BACKGROUND AND AIMS:Alcohol-associated liver disease (ALD) represents a global health burden with limited therapeutic strategies. While the hepatocyte transcription factor CCAAT/enhancer-binding protein α (CEBPA) regulates hepatic gene expression and liver fibrosis, its role in ALD pathogenesis remains undefined. Here, hepatocyte CEBPA was examined for its modulation of alcohol-associated hepatic steatosis and ALD. APPROACH AND RESULTS:Hepatocyte-specific CEBPA knockout mice, adeno-associated virus serotype transduction studies, and reporter gene assays were carried out using acute and chronic mouse ALD models. Western blotting was performed on liver tissues from human patients with ALD. Hepatic CEBPA expression decreased during ALD progression in human patient cohorts. Hepatocyte-specific Cebpa -knockout mice exhibited exacerbated alcohol-associated steatosis in both the acute and chronic ALD models. Inducible ablation of CEBPA in hepatocytes during late-stage ALD, accelerated disease progression, demonstrating the persistent protective function of CEBPA. Global transcriptomics identified Orm1 encoding orosomucoid 1 (ORM1) as the top CEBPA-upregulated gene in hepatocytes, while reporter assays and chromatin immunoprecipitation (ChIP) revealed that CEBPA directly activated Orm1 transcription by binding CEBPA response elements upstream of the Orm1 promoter. Loss of hepatocyte ORM1 potentiated the severity of ALD in mice. Conversely, restoring CEBPA or ORM1 via i.v. adeno-associated virus serotype 8 delivery or i.p. administeration of recombinant ORM1 protein rescued hepatic lipid accumulation and reduced disease progression. Consistently, serum ORM1, a hepatocyte-secreted hepatokine, inversely correlated with ALD severity in patients. CONCLUSIONS:These findings identify the hepatocyte CEBPA-ORM1 axis as a critical suppressor of ALD, offering therapeutic targets and nominating serum ORM1 as a potential biomarker for staging ALD severity.

Why is fatty liver disease associated with hyperglycemia? In this issue, Ye, Wan, Liu, Deng, Zhang et al.1 propose an unexpected mechanism: hepatic alkaline phosphatase released from diseased liver suppresses intestinal stem cell differentiation into GLP-1-secreting L-cells. This study reveals a new pathogenic route of liver-intestine communication.

Introduction:Lung cancer in never-smokers is a growing, biologically distinct entity lacking non-invasive markers. Established urinary markers-creatine riboside (CR) and N-acetylneuraminic acid (NANA)-report tumor-intrinsic metabolism, not carcinogen processing. We investigated 27-nor-5β-cholestane-3α,7α,12α,24R,25S-pentol glucuronide (CPG), a bile-acid glucuronide linked to aryl-hydrocarbon-receptor (AhR)/CYP xenobiotic metabolism. Methods:Urinary CPG was quantified by UPLC-tandem mass spectrometry in an exploratory (NCI-Maryland; n=846) and validation (Colorado; n=505) cohort of non-small-cell lung cancer cases and frequency-matched controls. Associations with case status, smoking stratum, survival, and discrimination were assessed, using tumor RNA sequencing (n=83) and gene-set enrichment analysis (GSEA). Results:Urinary CPG was higher in cases than controls in both cohorts (P<0.0001). In never-smokers, cases exceeded smoking-matched controls (P<0.001 and P<0.0001), indicating elevation independent of tobacco exposure. After mutual adjustment for CR and NANA, CPG remained independently associated with case status (exploratory OR 1.58, 95% CI 1.15-2.16; validation OR 3.92, 95% CI 2.47- 6.29), with a modest gain in discrimination. High CPG identified never-smokers with worse survival in both cohorts (P<0.001 and P=0.04), remaining significant after multivariable adjustment only in the exploratory cohort. GSEA showed AhR/CYP xenobiotic and Nrf2 oxidative-stress enrichment in high-CPG tumors; the CPG aglycone carried disease-specific 24R,25S stereochemistry. Conclusions:Urinary CPG was associated with NSCLC in two retrospective case-control cohorts, including in a smoking-matched never-smoker comparison. High CPG also identified never-smokers with worse survival, remaining independently prognostic after adjustment in the exploratory cohort. Tumor expression does not establish tissue of origin. Prospective validation against CR and NANA is required.

