PIEZO1 is a mechanosensitive cation channel expressed throughout the vasculature that converts shear stress into calcium-dependent vasodilatory signals governing endothelial nitric oxide (NO) production and vascular tone. While impaired mechanotransduction is a recognized contributor to diabetic vascular dysfunction, the progression of PIEZO1 signaling deficits from prediabetes to overt diabetes remains poorly defined. We hypothesized that worsening metabolic status across the prediabetic–diabetic transition is linked to endothelial dysfunction and a selective loss of PIEZO1-mediated vasorelaxation in diabetes.Male Sprague–Dawley (SD) and UCD-T2DM rats (control, prediabetic, diabetic) underwent metabolic and hemodynamic characterization, including body weight, adiposity, fasting glucose, HbA1c, glucose tolerance, triglycerides, insulin, HOMA-IR, and blood pressure. Mesenteric arterial function was evaluated using wire myography to measure acetylcholine (ACh)- and sodium nitroprusside (SNP)-induced relaxation, phenylephrine (PE)-induced contraction, and Yoda1-evoked PIEZO1-dependent relaxation with or without L-NAME. Piezo1, nitric oxide synthase 3 (Nos3), and guanylyl cyclase 1 subunits (Gucy1α1 and Gucy1β1) gene expression levels were measured by qPCR.Diabetic group exhibited reduced body weight and adiposity but marked elevations in fasting glucose, HbA1c, triglycerides, and blood pressure. Glucose intolerance was present in both diseased groups, with prediabetic rats showing elevated insulin and diabetic group had the highest HOMA-IR. ACh-induced vasorelaxation was impaired in prediabetic and diabetic arteries, with the lowest maximal relaxation observed in diabetics. PE-induced contraction was enhanced in diabetics, as indicated by increased sensitivity and maximal tension. Yoda1 relaxation was impaired only in diabetic rats; L-NAME caused a marked rightward shift in prediabetes but only a minimal shift in diabetes, indicating progressive loss of PIEZO1–NO signaling. SNP-induced relaxation was diminished in diabetics, suggesting smooth muscle dysfunction in this group. qPCR analyses demonstrated marked reductions in Piezo1 and Nos3 expression in diabetic arteries, decreased Nos3 in prediabetics, and downward trends in Gucy1α1 in diabetics, collectively reflecting progressive disruption of endothelial NO production and downstream cGMP signaling.In conclusion, prediabetes to diabetes progression is characterized by worsening metabolic abnormalities, hypertension, and impaired endothelial NO-mediated vasorelaxation. Nos3 expression is reduced in prediabetes, reflecting early disruption of NO signaling, whereas PIEZO1-dependent relaxation remains intact until diabetes, where it becomes selectively impaired alongside reduced Piezo1 expression. This pattern suggests that early NO pathway dysfunction precedes overt loss of PIEZO1–NO mechanotransduction and identifies this axis as a potential therapeutic target in diabetic vascular disease. Support or Funding Information:Faculty Bridge Grant Award, Thomas J. Long School of Pharmacy, University of the Pacific This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Preservation of the insulin-sensitive glomerular podocyte is imperative for normal kidney function. The protein tyrosine phosphatases (PTPs), protein tyrosine phosphatase 1B (PTP1B), T-cell protein tyrosine phosphatase (TCPTP), and Src homology phosphatase 2 (SHP2) are established regulators of insulin signaling in vivo and implicated in renal function. However, knowledge gaps exist regarding the roles of these enzymes and their integrated modulation of signaling in podocytes. Accordingly, uncovering the mediators of PTP function is critical to elucidate their modes of action and help develop mechanism-based interventions for podocytopathies. We generated E11 podocyte cell lines expressing the substrate-trapping mutants of these PTPs and then used immunoprecipitation and mass spectrometry to identify their putative substrates. Bioinformatic analyses were used to decipher the pathways affected by these enzymes in the insulin-stimulated podocytes. We identified known and novel targets, some common across the three PTPs, others shared between two PTPs, and others unique to a single phosphatase. Additionally, cytoskeleton and cellular junction-associated pathways were significantly enriched among the phosphatases and their putative substrates. Moreover, we uncovered a signaling node that is likely key to the action of these PTPs, comprising the protein tyrosine kinase Src, cortactin, and lamin A/C, interconnected via vimentin. To further validate this, we demonstrated that vimentin is a substrate of SHP2 in podocytes. The current findings suggest that PTP1B, TCPTP, and SHP2 act coordinately and engage numerous targets to orchestrate an integrated response to insulin in podocytes. Notably, these enzymes are components of a crucial signaling node that modulates cytoskeletal and junctional proteins, thereby influencing podocyte function.

