Search Results (813)

Early weaning in intensive lamb production improves reproductive efficiency but predisposes lambs to diarrhea, oxidative stress, and intestinal barrier dysfunction, highlighting the need for non-antibiotic strategies to protect gut health. This study evaluated whether a sheep-derived mixed probiotic could alleviate early weaning–induced intestinal injury and clarified its potential molecular mechanisms. Early weaning reduced body weight, average daily gain and feed efficiency, increased diarrhea, decreased plasma and colonic catalase (CAT), glutathione peroxidase (GSH-PX), and superoxide dismutase (SOD) activities, increased malondialdehyde (MDA), elevated interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), reduced interleukin-10 (IL-10) and transforming growth factor-β (TGF-β), increased plasma and mucosal immunoglobulin A, M, and G (IgA, IgM, IgG), and increased colonic lipopolysaccharide (LPS) with reduced diamine oxidase (DAO). Intestinally, EW induced villus atrophy, deeper crypts, lower villus height-to-crypt depth ratios, goblet cell loss, higher histopathological scores, and decreased colonic mucin 2, zonula occludens-1, claudin-1, and occludin. Probiotic supplementation partially reversed these alterations, restoring antioxidant enzyme activities, improving villus architecture and barrier protein expression, and rebalancing cytokine and immunoglobulin profiles. Transcriptomic and network analyses showed that early weaning activated Cytokine–cytokine receptor, NF-κB, TNF and Th17 pathways, whereas probiotics suppressed a weaning-responsive inflammatory gene module, downregulated key hub genes, and enhanced peroxisome proliferator-activated receptor (PPAR) signaling. These results show that supplementing early-weaned lambs with a mixed probiotic generated from sheep is an efficient nutritional strategy to reduce intestinal oxidative and inflammatory damage associated with weaning and to enhance their health and performance. Full article

Background: Pulmonary fibrosis (PF) currently lacks effective therapeutic interventions. Roxadustat, an oral small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase, has been shown in several studies to attenuate the progression of fibrotic diseases. However, its therapeutic efficacy in PF remains to be fully elucidated. The aim of this study was to evaluate roxadustat’s therapeutic benefits on PF as well as the underlying mechanisms of action. Methods: Bleomycin was administered intraperitoneally to establish a PF mouse model. H&E staining, Masson staining, and immunohistochemistry (IHC) were used to assess histopathological and fibrotic changes. Changes in the expression levels of inflammatory mediators, including IL-1β, TGF-β1, and TNF-α, were examined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Network pharmacology combined with transcriptomic analysis was employed to identify potential target genes and associated signaling pathways. Subsequently, RT-qPCR and Western blot analyses were carried out to experimentally validate the predicted targets and pathways and to verify the protective effects of roxadustat in PF mice. Results: Roxadustat markedly ameliorated bleomycin-induced pulmonary fibrosis in mice. The therapeutic effect was evidenced by a reduction in alveolar damage, thinner alveolar septa, diminished infiltration of inflammatory cells, and decreased collagen deposition. Concomitantly, the expression levels of inflammatory mediators, including IL-1β, TGF-β1, and TNF-α, were significantly lowered. Integrated network pharmacology and transcriptomic analyses revealed the involvement of critical signaling pathways, specifically nuclear factor-kappa B (NF-κB) and peroxisome proliferator-activated receptor (PPAR). Experimental validation further demonstrated that roxadustat downregulated the expression of key genes (S100A8, S100A9, and Fos) in murine lung tissues. It also suppressed the protein ratios of phosphorylated p65 to total p65 and phosphorylated IκBα to total IκBα. Moreover, roxadustat treatment upregulated PPARγ protein expression. Conclusions: These data indicate that roxadustat ameliorates bleomycin-induced PF in mice, an effect associated with modulation of the NF-κB and PPAR signaling pathways. The findings provide a preclinical rationale for further investigation of roxadustat as a potential treatment for PF. Full article