Biliary epithelial cells have long been viewed as passive conduits for bile transport. A study in mice now reveals that FXR signalling in these cells maintains a protective barrier, with implications for liver fibrosis therapy.

Abstract Background Building on evidence linking urinary glyphosate to chronic liver disease (CLD) and hepatocellular carcinoma (HCC), we developed urinary pesticide profiling integrated with machine learning risk prediction (MLRP) to stratify risk in high-exposure populations.Methods We conducted a case-control study within the Thailand Initiative in Genomics and Expression Research for Liver Cancer (TIGER-LC; 2011-2016; n=593): 228 CLD, 116 HCC, and 249 controls. Eight urinary pesticides were quantified by LC-MS/MS (pendimethalin, oxadiazon, metsulfuron-methyl, butachlor, 2,4-dichlorophenoxyacetic acid [2,4-D], cypermethrin, flocoumafen, bromadiolone). A composite Pesticide Load Score (PLS), with and without glyphosate, estimated burden. Two predictive models were developed: a logistic-regression Pesticide-Informed Liver Cancer Risk Score (PILCRS) and an Extreme Gradient Boosting (XGBoost) classifier that incorporated age, sex, alcohol use, occupation, and PLS. Internal validity used 1,000 bootstrap resamples with optimism-corrected calibration.Findings Predicted CLD probability increased from 30% in the lowest PLS quartile to over 70% in the highest, and HCC from 10% to 40% (p<0ꞏ0001). Relative estimates were consistent; the highest versus lowest quartile yielded odds ratios of 2ꞏ84 (95% CI 1ꞏ66-4ꞏ91) for CLD and 4ꞏ76 (2ꞏ30- 10ꞏ29) for HCC. Cypermethrin remained independently associated. After optimism correction, both models demonstrated strong discrimination and calibration.Interpretation This framework establishes a scalable, exposure-informed tool for liver disease prediction. Findings underscore pesticide burden as a modifiable risk factor and align with Sustainable Development Goal 3ꞏ9 and WHO-FAO priorities in low- and middle-income countries (LMICs). External validation is essential. Citation Format: Daxeshkumar P. Patel, Christopher Loffredo, Majda Haznadar, Mohammed Khan, Amelia Parker, Benjarath Pupacdi, Siritida Rabibhadana, Panida Navasumrit, Nirush Lertprasertsuke, Anon Chotirosniramit, Chawalit Pairojkul, Vor Luvira, Ake Pugkhem, Wattana Sukeepaisarnjaroen, Teerapat Ungtrakul, Thaniya Sricharunrat, Kannika Phornphutkul, Frank J. Gonzalez, Anuradha Budhu, Chulabhorn Mahidol, Xin Wei Wang, Mathuros Ruchirawat, Curtis C. Harris, TIGER-LC Consortium.. Urinary pesticide biomarkers and liver disease risk in Thailand: A machine-learning-based risk-prediction model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2443.

Abstract Early-life microbiota represent an indispensable factor for the proper development and function of host metabolism and the immune system. We have demonstrated that neonatal exposure to antibiotics for the first 3 weeks (NeoATB) leads to obesity in adulthood, characterized by gut microbiota dysbiosis and dysregulated immune responses. Here, we demonstrate that feeding D-mannose suppresses NeoATB-induced obesity, accompanied by improved glucose tolerance and decreased insulin resistance. Mechanistically, D-mannose feeding decreased hypoxia and increased oxygenation and recovery of metabolic activity of adipocytes. D-mannose restored CD4 + Foxp3 + ST2 + Tregs, leading to a reduction of Th1 pro-inflammatory cells in the adipose tissue of NeoATB mice. Significantly, we revealed that D-mannose treatment reversed the dysregulated ratios of phylum Firmicutes to phylum Bacteroidetes in obese NeoATB mice, which was surprisingly attributed to D-mannose-mediated suppression of the growth of Firmicutes rather than an increase in the growth of Bacteroidetes. These findings should have therapeutic implications for the treatment of obesity in human patients.