Polystyrene (PS), a widely used synthetic polymer, breaks into micro- and nanoscale particles that can enter the body and accumulate in tissues. Conventional methods provide bulk chemical information, but lack spatial and metabolic context. Here, we use matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) with trapped ion mobility spectrometry (TIMS) to localize PS across whole-body murine sections and individual organs, allowing differentiation of PS chain lengths and associated metabolic shifts. Oral PS exposure produced clear organ-specific lipid remodeling. In the stomach, increases in phosphatidylcholine (PC(30:2)), phosphatidic acid (PA(36:1)), and sphingomyelin (SM(34:1; O2)) suggest epithelial stress and barrier disruption. In the liver, PC(32:1) decreased, and higher PC(30:2) and PA(36:2) indicate impaired lipid export alongside compensatory adjustments to maintain membrane stability, with potential effects on systemic lipid balance. In the heart, reductions in SM(32:1; O2), ether-linked phosphatidic acid (PA(O-34:1)), and hexosylceramide (HexCer(30:1; O2)) reflect disrupted sphingolipid and ether-linked lipid species metabolism and altered lipid transport. Together, these findings reveal dynamic, tissue-specific lipid responses to PS exposure. This study shows that MALDI TIMS MSI provides high-resolution, label-free mapping of PS and its metabolic footprint and can be extended to other low-abundance synthetic compounds.

Cardiovascular diseases (CVDs), many of which are influenced by exposure to environmental xenobiotics, lack physiologically relevant in vitro models for cardiotoxicity assessment. Although some pollutants have established associations with CVD, the effects of a wide range of potential toxicants remains unknown. Here, we developed a three-dimensional recellularized humanized engineered heart tissue (rHHT) platform by integrating decellularized human left ventricular extracellular matrix with human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), yielding spontaneously contracting tissues that recapitulate key features of native ventricular myocardium. We also generated a hiPSC line stably expressing the calcium indicator GCaMP6f, enabling real-time and longitudinal monitoring of calcium transients. Using ethanol and rotenone as examples, we demonstrate that the rHHT platform provides a sensitive system for evaluating cardiotoxicity and is more stringent than conventional monolayer approaches. This study presents a scalable platform for xenobiotic cardiotoxicity assessment, with potential applicability to high-throughput screening, mechanistic studies, and future personalized medicine applications.

Introduction:Alzheimer's disease (AD) is characterized by progressive neurodegeneration and impaired glucose metabolism. While most studies focus on heavily affected brain regions such as the hippocampus and prefrontal cortex, the visual cortex remains relatively preserved in early AD and provides an opportunity to examine metabolic alterations that precede widespread pathology. Methods:Postmortem human visual cortex samples were obtained from control, mild cognitive impairment (MCI), and AD subjects without non-AD neuropathologic conditions. Untargeted metabolomics was performed using liquid chromatography-mass spectrometry, and expression of key metabolic, inflammatory, and AD-related genes was measured by quantitative PCR. Data analysis was conducted using MetaboAnalyst and R. Results:Metabolomic profiling revealed progressive disruptions in glucose metabolism, and mitochondrial function across MCI and AD subjects. Gene expression analyses showed reduced levels of glycolytic enzymes (HK1, PFKM, PKM1), mitochondrial regulators (PDHA1, NDUFC1), and the neuronal glucose transporter SLC2A3. Insulin signaling was altered, with decreased IDE and increased INSR and PTPN1 gene expression. Inflammatory markers including TNF, IL1B, and GFAP were elevated in AD. Sex-stratified analyses revealed both shared and distinct metabolic signatures, particularly within glucose and mitochondrial pathways. Several metabolic gene changes correlated negatively with Braak stage, highlighting a progressive decline in energy metabolism alongside tau pathology. Discussion:These findings demonstrate early and progressive metabolic dysfunction in the visual cortex of MCI and AD subjects. Even in a region with limited structural pathology, profound alterations in energy metabolism were observed, underscoring its central role in AD pathogenesis and highlighting improving neuronal metabolic function as a promising target for therapeutic intervention.

Metabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of liver-related morbidity and mortality. The current interventions are limited, underscoring the need for novel mechanism-based therapies. Protein tyrosine phosphatase 1B (PTP1B) regulates phosphotyrosine signaling and hepatic metabolism, but its role in MASH remains incompletely understood. To elucidate the impact of modulating PTP1B expression in MASH, we used mice with hepatocyte-specific PTP1B disruption in the fast-food diet (FFD) model of the disease and then monitored alterations in inflammation, steatosis, and fibrosis. In this study, we observed elevated hepatic PTP1B expression in the FFD mouse model of MASH and in liver biopsies from MASH patients. PTP1B deficiency ameliorated FFD-induced hepatic injury and inflammation as evidenced by lower alanine aminotransferase, Tnf and Il1b, and NFκB phosphorylation. Additionally, PTP1B deficiency partially rebalanced the hepatic and systemic lipid dysregulation under the FFD-fed state. Notably, PTP1B deficiency alleviated the hepatic fibrosis induced by the prolonged FFD regimen. Moreover, mice with hepatic PTP1B deficiency exhibited improved glucose control under FFD independently of body weight changes. Mechanistically, PTP1B deficiency was associated with enhanced hepatic insulin signaling and decreased oxidative stress. Collectively, these findings establish that PTP1B deficiency in hepatocytes modulates several pathways implicated in MASH and confers improvements that may curtail disease progression. Further investigation is warranted into targeting this phosphatase as part of the armamentarium in the therapeutic landscape for MASH.

Trans-vaccenic acid (VA, trans-11-18:1) and rumenic acid (RA, cis-9, trans-11-18:2) are the predominant rumen-derived trans fatty acids found in beef fat from cattle fed forage-based diets. Unlike industrial trans fatty acids, these two are considered beneficial, as they have been associated with health benefits, such as a decreased risk of type 2 diabetes (T2D). The objective of this study was to compare the effects of VA+RA-enriched tallow (ET) from steers finished on a forage-based diet containing 15% extruded flaxseeds with a control tallow (CT) from beef cattle finished on a typical corn-grain-based ration on glucose homeostasis in high-fat diet-induced obese mice, which are considered a translatable model for prediabetes. Forty-eight male 6-week-old C57BL/6J mice were randomly assigned to one of four treatments for 20 weeks: a low-fat (10% Cal from fat) diet containing CT (LFD-CT), a low-fat diet containing ET (LFD-ET), a high-fat (45% Cal from fat) diet containing CT (HFD-CT), or a high-fat diet containing ET (HFD-ET). Body weight and food intake were measured weekly. At weeks 10 and 20, blood samples were collected from fed and 12-hour fasted mice to test for blood glucose and insulin concentrations. Fasted blood glucose and insulin levels were used to calculate the homeostatic model assessment for insulin resistance (HOMA-IR). At weeks 16 and 19, glucose tolerance tests (GTT) and insulin tolerance tests (ITT) were performed, respectively. Both HFD treatments resulted in greater (P< 0.01) fasted blood glucose and insulin concentrations, as well as HOMA-IR, compared to the LFD treatments at week 10. The HFD-ET group showed lower (P< 0.05) fasted insulin concentrations and HOMA-IR compared to the HFD-CT group at week 10. By week 19, both HFD treatments resulted in significantly greater (P< 0.01) body weight gain, fasted blood glucose, insulin, HOMA-IR, and area under the curve (AUC) for ITT and GTT compared to the LFD groups. However, no significant differences were observed within the LFD and HFD groups. Our findings suggest that beef fat enriched with VA and RA can prevent hyperinsulinemia and insulin resistance in the short term, but these effects are not sustained in the long term.

