emerging evidence suggests that organic anion transporting polypeptide 1A2 (OATP1A2) and its rodent counterparts, such as Oatp1a4, may participate in the influx component of Aβ transport. Nuclear factor erythroid 2–related factor 2 (Nrf2) and pregnane X receptor (PXR) are important transcriptional regulators of oxidative stress responses, xenobiotic metabolism, and transporter expression and may therefore modulate OATP1A2 and P-gp expression at the BBB. However, the mechanisms by which Nrf2–PXR crosstalk may regulate OATP1A2/P-gp expression in BBB endothelial cells under AD-relevant pathological conditions, as well as the consequences of this regulation for Aβ transport homeostasis, remain incompletely understood. This review summarizes current evidence linking P-gp, OATP1A2/Oatp1a4, Nrf2, and PXR to BBB transporter homeostasis in AD. A “net-effect” model is further proposed, in which Nrf2–PXR crosstalk may shift the BBB transporter balance toward enhanced P-gp-mediated efflux and reduced OATP1A2-associated influx. Because several key components of this model, particularly OATP1A2-mediated Aβ influx and BBB-specific Nrf2–PXR regulation, remain insufficiently validated, this model should be regarded as a mechanistic framework for future experimental investigation rather than as an established pathogenic pathway. Clarifying this regulatory axis may provide new insights into BBB dysfunction and impaired Aβ clearance in AD and may help identify potential molecular targets for therapeutic intervention. Full article

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear transcription factors comprising three isoforms—PPARα, PPARγ, and PPARβ/δ—that regulate hepatic lipid metabolism, glucose homeostasis, inflammation, bile acid synthesis, and fibrogenesis. Because liver diseases involve overlapping metabolic, inflammatory, cholestatic, and fibrotic pathways, PPAR agonists have emerged as a versatile therapeutic class across a spectrum of hepatic conditions. PPARα agonists (e.g., fenofibrate) promote fatty acid β-oxidation and suppress de novo lipogenesis; PPARγ agonists (e.g., pioglitazone) improve insulin sensitivity and exert anti-inflammatory and antifibrotic effects; and PPARδ agonists (e.g., seladelpar) regulate bile acid and cholesterol metabolism. Dual agonists (elafibranor [PPARα/δ] and saroglitazar [PPARα/γ]) and pan-PPAR agonists (lanifibranor [PPARα/γ/δ] and bezafibrate) aim to simultaneously address multiple pathogenic mechanisms. In primary biliary cholangitis (PBC), elafibranor and seladelpar received accelerated FDA approval in 2024 based on phase 3 trials (ELATIVE and RESPONSE, respectively), demonstrating significant biochemical response rates of 51% and 62% versus 4% and 20% with the placebo. Long-term open-label extension data from the ELATIVE trial have demonstrated sustained improvements in cholestatic biomarkers and stabilization of fibrosis markers over three years, with durable benefits on fatigue and pruritus. The ASSURE open-label study has confirmed the durability of seladelpar’s effects on biochemical response and pruritus through up to two years of treatment. Saroglitazar, a dual PPARα/γ agonist, has shown positive topline phase 3 results in the EPICS-III trial and received an FDA priority review designation. Bezafibrate has shown a survival benefit in large retrospective analyses and is used as a second-line therapy in Europe and Japan; notably, bezafibrate functions as a dual PPAR/pregnane X receptor (PXR) agonist, inducing CYP3A4 and efflux transporters that contribute to bile acid detoxification. In metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH), pioglitazone remains the most extensively studied PPAR agonist, with meta-analytic evidence supporting MASH resolution and fibrosis reduction regardless of diabetes status. Lanifibranor demonstrated histological improvement in the phase 2b NATIVE trial and is currently in phase 3 development (NATiV3). PPAR agonists have also demonstrated therapeutic effects on liver fibrosis inhibition through direct modulation of hepatic stellate cell activation and suppression of fibrogenic signaling. This narrative review synthesizes the molecular pharmacology of PPAR isoforms; the available clinical and preclinical evidence for mono-, dual-, and pan-PPAR agonists; and their therapeutic applications across MASLD/MASH, alcohol-associated liver disease (ALD), PBC, primary sclerosing cholangitis (PSC), intestinal failure-associated liver disease (IFALD), and advanced chronic liver disease (ACLD). The evolution from single-isoform to multi-isoform PPAR agonism reflects the recognition that overlapping pathogenic mechanisms in liver diseases may require broader receptor coverage for optimal therapeutic efficacy. Full article