Oxidative stress and impaired mitochondrial homeostasis are critical drivers of drug-induced liver injury (DILI), both of which are negatively regulated by Kelch-like ECH-associated protein 1 (KEAP1). In this study, a dual-action strategy was adapted to develop a novel KEAP1 degrader with high liver exposure for mitigating DILI through concurrent activation of the NRF2 and PGAM5 signaling pathways. Following screening of a natural product library using complementary KEAP1 thermal shift and NRF2 luciferase reporter assays, cardamonin (CAD) was identified as a natural KEAP1 binder. A series of CAD-derived proteolysis-targeting chimeras (PROTACs) was subsequently designed and synthesized, leading to the discovery of compound 8L that effectively degraded KEAP1 in hepatocytes. In vivo, 8L exhibited marked preferential distribution in the liver, a favorable safety profile, and significant hepatoprotective effects in both acetaminophen- and cisplatin-induced liver injury mouse models. Notably, targeted degradation of hepatic KEAP1 by 8L concurrently activated the NRF2-mediated antioxidative program and the PGAM5-regulated mitochondrial integrity program, which cooperatively restored mitochondrial homeostasis and counteracted oxidative stress. Collectively, a liver-preferential KEAP1 degrader was developed to mitigate DILI by dual activation of the NRF2 and PGAM5 pathways, offering a promising therapeutic agent and more in-depth mechanistic insights into KEAP1-targeted degradation for enhanced anti-DILI therapy.

As solid tumors progress, the tumor microenvironment (TME) becomes increasingly immunosuppressive, impairing cytotoxic T-cell activity and limiting the efficacy of the immune checkpoint blockade. However, the mechanistic drivers of this immunosuppression remain poorly understood. Here, we identify a tumor-derived lipid-neutrophil-adenosine axis as a critical regulator of immune suppression in advanced colorectal cancer (CRC). We show that fatty acids enriched in tumor interstitial fluid reprogram neutrophils to generate adenosine via PPARα activation, leading to T-cell suppression. Using AB928, a dual A2aR/A2bR adenosine receptor antagonist currently in clinical trials, we restored T-cell proliferation, effector function, and tumor-killing capacity in vitro and in vivo. Importantly, AB928 synergized with anti-PD-1 therapy to enhance survival in an autochthonous model of metastatic CRC. Our findings define a metabolic immune evasion mechanism in the TME and provide a rationale for targeting neutrophil-derived adenosine signaling to improve immunotherapy responses in CRC and other solid tumors.

Metabolic-dysfunction-associated steatohepatitis (MASH) remains a major health challenge. Herein, we identify sphingomyelin phosphodiesterase 3 (SMPD3) as a key driver of hepatic ceramide accumulation through increasing sphingomyelin hydrolysis at the cell membrane. Hepatocyte-specific Smpd3 gene disruption or pharmacological inhibition of SMPD3 alleviates MASH, whereas reintroducing SMPD3 reverses the resolution of MASH. Although healthy livers express low-level SMPD3, lipotoxicity-induced DNA damage suppresses sirtuin 1 (SIRT1), triggering an upregulation of SMPD3 during MASH. This disrupts membrane sphingomyelin-ceramide balance and promotes disease progression by enhancing caveolae-dependent lipid uptake and extracellular vesicle secretion from steatotic hepatocytes to exacerbate inflammation and fibrosis. Consequently, SMPD3 acts as a central hub integrating key MASH hallmarks. Notably, we discovered a bifunctional agent that simultaneously activates SIRT1 and inhibits SMPD3, which shows significant therapeutic potential in MASH treatment. These findings suggest that inhibition of hepatic SMPD3 restores membrane sphingolipid metabolism and holds great promise for developing novel MASH therapies.

The proximal tubule (PT) of the kidney is a highly metabolic organ that regulates systemic homeostasis through ketogenesis and gluconeogenesis. Peroxisome proliferator-activated receptor alpha (PPARα), a nuclear receptor controlling fatty acid oxidation (FAO) and homeostasis, is expressed in the PT and is activated by fasting. Although the activation of systemic PPARα is essential for renal and systemic energy metabolism, the role of PPARα in PT has not been established. In this study, kidney PT-specific PPARα knockout mice (Ppara∆KPT) were generated, and the metabolic changes caused by 48 h of fasting were compared between Ppara∆KPT mice and controls. In Ppara∆KPT mice, renal FAO and ketogenesis were severely impaired, leading to lipid accumulation in the kidney after 48 h of fasting. The increase in the renal expression of gluconeogenesis-associated genes due to fasting was insufficient in Ppara∆KPT mice, causing a decrease in serum glucose levels and liver glycogen content. Fasting caused hepatic micro-steatosis and significantly increased the expression of genes linked to FAO and ketogenesis in the liver of Ppara∆KPT mice, as well as those associated with lipolysis in the white adipose tissue. These activities likely compensate for the impaired kidney FAO and ketogenesis in Ppara∆KPT mice and show that PPARα in PT regulates renal and systemic lipid and glucose metabolism during fasting. PPARα in PT may be a critical component in systemic lipid and glucose homeostasis during fasting.