Piglets weaning is a critical developmental stage marked by significant metabolic and inflammatory challenges. The hepatic responses during this period may differ among pig breeds with distinct genetic backgrounds. To explore the phenotypic and molecular differences in the livers between the Zaozhuang Heigai (HG) pig and Duroc×Landrace×Yorkshire (DLY) piglets and elucidate the regulatory mechanisms of genetic background on liver function, five 35-day-old piglets from each breed were selected. Body weight and liver coefficients were measured; histological features of liver sections were observed, and the transcriptome and metabolome of the liver were determined using mRNA sequencing and non-targeted metabolomics analysis. The results showed that HG piglets had significantly lower body weight (p < 0.01) and slightly higher liver coefficients than DLY piglets. Histological examination revealed that the hepatic lobule structure was intact in both breeds, while mild hepatic congestion was observed in some DLY piglets. Transcriptome analysis identified 429 differentially expressed genes (DEGs) with criteria of FDR adjusted p-values < 0.01 and |log₂(Fold Change)| > 1, and they were significantly enriched in oxidoreductase activity, peroxisome proliferator-activated receptor (PPAR) signaling, and arachidonic acid metabolism pathways. Metabolome analysis identified 169 differentially expressed metabolites (DEMs) with criteria of p < 0.05, VIP > 1, and |log₂(Fold Change)| > 1, and they were significantly enriched in nucleotide metabolism, arginine biosynthesis, and arachidonic acid metabolism pathways. Integrative analysis of DEGs and DEMs showed that arachidonic acid metabolism was the common pathway. Within this pathway, key genes (GPX3, ALOX5, and CBR3) were significantly associated with specific metabolites (15-deoxy-PGJ₂ and phosphatidylcholines) (FDR adjusted p < 0.05), suggesting a gene–metabolite interaction network that coordinates inflammatory regulation and oxidative stress. These findings provide molecular evidence for breed-specific hepatic metabolic regulation during the weaning period and are therefore conducive to the management of weaned piglets and the investigation of local pig characteristics. Full article

Background/Objectives: Significant heterogeneity in the treatment response to peroxisome proliferator-activated receptor γ (PPARγ) agonists exists, and predictive factors for their efficacy remain unclear. We aimed to assess the relationships between routinely available clinical features and the efficacy of PPARγ agonists and pan-PPAR agonists by meta-regression analysis. Methods: We searched PubMed, Embase, Cochrane Library, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) and included randomised controlled trials involving type 2 diabetes patients with 12-week or longer treatment durations with PPARγ agonists or pan-PPAR agonists published before 11 November 2023 (PROSPERO registration number: CRD42024578987). We conducted mixed-effect meta-regression analyses between baseline variables and treatment response. Moreover, we developed a machine learning-based meta-forest model and ranked the relative importance of each variable. Results: In 147 studies involving 29,250 participants, PPARγ and pan-PPAR agonists significantly reduced HbA1c (mean difference(MD) = −0.8876 [95% confidence interval (CI): −0.8999, −0.8754]; p < 0.0001, I² = 96.0%) and FPG = (MD = −1.7900 [95% CI: −1.9137, −1.6663]; p < 0.0001, I² = 92.0%). Multivariable association analysis suggested that a greater proportion of female participants (β = 0.0066 [95% CI: 0.0012, 0.0121]; p = 0.017), younger age (β = −0.0314 [95% CI: −0.05, −0.0129]; p = 0.0009) and lower HDL-C levels (β = −0.9304 [95% CI: −1.5176, −0.3431]; p = 0.0019) were significantly associated with a greater decrease in HbA1c. A greater proportion of female participants (β = 0.0112 [95% CI: 0.0019, 0.0205]; p = 0.0178) and lower baseline HDL-C levels (β = −1.8722 [95% CI: −2.812, −0.9323]; p < 0.0001) were significantly associated with a greater decrease in FPG. These variables also ranked among the top five most important predictors of drug response in the meta-random forest models. Conclusions: Our study demonstrated that female sex, younger age, and lower HDL-C levels were associated with greater glycaemic lowering effect from PPARγ and pan-PPAR agonists. Full article