As a commonly present organophosphorus flame retardant and persistent organic pollutant, 2-ethylhexyl diphenyl phosphate (EHDPP) has been observed to be genotoxic in cultured human hepatoma (HepG2) cells which depends on CYP activities. Yet, its impacts on hepatic Cyp expression, hepatotoxicity and genotoxicity in intact mammalians remain unidentified. In this study, adult male C57BL/6J mice received EHDPP by gastric gavage at doses of 50, 100, and 150 mg/kg (b.w.)/d for 7 d, then the hepatic expression of several Cyp proteins, aryl hydrocarbon receptor (AhR) and pregnane X receptor (PXR) was analyzed by Western blotting; hepatoxicity was determined by serum ALT/AST activities and hepatic histological examination, while genotoxicity by comet assay, phosphorylated histone (γ-H2AX) protein, micronucleus test, and Pig-a assay. A micronucleus test in mouse hepatoma (Hepa1-6) cells in vitro was employed to observe the modulating effect of PCB 126 (100 nM)/BAY-218 (700 nM) (Ahr-Cyp1a1 activator/inhibitor). The results indicated that EHDPP induced hepatic Cyp1a1, 2e1, AhR, Cyp1a2, Cyp3a4 and PXR proteins and histologic liver damage at 50 mg/kg/d and/or higher doses, while at the highest dose (150 mg/kg/d) with hepatic DNA damage and micronucleus formation in bone marrow polychromatic erythrocytes. The result of Pig-a assay (at 14 and 28 d) was negative. In Hepa1-6 cells EHDPP induced micronucleus marginally; however, this effect was enhanced by PCB 126, while abolished by BAY-218. This study suggests that EHDPP may enhance protein expression of hepatic Cyp1a1, Cyp2e1, AhR and PXR and induce liver damage and DNA/chromosome damage in mice; Cyp1a1 might be a major activating enzyme. Full article

Pyrrolizidine alkaloids (PAs), a category of naturally occurring secondary metabolites, are commonly found in various botanical sources. Accumulating evidence indicates that PAs and their biologically active metabolites can interact with cellular components and trigger a variety of toxic effects in animals and humans. Notably, PAs exhibit significant hepatotoxic potential via nutritional supplements, environmental dissemination, food chain contamination, and broader ecological pollution. In this review, we summarize PA-induced hepatotoxicity in humans and animals and the underlying molecular mechanisms. It involves oxidative stress, mitochondrial dysfunction, apoptosis, ER stress, inflammation, autophagy, and ferroptosis. Several key signaling pathways, such as nuclear factor-erythroid 2 related factor 2 (Nrf2), mitogen-activated protein kinase (MAPK), protein kinase RNA-like endoplasmic reticulum kinase (PERK), toll like receptor 4 (TLR4), nuclear factor kappa-B (NF-κB), transforming growth factor beta (TGF-β), p53, farnesoid X receptor (FXR), and pregnane X receptor (PXR), are also implicated. Furthermore, this review discusses diagnostic approaches, metabolic activation pathways, and detoxification strategies targeting PA-induced liver injury. Collectively, this review provides a comprehensive understanding of the molecular basis of PA hepatotoxicity and underscores the urgent need for improved risk assessment, early diagnosis, and effective detoxification interventions to mitigate PA-related liver diseases in humans and animals. Full article