We previously demonstrated that a clinically relevant dose of pemafibrate (PEM), a selective peroxisome proliferator-activated receptor α (PPARα) modulator (SPPARMα), reduces serum triglyceride (TG) levels in mice via hepatic PPARα activation. However, the specific contribution of hepatocyte PPARα remains unclear. To address this, male Ppara-floxed (Pparafl/fl) and hepatocyte-specific Ppara-disrupted (PparaΔHep) mice were fed a diet with or without a clinically relevant dose of PEM (0.00005%) for four weeks. In Pparafl/fl mice, PEM significantly reduced circulating TG and non-esterified fatty acid levels by enhancing hepatic fatty acid uptake and β-oxidation. In contrast, these effects were absent in PparaΔHep mice. Notably, PEM did not activate PPARα in extrahepatic tissues, including white/brown adipose tissue, kidney, and skeletal muscle in either genotype. These findings underscore the essential role of hepatocyte PPARα in mediating the pharmacological effects of PEM at clinically relevant doses.

Background:Five-year survival from lung cancer exceeds 60% at stage I-II but falls below 10% once metastasis occurs. Low-dose CT (LDCT) screening reduces mortality in heavy smokers but carries a false-positive rate of approximately 29% and is restricted to smoking-based eligibility, leaving most cases undetected. We aimed to develop and independently validate an interpretable machine-learning urinary metabolite risk index (uLCI) for non-invasive lung cancer detection. Methods:Four urinary metabolites-creatine riboside (CR), N-acetylneuraminic acid (NANA), 27-nor-5β-cholestane-3α,7α,12α,24R,25S-pentol (CP), and cortisol sulfate (CS)-and three clinical variables (age, race, smoking) were integrated by Lasso-regularised logistic regression into a uLCI score. The model was developed under 10-fold cross-validation in the NCI-Maryland (NCI-MD) cohort (n=845; 470 controls, 375 cases, stages I-IV) and applied without refitting to the independent Colorado Lung Cancer Cohort (n=488; 211 controls, 277 cases). Analyses were prespecified; reporting followed TRIPOD+AI. Findings:uLCI achieved an area under the curve (AUC) of 0·906 (95% CI 0·887-0·926) in NCI-MD and 0·748 (0·701-0·793) in the independent Colorado cohort. Scores rose monotonically across stages in both cohorts (Spearman ρ=0·69 and 0·45; both p<0·0001). Stage-specific discrimination was preserved from stage I to IV (NCI-MD 0·900-0·927; Colorado 0·722-0·843). Net reclassification improvement over clinical variables was 1·24 (1·14-1·36) and 0·74 (0·56-0·90). uLCI tertiles stratified post-resection survival in stage I-II disease (adjusted hazard ratio 2·03, 1·26-3·27). Interpretation:uLCI is an independently validated, interpretable urinary risk index that detects lung cancer across all stages, with monotonic stage progression and post-resection prognostic value. Its false-positive rate compares favourably with published estimates for LDCT and cell-free-DNA assays, supporting prospective head-to-head evaluation as a non-invasive triage tool, including in screening-ineligible populations.

Liver organoids have rapidly advanced as human-relevant systems for modeling liver development, metabolic disease, and drug responses. Recent studies have established expandable adult hepatocyte organoids with sustained proliferative capacity, engineered induced pluripotent stem cell-derived organoids exhibiting metabolic zonation through controlled signaling gradients, and constructed multicellular assembloids that incorporate non-parenchymal cell types to recapitulate physiological periportal architecture and model cholestatic fibrotic microenvironments. These developments have enhanced scalability, structural organization, and disease modeling fidelity, supporting applications in translational research. Despite these advances, several challenges remain. Current evaluation of liver organoids largely relies on terminal functional outputs, while the upstream regulatory hierarchies that specify hepatic identity, zonation, and metabolic competence remain insufficiently reconstructed and validated. Limitations in long-term stability, spatial precision, and standardization further constrain predictive performance. This Review summarizes recent technological progress, discusses strategies to improve regulatory fidelity and functional benchmarking, and outlines future directions toward developing liver organoids as more reliable platforms for disease modeling and precision hepatology.