Alcohol-associated hepatitis (AH) is a form of acute-on-chronic liver failure characterized by intrahepatic neutrophilic inflammation. In hepatocytes, IL-6 signals through either membrane-bound (classical signaling) or soluble (trans-signaling; TS) IL-6 receptors (IL-6Rs) to regulate liver injury responses. This study investigated the role of IL-6TS in the pathophysiology of AH. RNA sequencing of liver biopsies from patients with alcohol-related liver disease demonstrated a progressive decline in IL-6R expression correlating with increasing AH severity. Transforming growth factor (TGF)-β1 emerged as the most potent negative regulator of IL-6R expression. Notably, STAT3-dependent gene expression was increased in severe AH. In vitro, treatment of HepG2 cells with TGF-β1 suppressed IL-6R expression. Subsequent treatment with either IL-6 to stimulate classical signaling, or hyper-IL-6, a recombinant IL-6/IL-6R α peptide, to activate trans-signaling activated STAT3. Hyper-IL-6, but not IL-6, restored STAT3 activation in the face of suppressed IL-6R. RNA sequencing of hyper-IL-6 stimulated cells identified a gene signature that stratified a subset of AH patients with: i) enhanced IL-6TS activity, ii) increased intrahepatic neutrophilic infiltration, and iii) transcriptional enrichment of leukocyte migration pathways. Female mice treated with 10-day chronic-plus-binge ethanol exhibited enhanced STAT3 activation despite reduced hepatic IL-6R expression, leading to increased expression of neutrophilic activators, with colocalization of Ly6G+ leukocytes and STAT3+ hepatocytes. Collectively, these results indicate that IL-6TS preserves hepatocyte STAT3-dependent gene expression and promotes neutrophilic inflammation in AH.

AIMS:Chronic excessive alcohol intake is a significant cause of alcohol-associated liver disease (ALD), a leading contributor to liver-related morbidity and mortality. The Src homology phosphatase 2 (Shp2; encoded by Ptpn11) is a widely expressed protein tyrosine phosphatase that modulates hepatic functions, but its role in ALD is mostly uncharted.MAIN METHODS:Herein, we explore the effects of liver-specific Shp2 genetic disruption using the established chronic-plus-binge mouse model of ALD.KEY FINDINGS:We report that the hepatic Shp2 disruption had beneficial effects and partially ameliorated ethanol-induced injury, inflammation, and steatosis in the liver. Consistently, Shp2 deficiency was associated with decreased ethanol-evoked activation of extracellular signal-regulated kinase (ERK) and oxidative stress in the liver. Moreover, primary hepatocytes with Shp2 deficiency exhibited similar outcomes to those observed upon Shp2 disruption in vivo, including diminished ethanol-induced ERK activation, inflammation, and oxidative stress. Furthermore, pharmacological inhibition of ERK in primary hepatocytes mimicked the effects of Shp2 deficiency and attenuated oxidative stress caused by ethanol.SIGNIFICANCE:Collectively, these findings highlight Shp2 as a modulator of hepatic oxidative stress upon ethanol challenge and suggest the evaluation of this phosphatase as a potential therapeutic target for ALD.

Trans vaccenic acid (TVA, trans11-18 : 1) and cis9, trans11-CLA (also known as rumenic acid; RA) have received widespread attention as potentially beneficial trans-FA due to their putative health benefits, including anti-diabetic properties. The objective of this study was to determine the effects of beef fat naturally enriched with TVA and RA on parameters related to glucose homoeostasis and associated metabolic markers in diet-induced obese (DIO) mice. Thirty-six male C57BL/6J mice (8 weeks old) were fed for 19 weeks with either a control low-fat diet (CLF), a control high-fat diet (CHF), or a TVA+RA-enriched high-fat diet (EHF). Compared with CLF, feeding either CHF or EHF resulted in adverse metabolic outcomes associated with high-fat diets, including adiposity, impaired glucose control and hepatic steatosis. However, the EHF diet induced a significantly higher liver weight TAG content and elevated plasma alanine transaminase levels compared with the CHF diet. Collectively, the findings from this study suggest that EHF does not improve glucose tolerance and worsens liver steatosis in DIO mice. However, the adverse effects of EHF on the liver could be in part related to the presence of other trans-FA in the enriched beef fat.