Tryptophan (TRP) is a proteinogenic and nutritionally essential amino acid involved in the formation of numerous bioactive substances. A crucial role in the TRP molecule is played by indole, a bicyclic ring formed by benzene and pyrrole, which confers hydrophobic and antioxidant properties and the ability to act as a ligand for aryl hydrocarbon and pregnane X receptors. The first parts of the article examine sources, nutritional requirements, and three pathways of TRP catabolism. Physiologically, ~5% of dietary TRP is catabolized through the pathway forming serotonin and melatonin in the brain and enterochromaffin cells of the gut, ~85% through the pathway resulting in the formation of nicotinamide nucleotides and kynurenine and its derivatives in the liver and immune cells, and ~10% in gut microbiota to indole derivatives. Alterations of individual TRP catabolism pathways in aging, alcoholism, inflammatory bowel disease, metabolic syndrome, renal insufficiency, liver cirrhosis, cancer, and nervous diseases, e.g., depression, Alzheimer’s and Parkinson’s diseases, multiple sclerosis, and schizophrenia, are examined in the central section. The final sections are devoted to the benefits and adverse effects of TRP supplementation, the therapeutic use of various TRP metabolites, and the pharmacological targeting of enzymes, transporters, and receptors involved in TRP catabolism. It is concluded that all pathways of TRP catabolism are altered across a broad spectrum of human illnesses, and further investigation is needed to understand their role in disease pathogenesis better. The goal for clinical research is to explore options for TRP-targeted therapies and their integration into new therapeutic strategies. Full article

Steatotic liver disease (SLD) represents a major global health burden, with environmental toxicants emerging as critical contributors alongside metabolic dysfunction. Bisphenol F (BPF), an increasingly prevalent replacement for bisphenol A, is widely detected in human biological samples and environment, yet its hepatotoxic mechanisms remain incompletely characterized. This review synthesizes current evidence on BPF-induced SLD, with a particular focus on resolving the “pregnane X receptor (PXR) paradox”, the mismatch between BPF’s weak direct activation of PXR and the PXR-like metabolic effects observed in vivo. Comprehensive analysis of mechanistic pathways reveals that BPF-induced SLD develops predominantly through PXR-independent mechanisms involving oxidative stress, endoplasmic reticulum dysfunction, Drp1-mediated mitochondrial fission, NLRP3/NF-κB-driven inflammation, dysregulated post-translational modifications, and epigenetic remodelling. These converging pathways collectively disrupt hepatic lipid metabolism, promote triglyceride accumulation, and establish a self-perpetuating cycle of metabolic dysfunction. Notably, weak indirect PXR modulation via oxidative stress represents a secondary, non-causal mechanism unsupported by functional validation. This framework distinguishes toxicant-induced steatosis from metabolic dysfunction-associated steatotic liver disease while highlighting critical evidence gaps—particularly the absence of causal PXR validation studies and human epidemiological data. Therapeutic opportunities exist at validated convergence points including mitochondrial dynamics (Drp1), inflammatory signalling (NLRP3/NF-κB), and energy metabolism (AMPK-mTOR), though combination strategies targeting multiple pathways will likely be required for durable disease reversal. These findings necessitate the expansion of regulatory screening paradigms to incorporate cellular stress pathway biomarkers alongside traditional nuclear receptor endpoints, ensuring comprehensive hepatotoxic risk assessment of emerging BPA substitutes. Full article