Dietary fat reshapes host-microbiota interactions, yet the upstream events that mediate overnutrition-driven microbiome alterations and metabolic dysfunction remain unclear. Here we compared mouse models of diet-induced and genetic obesity using multi-omics to identify the colonic mucus niche as an early, diet-sensitive driver of metabolic dysfunction. Excessive dietary lipids impaired glutamine metabolism and redox homeostasis in goblet cells, thinning the mucus layer and depleting the mucus-adapted symbiont Akkermansia muciniphila while expanding the bile-acid-transforming bacterium Clostridium scindens. Altered bile acid composition along the enterohepatic axis activates FXR-PLIN2 signalling in the small intestine and increases fat absorption. In parallel, enterocytes upregulate the PPARα-dependent uptake pathway that supports luminal lipid entry. Supplementation with glutamine restored goblet cell function and the gut microbiota-derived bile acid pool, thereby reducing intestinal FXR activation and lipid uptake. These findings reveal that dietary fat impairs colonic goblet cell function and reshapes microbial bile acid metabolism, influencing small-intestinal fat absorption.

Background/Objectives: Hepatocellular carcinoma (HCC) remains a major malignancy with high incidence and mortality, in part due to its diverse etiology and intratumoral heterogeneity, which contributes to drug resistance and frequent recurrence. SALL1 (Spalt-Like Transcription Factor 1), a zinc-finger transcription factor, was reported to function as a tumor suppressor in several cancers, including breast cancer and glioma, and accumulating evidence support its involvement in tumor biology. In this study, the role of SALL1 in HCC was examined. Methods: Public RNA and protein databases derived from human HCC were interrogated. Western blotting quantification of clinical HCC for SALL1 levels was carried out. Cell culture and xenograft studies were performed using genetically modified HCC tumor cells. Results: As revealed by pubic RNA and protein database analysis and further western blotting quantification of clinical samples of HCC, SALL1 is decreased in human HCC. The effect of reduced SALL1 expression on the tumorigenic properties and transcriptional regulation in HCC was then examined. Knockdown of SALL1 in the HCC cell lines Huh7 and Hep3B, enhanced cell proliferation in vitro and accelerated tumor growth in a xenograft mouse model, suggesting that lower SALL1 expression increases cell proliferation and tumorigenesis in HCC. RNA-seq and ChIP analyses further identified three novel candidate target genes (SLC6A14, GABRG1, and AKR1B10), suggesting that SALL1 may exert a tumor-suppressive effect, at least in part, through negative regulation of these genes. Conclusions: These findings establish SALL1 as a possible tumor suppressor and provide new insights into the biological significance of SALL1 downregulation in HCC. SALL1 could be a candidate prognostic marker and a potential therapeutic target.

Ketogenic diet (KD) is widely recognized for its immunomodulatory and metabolic benefits, but the impact on inflammatory bowel disease remains controversial. Here, we demonstrate that KD maintains homeostasis under physiological conditions but exacerbates colitis by triggering a ketogenesis-microbe-immune cascade upon mucosal injury. Mechanistically, KD elevates luminal β-hydroxybutyrate (β-HB), promoting the expansion of Thomasclavelia spiroformis (T. spiroformis). In turn, T. spiroformis activates colonic γδ17 T cells via cell wall components, ultimately driving IL-17A-mediated iinflammation. Adoptive transfer of γδ17 T cells into Tcrd-/- mice confirmed their pathogenicity. Ketogenesis or IL-17A blockades abolish KD-exacerbated colitis, whereas β-HB supplementation or ketogenesis activation recapitulated disease exacerbation. Clinically, T. spiroformis abundance correlates with fecal β-HB and serum IL-17A in ulcerative colitis (UC) patients, but not Crohn's disease, supporting a UC-specific β-HB-T. spiroformis-γδ17 T cell axis. Thus, we identify a diet-induced immunometabolic circuit linking ketogenesis to colitis, highlighting ketone metabolism and IL-17A signaling as potential therapeutic targets.