Alcohol-associated liver disease (ALD) is a leading factor of liver-related death worldwide. ALD has various manifestations that include steatosis, hepatitis, and cirrhosis and is currently without approved pharmacotherapies. The Src homology phosphatase 2 (Shp2) is a drug target in some cancers due to its positive regulation of Ras-mitogen-activated protein kinase signaling and cell proliferation. Shp2 pharmacological inhibition yields beneficial outcomes in animal disease models, but its impact on ALD remains unexplored. This study aims to investigate the effects of Shp2 inhibition and its validity using a preclinical mouse model of ALD. We report that the administration of SHP099, a potent and selective allosteric inhibitor of Shp2, partially ameliorated ethanol-induced hepatic injury, inflammation, and steatosis in mice. Additionally, Shp2 inhibition was associated with reduced ethanol-evoked activation of extracellular signal-regulated kinase (ERK), oxidative, and endoplasmic reticulum (ER) stress in the liver. Besides the liver, excessive alcohol consumption induces multi-organ injury and dysfunction, including the intestine. Notably, Shp2 inhibition diminished ethanol-induced intestinal inflammation and permeability, abrogated the reduction in tight junction protein expression, and the activation of ERK and stress signaling in the ileum. Collectively, Shp2 pharmacological inhibition mitigates the deleterious effects of ethanol in the liver and intestine in a mouse model of ALD. Given the multifactorial aspects underlying ALD pathogenesis, additional studies are needed to decipher the utility of Shp2 inhibition alone or as a component in a multitherapeutic regimen to combat this deadly malady.

Glomerular podocytes are instrumental for the barrier function of the kidney, and podocyte injury contributes to proteinuria and the deterioration of renal function. Protein tyrosine phosphatase 1B (PTP1B) is an established metabolic regulator, and the inactivation of this phosphatase mitigates podocyte injury. However, there is a paucity of data regarding the substrates that mediate PTP1B actions in podocytes. This study aims to uncover novel substrates of PTP1B in podocytes and validate a leading candidate. To this end, using substrate-trapping and mass spectroscopy, we identified putative substrates of this phosphatase and investigated the actin cross-linking cytoskeletal protein alpha-actinin4. PTP1B and alpha-actinin4 co-localized in murine and human glomeruli and transiently transfected E11 podocyte cells. Additionally, podocyte PTP1B deficiency in vivo and culture was associated with elevated tyrosine phosphorylation of alpha-actinin4. Conversely, reconstitution of the knockdown cells with PTP1B attenuated alpha-actinin4 tyrosine phosphorylation. We demonstrated co-association between alpha-actinin4 and the PTP1B substrate-trapping mutant, which was enhanced upon insulin stimulation and disrupted by vanadate, consistent with an enzyme-substrate interaction. Moreover, we identified alpha-actinin4 tandem tyrosine residues 486/487 as mediators of its interaction with PTP1B. Furthermore, knockdown studies in E11 cells suggest that PTP1B and alpha-actinin4 are modulators of podocyte motility. These observations indicate that PTP1B and alpha-actinin4 are likely interacting partners in a signaling node that modulates podocyte function. Targeting PTP1B and plausibly this one of its substrates may represent a new therapeutic approach for podocyte injury that warrants additional investigation.

Trans vaccenic acid (TVA, trans11-18:1) is a natural trans fatty acid that is exclusively found in ruminant fats such as dairy, beef, and lamb. Increased circulating concentrations of TVA and its metabolites are epidemiologically related to a reduced risk of insulin resistance and type 2 diabetes (T2D). However, direct causative evidence is lacking, and the mechanisms are poorly understood. The objective of this study was to evaluate whether TVA can alleviate insulin resistance in diet-induced obese mice when compared with oleic acid (OA, cis9-18:1, the major dietary cis 18:1 isomer) or trans10-18:1 (a major industrial trans fatty acid isomer). Forty-eight male C57BL/6J mice (7 weeks old) were fed either a low-fat diet (LFD,10% kcal total fat), a high-fat diet (HFD) enriched with OA (HFD-OA; 45% kcal total fat, 6% kcal from pure OA), an HFD enriched with TVA (HFD-TVA; 45% kcal total fat, 6% kcal from pure TVA), or an HFD enriched with trans-10 18:1 (HFD-T10; 45% kcal total fat, 6% kcal from pure trans-10 18:1) for 19 weeks. The metabolic phenotype was characterized using a glucose tolerance test (GTT) and insulin tolerance test (ITT). Insulin-sensitive tissues (muscle, liver, and adipose) were harvested and extracted for protein, which was analyzed for protein kinase B (Akt) and phosphorylated Akt (pAKT) by western blot using Vinculin as a loading control. The resulting band intensities were quantitated using the FluorChem 9900 program (Alpha Innotech). pAkt expression was normalized to Akt. Data were analyzed using one-way analysis of variance (ANOVA) followed by Tukey’s test. Our GTT results suggested a greater (P < 0.05) glucose intolerance in both HFD-TVA and HFD-T10 groups compared with the LFD group. Whereas HFD-OA-fed mice maintained their glucose tolerance and insulin sensitivity despite greater body weight and adiposity. In agreement with GTT and ITT results, we found reduced (P < 0.05) Akt phosphorylation in the muscle of both HFD-TVA and HFD-T10 groups compared with LFD while there was no difference in phosphorylation level in the liver and adipose. In conclusion, this work demonstrates that contrary to our initial hypothesis, a large dose of TVA (6% of calorie intake) promotes glucose intolerance and insulin resistance in HFD-fed mice. Further studies using the typical intake of TVA in humans (0.5 to 1% of calorie intake) are required to better understand the effects of TVA on glucose homeostasis.