In recent years, gut–brain axis signaling has been recognized as an essential factor modifying behavior, mood, cognition, and cellular viability under physiological and pathological conditions. Consequently, the intestinal microbiome has become a potential therapeutic target in neurological and psychiatric disorders. The microbiota-derived metabolite of tryptophan (Trp), indole-3-propionic acid (IPA), was discovered to target a number of molecular processes and to impact brain function. In this review, we outline the key mechanisms by which IPA may affect neuronal activity and survival and provide an update on the evidence supporting the neuroprotective action of the compound in various experimental paradigms. Accumulating data indicates that IPA is a free radical scavenger, a ligand of aryl hydrocarbon receptors (AhR) and pregnane X receptors (PXR), and an anti-inflammatory molecule. IPA decreases the synthesis of the proinflammatory nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), tumor necrosis factor-α (TNF-α), and other cytokines, reduces the generation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome, and enhances the synthesis of neurotrophic factors. Furthermore, produced in the gut, or administered orally, IPA boosts the central levels of kynurenic acid (KYNA), a neuroprotective metabolite of Trp. IPA reduces the release of proinflammatory molecules in the gut, breaking the gut–inflammation–brain vicious cycle, which otherwise leads to neuronal loss. Moreover, as a molecule that easily enters central compartment, IPA may directly impact brain function and cellular survival. Overall, the gathered data confirms neuroprotective features of IPA, and supports its potential use in high-risk populations, in order to delay the onset and ameliorate the course of neurodegenerative disorders and cognitive impairment. Clinical trials evaluating IPA as a promising therapeutic add-on, able to slow down the progress of neurodegenerative disorders such as Alzheimer’s or Parkinson’s disease and to limit the morphological and behavioral consequences of ischemic stroke, are urgently needed. Full article

The pregnane X receptor (PXR), a ligand-activated nuclear receptor, plays a central role in regulating the metabolism of both endogenous substances and xenobiotics. In recent years, increasing evidence has highlighted its involvement in chronic diseases, particularly metabolic disorders and cancer. PXR modulates drug-metabolizing enzymes, transporters, inflammatory factors, lipid metabolism, and immune-related pathways, contributing to the maintenance of hepatic–intestinal barrier homeostasis, energy metabolism, and inflammatory responses. Specifically, in type 2 diabetes mellitus (T2DM), PXR influences disease progression by regulating glucose metabolism and insulin sensitivity. In obesity, it affects adipogenesis and inflammatory processes. In atherosclerosis (AS), PXR exerts protective effects through cholesterol metabolism and anti-inflammatory actions. In metabolic dysfunction-associated steatotic liver disease (MASLD), it is closely associated with lipid synthesis, oxidative stress, and gut microbiota balance. Moreover, PXR plays dual roles in various cancers, including hepatocellular carcinoma, colorectal cancer, and breast cancer. Currently, PXR-targeted strategies, such as small molecule agonists and antagonists, represent promising therapeutic avenues for treating metabolic diseases and cancer. This review comprehensively summarizes the structural features, signaling pathways, and gene regulatory functions of PXR, as well as its role in metabolic diseases and cancer, providing insights into its therapeutic potential and future drug development challenges. Full article

Pregnane X receptor (PXR) is an important nuclear receptor that regulates diverse physiological functions, including drug metabolism. Although PXR activation is potentially involved in adverse events, the full scope of its impact has yet to be elucidated. In this study, we developed a machine learning model to predict the activity of PXR agonists and applied the model to drugs listed in the US Food and Drug Administration Adverse Event Reporting System database. Analysis of the predicted agonist–active drug interactions and adverse event reports revealed statistically significant risks (lnROR > 1 and −logp > 1.3) for multiple cardiac disorders. These findings suggest that PXR activity is involved in cardiovascular adverse effects and may contribute to drug safety through the early identification of risks. Full article

Background and Objectives: Colorectal cancer (CRC) is one of the most frequently diagnosed malignancies worldwide. Although chemotherapy is an effective treatment for colorectal cancer (CRC), its effectiveness is frequently hindered by the emergence of resistant cancer cells. Studies have demonstrated a linkage between drug resistance and the pregnane X receptor (PXR), which influences the metabolism and the transport of chemotherapeutic agents. Likewise, autophagy is also a well-established mechanism that contributes to chemotherapy resistance, and it is closely tied to tumor progression. This pre-clinical study aims to investigate the role of mtKRAS-dependent autophagy with PXR expression after treatment with Irinotecan in colorectal cancer. Methods: CRC lines were treated with specific inhibitors, such as 3-methyladeninee, hydroxychloroquine PI-103, and irinotecan hydrochloride, and subjected to various assays, including MTT for cell viability, Western blot for protein expression, siRNA-mediated PXR knock-out, and confocal microscopy for autophagic vacuole visualization. Protein quantification, gene knockdown, and subcellular localization studies were performed under standardized conditions to investigate treatment effects on autophagy and apoptosis pathways. Conclusions: Our experiments showed that PXR knockdown does not alter autophagy levels following Irinotecan treatment, but it promotes apoptotic cell death despite elevated autophagy. Moreover, late-stage autophagy inhibition reduces PXR expression, whereas induction through PI3K/AKT/mTOR inhibition leads to increased expression of PXR. Our experiments uncover a mechanism by which autophagy facilitates the nuclear translocation of the PXR, thereby promoting resistance to Irinotecan across multiple cell lines. Full article