Metabolic nuclear receptors (NRs) are ligand-activated transcription factors central to metabolic homeostasis and detoxification. While their roles in chronic liver diseases have been reviewed, comprehensive reviews specifically addressing the role of metabolic NRs in acute liver injury (ALI) are limited. This review summarizes how metabolic NRs modulate ALI, focusing on well-characterized NRs including the farnesoid X receptor, peroxisome proliferator-activated receptors and pregnane X receptor, as well as on the less-studied ones such as the liver X receptor and constitutive androstane receptor. Current evidence indicates that activation of farnesoid X receptor, peroxisome proliferator-activated receptor α, and liver X receptor is hepatoprotective against ALI, while activation of proliferator-activated receptor γ, pregnane X receptor, and constitutive androstane receptor potentiate acetaminophen-induced hepatotoxicity and ALI, albeit conclusions from some studies are context-dependent and not definitive. The current review summarizes the roles and mechanisms for how metabolic NRs influence ALI, which would help guide future research on the potential for metabolic NRs in treating ALI.

Exposure of perfluorohexane sulfonate (PFHxS) is associated with hepatomegaly and accumulation of lipids that may be mediated by nuclear receptors like peroxisome proliferator-activated receptor-α (PPARα), constitutive androstane receptor (CAR), or pregnane X receptor (PXR). This study tested the hypotheses that: (i) PFHxS causes changes in liver by activating PPARα, CAR, or PXR, and (ii) there is a species difference in PPARα activity by PFHxS. Wild-type, Ppara-null, and PPARA-humanized mice were fed either a control diet, or one containing 2.2 mg PFHxS/kg diet or 25.8 mg PFHxS/kg diet for either 7 or 28 days, and target gene expression was examined. Relative liver weights were similar after 7 days with either 2.2 or 25.8 mg PFHxS/kg dietary exposure compared with controls. Relative liver weights were higher after treatment for 28 days in all 3 genotypes fed 25.8 mg PFHxS/kg diet compared with controls. The concentration of PFHxS was dose-dependently increased in serum and liver compared with controls. PFHxS exposure of 2.2 and 25.8 mg PFHxS/kg diet caused an increase in expression of PPARα target genes in wild-type mice and this effect was not observed in similarly treated Ppara-null mice or PPARA-humanized mice. Administration of PFHxS caused increased expression of the CAR target gene Cyp2b10 in all 3 genotypes at both timepoints, and the PXR target gene Cyp3a11 in all 3 genotypes after 28 days. Exposure to PFHxS can increase liver weight due in part to the activation of mouse, but not human, PPARα. Activation of CAR and PXR by PFHxS also likely contributes to the observed hepatomegaly in all 3 genotypes.

Pregnane X receptor (PXR) primarily regulates enzymes that detoxify xenobiotics and therapeutic drugs, but its surprising role in diabetes has recently emerged. In this study we treated male wild-type (WT) and Pxr-null (PXR-KO) mice for 14 weeks with control or obesity- and type 2 diabetes-promoting high-fat diet (HFD), followed by a single dose of vehicle or 100 mg/kg of the pancreatic beta cell-specific toxin streptozotocin (STZ) and two more weeks of their respective diets. Mice were evaluated for hyperglycemia and serum and tissue markers of metabolic syndrome to characterize potential PXR modulation of type 1 (T1DM, STZ + control diet) and type 2 diabetes mellitus (T2DM, STZ + HFD). In the WT but not PXR-KO mouse T1DM and T2DM models, we observed hyperglycemia, reduced insulin levels, weight loss, pancreatic beta-cell destruction, elevated phosphoenolpyruvate carboxykinase 1, reduced glucokinase and liver fatty acid binding protein 1, and lower fibroblast growth factor 21 mRNA. In WT but not PXR-KO T2DM model mice, farnesoid X receptor mRNA was decreased, while glucose 6-phosphatase mRNA, cholesterol-7a-hydroxylase (CYP7A1) and cytochrome P450 2E1 proteins, serum liver injury markers, hepatic triglycerides and non-esterified fatty acids were increased. HFD-fed WT mice developed obesity, dyslipidemia, hyperinsulinemia, hepatotoxicity, and lipogenesis but not PXR-KO mice. In contrast, T2DM PXR-KO mice showed elevated glucose transporters (GLUT1, 2, and 4) and phosphorylated-adenosine monophosphate-activated protein kinase α (p-AMPKα) proteins associated with reduced hyperglycemia and lipogenesis. These data revealed that PXR contribute to STZ-induced pathologies, identifying this receptor as a potential therapeutic target for the prevention and treatment of diabetes.