Obesity has reached epidemic proportions, driven by energy imbalance and limited capacity for adaptive thermogenesis. Brown (BAT) and beige adipose tissues dissipate energy through non-shivering thermogenesis (NST), primarily via uncoupling protein-1 (UCP1), making them attractive targets for increasing energy expenditure (EE). The canonical β-adrenergic pathway robustly activates NST in rodents through β3 adrenoceptors; however, translational success in humans has been limited by low β3 expression, off-target cardiovascular effects, and the emerging dominance of β2-mediated signaling in human BAT. Consequently, attention has shifted to non-adrenergic and UCP1-independent mechanisms that offer greater tissue distribution and improved safety profiles. This review examines a broad spectrum of alternative receptors and pathways—including GPRs, TRP channels, TGR5, GLP-1R, thyroid hormone receptors, estrogen receptors, growth hormone, BMPs, sirtuins, PPARs, and interleukin signaling—as well as futile substrate cycles (Ca²⁺, creatine, and glycerol-3-phosphate) that sustain thermogenesis in beige adipocytes and skeletal muscle. Pharmacological agents (natural compounds, peptides, and small molecules) and non-pharmacological interventions (cold exposure, exercise, diet, and time shift) targeting these pathways are critically evaluated. We highlight the translational gaps between rodent and human studies, the promise of multimodal therapies combining low-dose adrenergic agents with non-adrenergic activators, and emerging strategies such as sarco/endoplasmic reticulum calcium ATPase protein (SERCA) modulators and tissue-specific delivery. Ultimately, integrating adrenergic and non-adrenergic approaches holds the greatest potential for safe, effective, and sustainable obesity management. Full article

Background: Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a multifactorial liver disease in which mitochondrial dysfunction, oxidative stress, and inflammation play key roles in driving the progression toward metabolic dysfunction-associated steatohepatitis (MASH) and hepatocellular carcinoma (HCC). Dysfunctional mitochondria generate excess reactive oxygen species (ROS), impair antioxidant defenses, activate pro-inflammatory pathways and hepatic stellate cells, and perpetuate liver injury. Mitochondrial Complex I is a major ROS source, particularly under conditions of dysregulated energy metabolism. Since Complex I inhibition by metformin was shown to reduce ROS and activate the adenosine monophosphate-activated protein kinase (AMPK), this study aimed to evaluate whether a novel Complex I Modulator (CIM, BI4500) could attenuate oxidative stress, inflammation, and consequently reduce lipid accumulation and fibrosis in a methionine- and choline-deficient diet (MCD)-fed rat model of MASH. Methods: Rats were fed an MCD or an isocaloric control diet for six weeks. From week four, animals received daily oral treatment with CIM (10 mg/kg) or vehicle (Natrosol). At the endpoint, liver tissue was collected for histological, biochemical, and molecular analyses. Lipid droplet area, inflammatory infiltration, and collagen deposition were evaluated on tissue sections; total lipid content and oxidative stress markers were assessed in homogenates and isolated mitochondria. Molecular pathways related to oxidative stress, lipid metabolism, and fibrosis were assessed at protein and mRNA levels. Results: CIM treatment significantly reduced oxidative stress (ROS, lipid peroxidation, nitrogen species), promoting AMPK activation and metabolic reprogramming. This included increased expression of peroxisome proliferator-activated receptor alpha (PPAR-α) and its target genes, and decreased sterol regulatory element binding protein-1c (SREBP-1c)-driven lipogenesis. These changes halted fibrosis progression, as confirmed by Picro-Sirius Red staining and fibrosis markers. Conclusions: these findings indicate that Complex I modulation may represent a promising strategy to counteract MASLD progression toward MASH. Full article

Fibroblasts play a fundamental role in maintaining tissue architecture, regulating repair processes, and adapting to metabolic and inflammatory stress. Increasing evidence indicates that endogenous bioelectrical states contribute to gene expression regulation and cellular homeostasis. In this study, we investigated the effects of Radio Electric Asymmetric Conveyer (REAC) Metabolic Optimization–Inside Blue Zone (MO-IBZ) treatment on key regulators of stress response and metabolic control in human foreskin fibroblasts (HFF-1). Cells were exposed to nine standardized REAC MO-IBZ sessions, and changes in gene and protein expression were evaluated. Quantitative RT-PCR revealed a significant downregulation of SIRT1 and an upregulation of PPAR-γ expression in treated cells compared with untreated controls. These findings indicate molecular changes involving stress-responsive and metabolic regulatory pathways; however, they should be interpreted primarily as transcriptional signatures, as no direct functional stress-response or metabolic assays were performed. Immunofluorescence analysis showed visually increased expression of mTOR, IGF-1 receptor, and cytochrome c in REAC-treated fibroblasts, supporting a qualitative indication of activation of pathways associated with anabolic signaling, mitochondrial function, and metabolic efficiency. Taken together, these findings indicate that REAC MO-IBZ induces a coordinated molecular profile compatible with changes in cellular metabolic regulatory capacity. Within the framework of current bioelectrical literature, these changes may plausibly reflect broader regulatory adaptations; however, the present work does not provide direct measurements of bioelectrical parameters, functional metabolic activity, or epigenetic regulation, and therefore such interpretations remain speculative. These results provide descriptive mechanistic evidence supporting further investigation of REAC-based bioelectrical modulation as a potential strategy to influence cellular pathways involved in metabolic balance and tissue repair, encouraging future studies incorporating direct bioelectrical, epigenetic, and functional analyses. Full article