The nuclear receptors pregnane X receptor (PXR), constitutive androstane receptor (CAR), and farnesoid X receptor (FXR) regulate the hepatic metabolism of androstenone, a testicular steroid that accumulates in the fat of intact male pigs and causes boar taint. This study evaluated natural product-derived compounds and conventional agonists targeting these nuclear receptors for their effects on androstenone metabolism in primary hepatocytes from slaughter-weight boars, to assess their potential as treatments for boar taint. Cells were incubated with natural products, conventional agonists, or dimethyl sulfoxide (DMSO; control), then being treated with androstenone. Culture media and cells were analyzed to assess changes in androstenone metabolism and gene expression. UGT1A6 was upregulated by treatments targeting both PXR and CAR and downregulated by FXR agonists. Additionally, PGC1α and NR2F1 were downregulated by compounds targeting PXR/CAR, while FXR and NR0B2 were upregulated and HNF4α downregulated by treatments acting on FXR. The natural products diallyl sulfide (DAS) and (Z)-guggulsterone (GUG) increased overall androstenone metabolism (DAS, GUG) and the production of Phase I androstenol metabolites (DAS), but only in hepatocyte culture replicates that responded positively to these treatments. Although gene expression was similar between positive-response and negative/non-responsive replicates following treatments, negative/non-responsive replicates for several treatments had higher basal expression of UGT2B31, UGT2A1, and SIRT1 and lower basal expression of FXR, PXR, and NR0B1 compared to positive-response replicates. These findings suggest that DAS and GUG may be promising treatments for boar taint, specifically in animals with lower basal rates of androstenone metabolism and higher expression of key nuclear receptors. Full article

Bifenthrin (BF) is a widely used pyrethroid pesticide recognized as an endocrine-disrupting chemical (EDC). Previous studies have confirmed that chronic exposure to BF is associated with various health risks. However, its potential association with recurrent implantation failure (RIF) and recurrent pregnancy loss (RPL) remains unclear. In this study, the potential targets of BF were identified using several databases, including the Comparative Toxicogenomics Database (CTD), TargetNet, GeneCards, SwissTargetPrediction, and STITCH. Differentially expressed genes (DEGs) associated with RIF were obtained from bulk RNA-seq datasets in the GEO database. Candidate targets were identified by intersecting the predicted BF-related targets with the RIF-associated DEGs, followed by functional enrichment analysis using the DAVID and g:Profiler platforms. Subsequently, hub genes were identified based on the STRING database and Cytoscape. A diagnostic model was then constructed based on these hub genes in the RIF cohort and validated in an independent recurrent pregnancy loss (RPL) cohort. Additionally, we performed single-cell type distribution analysis and immune infiltration profiling based on single-cell RNA-seq and bulk RNA-seq data, respectively. Molecular docking analysis using AutoDock Vina was conducted to evaluate the binding affinity between BF and the four hub proteins, as well as several hormone-related receptors. Functional enrichment results indicated that the candidate genes were mainly involved in apoptotic and oxidative stress-related pathways. Ultimately, four hub genes—BCL2, HMOX1, CYCS, and PTGS2—were identified. The diagnostic model based on these genes exhibited good predictive performance in the RIF cohort and was successfully validated in the RPL cohort. Single-cell transcriptomic analysis revealed a significant increase in the proportion of myeloid cells in RPL patients, while immune infiltration analysis showed a consistent downregulation of M2 macrophages in both RIF and RPL. Moreover, molecular docking analysis revealed that BF exhibited high binding affinity to all four hub proteins and demonstrated strong binding potential with multiple hormone receptors, particularly pregnane X receptor (PXR), estrogen receptor α (ESRα), and thyroid hormone receptors (TR). In conclusion, the association of BF with four hub genes and multiple hormone receptors suggests a potential link to immune and endocrine dysregulation observed in RIF and RPL. However, in vivo and in vitro experimental evidence is currently lacking, and further studies are needed to elucidate the mechanisms by which BF may contribute to RIF and RPL. Full article