Diabetic nephropathy (DN) is a significant complication of diabetes and the leading cause of end-stage renal disease. Hyperglycemia-induced dysfunction of the glomerular podocytes is a major contributor to the deterioration of renal function in DN. Previously, we demonstrated that podocyte-specific disruption of the Src homology phosphatase 2 (Shp2) ameliorated lipopolysaccharide-induced renal injury. This study aims to evaluate the contribution of Shp2 to podocyte function under hyperglycemia and explore the molecular underpinnings. We report elevated Shp2 in the E11 podocyte cell line under high glucose and the kidney under streptozotocin- and high-fat diet-induced hyperglycemia. Consistently, Shp2 disruption in podocytes was associated with partial renoprotective effects under hyperglycemia, as evidenced by the preserved renal function. At the molecular level, Shp2 deficiency was associated with altered renal insulin signaling and diminished hyperglycemia-induced renal endoplasmic reticulum stress, inflammation, and fibrosis. Additionally, Shp2 knockdown in E11 podocytes mimicked the in vivo deficiency of this phosphatase and ameliorated the deleterious impact of high glucose, whereas Shp2 reconstitution reversed these effects. Moreover, Shp2 deficiency attenuated high glucose-induced E11 podocyte migration. Further, we identified the protein tyrosine kinase FYN as a putative mediator of Shp2 signaling in podocytes under high glucose. Collectively, these findings suggest that Shp2 inactivation may afford protection to podocytes under hyperglycemia and highlight this phosphatase as a potential target to ameliorate glomerular dysfunction in DN.

Background & Aims: Alcohol-associated liver disease (ALD) is a significant cause of liver-related morbidity and mortality worldwide and with limited therapies. Soluble epoxide hydrolase (sEH; Ephx2) is a largely cytosolic enzyme that is highly expressed in the liver and is implicated in hepatic function, but its role in ALD is mostly unexplored. Methods: To decipher the role of hepatic sEH in ALD, we generated mice with liver-specific sEH disruption (Alb-Cre; Ephx2fl/fl). Alb-Cre; Ephx2fl/fl and control (Ephx2fl/fl) mice were subjected to an ethanol challenge using the chronic plus binge model of ALD and hepatic injury, inflammation, and steatosis were evaluated under pair-fed and ethanol-fed states. In addition, we investigated the capacity of pharmacologic inhibition of sEH in the chronic plus binge mouse model. Results: We observed an increase of hepatic sEH in mice upon ethanol consumption, suggesting that dysregulated hepatic sEH expression might be involved in ALD. Alb-Cre; Ephx2fl/fl mice presented efficient deletion of hepatic sEH with corresponding attenuation in sEH activity and alteration in the lipid epoxide/diol ratio. Consistently, hepatic sEH deficiency ameliorated ethanol-induced hepatic injury, inflammation, and steatosis. In addition, targeted metabolomics identified lipid mediators that were impacted significantly by hepatic sEH deficiency. Moreover, hepatic sEH deficiency was associated with a significant attenuation of ethanol-induced hepatic endoplasmic reticulum and oxidative stress. Notably, pharmacologic inhibition of sEH recapitulated the effects of hepatic sEH deficiency and abrogated injury, inflammation, and steatosis caused by ethanol feeding. Conclusions: These findings elucidated a role for sEH in ALD and validated a pharmacologic inhibitor of this enzyme in a preclinical mouse model as a potential therapeutic approach.