Medium- and long-chain fatty acids (MLFAs) are increasingly recognized not only as metabolic substrates but also as precursors of diverse bioactive metabolites generated through host and microbial transformations. Recent advances in analytical chemistry and microbiome research have revealed that gut microorganisms catalyze extensive modifications of dietary MLFAs—producing hydroxylated, conjugated, and keto-fatty acids with enhanced potency toward host receptors. These metabolites exhibit dual activity on classical metabolic receptors, including FFAR1/4 and PPARα/γ, as well as ectopically expressed chemosensory receptors such as olfactory receptors (ORs) and bitter taste receptors (TAS2Rs). This expanded receptor landscape establishes a previously unrecognized chemosensory–metabolic axis that integrates dietary signals, microbial metabolism, and host physiology. Microbial MLFA derivatives such as 10-hydroxyoctadecenoic acid and conjugated linoleic acid regulate incretin secretion, adipogenesis, macrophage polarization, and intestinal barrier function through coordinated activation of FFARs and PPARs. Concurrently, dicarboxylic acids such as azelaic acid activate Olfr544 to modulate lipolysis, ketogenesis, GLP-1 release, and feeding behavior. TAS2Rs also sense oxidized lipids, linking lipid metabolism to immune regulation and enteroendocrine signaling. Collectively, these pathways highlight the microbiome as a metabolic transducer that converts dietary lipids into signaling molecules influencing endocrine, immune, and gut–brain circuits. Understanding the mechanisms governing MLFA bioconversion and receptor engagement provides new opportunities for therapeutic and nutritional intervention. Targeting ORs and TAS2Rs, engineering probiotics to enhance beneficial FA-derived metabolites, and developing receptor-selective synthetic analogs represent promising strategies. Future progress will require integrative approaches combining physiology, biochemistry, metabolomics, and microbial genomics to elucidate receptor specificity and host variability. Full article

This study investigated the molecular and microbial factors behind the higher disease resistance of hybrid taimen by combining gut microbiome profiling with host transcriptomic analysis of intestinal and liver tissues. Both hybrid taimen and H. taimen were raised under the same recirculating aquaculture system (RAS) conditions. After recording survival rates following three enteritis outbreaks, samples of intestinal contents and tissues were collected from both groups. The gut microbiota was analyzed using full-length 16S rRNA sequencing in PacBio, and host gene expression was assessed with Illumina RNA-seq. Functional predictions were made using PICRUSt2 and Gene Set Enrichment Analysis (GSEA). Results showed that hybrids had significantly higher survival rates after enteritis (p < 0.05). Although microbial alpha diversity was similar, beta diversity revealed slight compositional differences. Hybrids showed higher levels of Hapalosiphon and Tepidimicrobium, microbes associated with antimicrobial compounds and the metabolism of short-chain fatty acids (SCFAs). Functional predictions indicated enrichment in selenocompound metabolism and ansamycin biosynthesis in hybrids. Transcriptomic analysis identified 4233 differentially expressed genes (DEGs) in the intestine and 3980 in the liver. In hybrids, intestinal tissues exhibited increased expression of immune pathways, including complement activation, lysosomal activity, and the transforming growth factor-beta (TGF-β) signaling pathway. Liver tissues demonstrated higher expression of genes related to cholesterol synthesis, fatty acid degradation, and the peroxisome proliferator-activated receptor (PPAR) signaling pathway. qRT-PCR validated the expression patterns of 20 selected DEGs. These findings tentatively suggest that the elevated disease resistance of hybrid taimen may be linked, at least in part, to a combination of microbial taxa inferred to produce antimicrobial metabolites and short-chain fatty acids, as well as an apparent intensification of intestinal immune and barrier-related gene expression, and hepatic pathways that possibly support energy supply and steroid-based immunity. However, this multi-omics data set is only correlational. We still do not know whether a single strain or a few host genes are enough to produce the resistant phenotype. Gnotobiotic trials, microbiota transplants, and targeted metabolomics will be necessary to turn these interesting associations into solid evidence. Full article