Overdose intake of acetaminophen (APAP) causes liver injury involving hepatic drug metabolism and activation of oxidative stress pathways, and forsythiaside A (FA) has hepatoprotective pharmacological activity, but knowledge of the mechanism of FA treatment for APAP liver injury is still lacking the literature. In this study, we investigated the effects of FA on the pregnane X receptor (PXR) by molecular docking and reporter gene assays. In addition, we explored the effects of FA on oxidative stress, endoplasmic reticulum stress (ERS), apoptosis, and hepatic pathology by interfering with PXR in ex vivo and in vivo models. The results showed that FA decreased the PXR protein expression level and effectively reduced the oxidative stress level in the APAP model. In addition, FA reduced the expression of ERS pathway ProteinkinaseR-likeERkinase (PERK)-translation initiation factor 2 (eIF-2α)-activating transcription factor 4 (ATF4) by inhibiting PXR, and at the same time, decreased the expression of apoptotic proteins C/EBP homologous protein (CHOP), Bax, Caspase 3, and Caspase 7, and elevated the expression of apoptosis-suppressing protein Bcl-2, which ultimately treated the hepatic pathology injury of APAP in mice. The present study confirmed that FA improved APAP metabolism by inhibiting PXR-mediated CYP1A2 and CYP3A11 and alleviated APAP-induced hepatic impairment by inhibiting hepatic oxidative stress, ERS, and apoptosis. Full article

PEG400 is widely used as a pharmaceutical excipient in the biomedical field. Increasing evidence suggests that PEG400 is not an inert drug carrier; it can influence the activity of various drug-metabolizing enzymes and transporters, thereby affecting the in vivo process of drugs. It can also alleviate obesity and adipose tissue inflammation induced by a high-fat diet. In this study, we employed proteomics to investigate the impact of PEG400 on hepatic protein expression in rats. We found that over 40 metabolic enzymes were altered, with UDP-glucuronosyltransferase 1a9 (Ugt1a9) showing the most significant upregulation. This observation is consistent with our previous findings. KEGG pathway enrichment analysis revealed that PEG400 influences retinol metabolism, steroid hormone biosynthesis, drug metabolism, bile secretion, fatty acid degradation, peroxisome proliferator-activated receptor (PPAR) signaling pathway, and pentose and glucuronate interconversions. Western blot and molecular docking were used to quantitatively analyze related proteins. The results demonstrated that PEG400 promotes the metabolism of retinol to produce retinoic acid; enhances bile secretion by upregulating bile acid synthesis and transporter proteins; and activates the PPARα signaling pathway to regulate the expression of fat metabolism-related proteins, thereby reducing lipid accumulation. Furthermore, as natural ligands for nuclear receptors, retinoic acid and bile acids may activate nuclear receptors and initiate the regulation of target gene expression. We found upregulation of the nuclear receptors PPARα, retinoid X receptor alpha (RXRα), and pregnane X receptor (PXR). RXRα can form a dimer with PPARα or PXR to regulate the expression of target genes, which may explain the changes in the expression of numerous metabolic enzymes. This study provides a comprehensive understanding of the effects of PEG400 on liver metabolism in rats, reveals its potential biological functions, and offers new insights into the application and development of PEG400. Full article