Major depressive disorder is increasingly recognized as a metabolic–immune disorder in which chronic inflammation diverts tryptophan (Trp) metabolism toward the kynurenine pathway (KP), reducing serotonin synthesis and producing neurotoxic metabolites such as quinolinic acid (QA). Elevated kynurenine (KYN)/Trp ratios and an altered QA/kynurenic acid (KYNA) balance have been consistently reported in depressed individuals, implicating the KP as a key therapeutic target. Exercise provides a unique, translationally relevant intervention: unlike pharmacological agents acting directly on neurotransmission, contracting skeletal muscle acts as a “kynurenine sink” by inducing kynurenine aminotransferases that convert circulating KYN into neuroprotective KYNA, thereby reducing brain KYN uptake and mitigating excitotoxicity. Clinical studies and meta-analyses confirm that aerobic, resistance, and high-intensity training produce antidepressant effects comparable to pharmacotherapy, while also improving cognition, fatigue tolerance, and cardiometabolic function. Beyond KP remodeling, exercise-induced myokines (irisin, IL-6, BDNF, apelin, FGF21) and adipokines (adiponectin, leptin modulators) coordinate systemic anti-inflammatory and neurotrophic adaptations that enhance resilience and brain plasticity. Furthermore, pharmacological “exercise mimetics” and metabolic modulators, such as PPAR agonists, AMPK activators, NAD⁺ boosters, meldonium, trimetazidine, and adiponectin receptor agonists, may be promising adjuncts for patients with low exercise capacity or metabolic comorbidities. This review provides a novel concept, positioning exercise as a systemic antidepressant that breaks the kynurenine lock of depression. Through proper interpretation of skeletal muscle as an endocrine organ of resilience, we integrate molecular, clinical, and translational findings to show how exercise remodels Trp–KYN metabolism and inflammatory signaling and how pharmacological mimetics may extend these benefits. This perspective consolidates scattered mechanistic and clinical data and outlines a forward-looking therapeutic framework that links exercise and lifestyle, metabolism, and drug discovery. We highlight that re-consideration of our understanding of depression, as a whole-body disorder, should provide new opportunities for precision interventions. Full article

Macrophages are versatile immune cells capable of modifying their functions based on their location and the specific requirements of the immune response. They polarize into the M1 phenotype when stimulated by inflammatory agents. In contrast to resolve inflammation and to facilitate tissue repair, macrophages polarize into the M2 phenotype. Polarization alters the cellular composition of the macrophages, including peroxisomes and peroxisome proliferator-activated receptors (PPARs). In macrophages, peroxisomes and PPARs perform at least three key roles: mediating inflammation, reducing oxidative stress, and regulating lipid metabolism. We review the functional role of peroxisomes and PPARs on macrophage biology focusing on adaptive mechanisms during these processes. The insights gained from this analysis are expected to lead to new advancements in treating inflammation and immune-related disorders, including autoimmune disorders, metabolic inflammation, and neurodegenerative conditions. Full article

Background: Lipid overaccumulation in the liver predisposes ducks to metabolic disorders. The molecular mechanism of oleic acid (OA)-induced hepatic steatosis in ducks is not fully elucidated. Methods: A cellular model of steatosis was established by treating primary duck hepatocytes with OA. Transcriptome sequencing was performed to identify key signaling pathways and candidate genes. The role of Apolipoprotein A1 (APOA1) was investigated through overexpression and knockdown experiments. Intracellular triglycerides (TGs) were quantified commercially; lipid droplets were visualized by Oil Red O staining. Results: Intracellular TG accumulation was induced by OA treatment in a dose-dependent manner. Through transcriptome analysis, 1045 differentially expressed genes (DEGs) were identified, with APOA1 being recognized as a key candidate within the peroxisome proliferator-activated receptor (PPAR) signaling pathway. The content of TGs and lipid droplets was increased by APOA1 overexpression, whereas these effects were suppressed by APOA1 knockdown. The expression of acetyl-CoA carboxylase alpha (ACACA) and fatty acid synthase (FASN) was upregulated by APOA1. Conversely, the expression of carnitine O-palmitoyltransferase 1 (CPT1), acyl-CoA oxidase 1 (ACOX1), and apolipoprotein B (APOB) was downregulated. Conclusions: This study demonstrates that OA upregulates APOA1, suggesting the involvement of the PPAR pathway and providing a theoretical basis for modulating hepatic fat deposition. Full article

There is a wealth of information available about endogenous fatty acid ligands for peroxisome proliferator-activated receptor α/δ/γ (PPARα/δ/γ); however, there are few comparative studies of PPARα/δ/γ activation using standardized experimental systems. This study investigated which of 14 major free long-chain fatty acids (LCFAs: C12:0–C22:6) and 15-deoxy-Δ^12,14-prostaglandin J2 (15d-PGJ2) activate PPARα/δ/γ using a coactivator recruitment assay. We recently discovered that eight different synthetic PPAR agonists recruit four different coactivator peptides (PGC1α, CBP, SRC1, TRAP220) with varying potency and efficacy, so we examined the ligand-concentration-dependent recruitment of these four coactivators. All 15 fatty acids (FAs) activated PPARα/δ at high concentrations, but only palmitic acid, stearic acid, oleic acid, and linoleic acid significantly activated PPARα/δ at physiologically relevant concentrations. Lauric acid, myristic acid, palmitic acid, and 15d-PGJ2 activated PPARγ at high concentrations, but only palmitic acid slightly activated PPARγ at physiologically relevant concentrations. FA ligands exhibited different coactivator preference compared to synthetic PPAR agonists, including approved drugs such as pemafibrate, seladelpar, and pioglitazone, suggesting that these agonists may regulate target gene transcription in a different manner than natural FA ligands. Such differences may be relevant to the pathogenesis of side effects of synthetic PPAR agonists occasionally observed in (pre)clinical studies. Full article

Objectives: Aqueous mulberry leaf extract (MLE) contains 1-deoxynojirimycin (DNJ) and L-leucine (LL). This study investigated the effects of MLE, DNJ, and LL on lipid accumulation caused by palmitic acid (PA) in human hepatoma HepG2 cells, pro-inflammatory cytokine levels, and regulation of lipogenesis. Methods: PA was applied to HepG2 cells to generate a fatty liver in vitro model. Then, the cells were treated with MLE, DNJ, or LL for 24 h. Western blot analysis was performed to determine the protein expression levels of peroxisome proliferator-activated receptor gamma (PPAR-γ) and fatty acid synthase (FAS) in HepG2 cells. Results: Staining with Oil Red O (ORO) indicated that MLE, DNJ, and LL significantly decreased excessive lipid accumulation in HepG2 cells. Cytokine ELISA assay indicated that MLE, DNJ, and LL significantly decreased excessive pro-inflammatory cytokine levels in HepG2 cells. In addition, MLE, DNJ, and LL decreased the protein expression levels of PPAR-γ and FAS, suggesting a potential suppression of lipogenesis. Conclusions: Our results suggest that MLE, DNJ, and LL reduce lipid accumulation, pro-inflammatory cytokine levels, and the protein expressions of FAS and PPAR-γ in PA-induced fatty liver cells. Full article

Prostaglandin E₂ (PGE₂) has been implicated in multiple biological processes during pregnancy in ruminants. However, the regulatory effects of PGE₂ on endometrial function during the diestrus period and its underlying molecular mechanisms remain poorly understood. Herein, PGE₂ treatment promoted the accumulation of lipid droplets and induced cytoskeletal reorganization in bEECs. As a well-established inducer of lipid droplet formation, oleic acid (OA) treatment significantly increased the number of lipid droplets in bEECs, altered the distribution of F-actin and disrupted the expression patterns of key adhesion-related proteins. Transcriptomic analysis revealed that the PPAR signaling pathway was the key pathway that responded to PGE₂ treatment in bEECs, and its downstream target gene FABP3 was markedly up-regulated. Knockdown of FABP3 led to a reduced number of BTC spheroids and down-regulation of adhesion-related proteins in bEECs while increasing the density of microvilli and up-regulating the expression of epithelial markers. Prostaglandin E receptor 4 (PTGER4) was the primary receptor that responded to PGE₂ treatment, and PTGER4 knockdown or pharmacological inhibition with GW-627368 suppressed FABP3 expression in bEECs. Moreover, uterine samples from dairy cows at different stages of the estrous cycle showed that FABP3 expression was significantly elevated in the endometrium tissue during mid-diestrus compared to metestrus, with predominant localization in the luminal and superficial glandular epithelium. Collectively, these findings indicate that FABP3 regulates lipid droplet accumulation and adhesion ability in bEECs via the PGE₂/PTGER4/PPAR signaling axis, providing new insights into the metabolic regulation of endometrial receptivity in ruminants. Full article