Search Results (97)

Elevated plasma lipoprotein(a) [Lp(a)] levels represent a predominantly genetically determined risk factor for atherosclerotic cardiovascular disease and calcific aortic valve disease (CAVD). Mechanistically, Lp(a) transports oxidized phospholipids, lysophosphatidylcholine, and autotaxin, components capable of promoting inflammation, oxidative stress, and valvular fibrocalcific remodeling. This review synthesizes the molecular, cellular, and clinical evidence linking Lp(a) to CAVD progression. Retention of Lp(a) and other apolipoprotein B-containing lipoproteins in the valvular matrix promotes endothelial activation, recruitment of cells of the monocytic lineage, and the release of proinflammatory mediators. Oxidized phospholipids and the autotaxin–lysophosphatidic acid axis activate redox-dependent pathways and promote the transition of valvular interstitial cells toward myofibroblastic and/or osteogenic phenotypes. These processes converge in alterations in cholesterol metabolism, the release of procalcifying extracellular vesicles, and hydroxyapatite nucleation. Genetic and imaging evidence supports an association between elevated Lp(a), microcalcifying activity, and accelerated hemodynamic progression. Although anti-Lp(a) therapies substantially reduce plasma Lp(a) concentrations, their effect on valvular outcomes has not yet been demonstrated. Full article

Major depressive disorder (MDD) is not reducible to a single neurotransmitter deficit. Current explanations commonly involve monoaminergic dysfunction, hypothalamic–pituitary–adrenal axis dysregulation, immune-inflammatory activation, impaired neuroplasticity and synaptic dysfunction, together with metabolic and neurovascular abnormalities. Lipidomic studies have repeatedly identified glycerophospholipid abnormalities in MDD, but their mechanistic meaning remains unresolved because changes in bulk lipid abundance do not explain how altered lipid metabolism becomes a receptor-level neural signal. This review develops a testable interpretation of the lysophosphatidylcholine (LPC)–autotaxin (ATX)–lysophosphatidic acid (LPA)–LPA receptor (LPAR) axis in which LPC species generated during phospholipid turnover provide ATX substrates, ATX activity determines local LPA generation, LPA production and inactivation shape ligand availability, and LPAR signaling links the lipid product to neural output. This structure shifts the focus from total lipid abundance to matched assessment of lipid species, enzyme activity, anatomical site and receptor subtype. Human studies report lower serum and cerebrospinal fluid (CSF) ATX in MDD, lower CSF LPA 22:6 in MDD and schizophrenia, and negative total LPA findings that caution against biomarker oversimplification. Depression-relevant and broader stress- or anxiety-related experimental studies show that ATX, LPA and LPAR perturbation can affect hippocampal function, synaptic physiology, emotional behavior and stress resilience. The key unresolved issue is whether brain-accessible LPC species, active ATX, locally generated LPA, LPA inactivation capacity and receptor-specific output can be demonstrated within the same MDD-relevant fluid, brain-interface site or neural circuit. Future work should therefore move from fluid-level association toward pathway closure through targeted and spatial lipidomics, anatomical ATX activity mapping, LPA inactivation assays, blood–brain barrier (BBB)/interface analysis, LPAR perturbation and matched circuit or behavioral readouts. Full article

Background: Idiopathic pulmonary fibrosis (IPF) is an incurable disease with limited therapeutic options and a poor prognosis. Current standard therapies are characterized by drugs or surgical strategies with limited effects, as they are either not curative or their use is restricted to a specific subset of the population. The aim of this scoping review is to evaluate the drugs currently under investigation in Phase II and Phase III trials and provide an overview of the mechanisms of new therapeutic strategies for IPF. Methods: The search strategy was conducted in accordance with PRISMA guidelines and included studies conducted on adults with IPF retrieved from the registered ClinicalTrials.gov database up to 31 December 2025. Results: Nineteen studies were included. The clinical trials investigate key signaling pathways and molecular targets, including MAPK, RhoA/ROCK, PDE4B/cAMP, Wnt/β-catenin, Hedgehog/SMO, IL-11/STAT3, and LPA/autotaxin, as well as extracellular receptors and mediators such as CSF1R, TBXA2R, and WISP1. Conclusions: Ongoing clinical research in IPF reflects a broad diversification of molecular targets; however, translational success remains limited. Current evidence suggests that biological complexity, pathway redundancy, and systemic constraints significantly restrict the clinical impact of single-target strategies. Future progress will likely depend on improved patient stratification, combination approaches, and biomarker-guided trial design rather than isolated pathway modulation. Full article

Abnormal intestinal mucosal immunity plays a crucial role in ulcerative colitis (UC). Autotaxin (ATX) can promote T cell migration and was reported to have a regulatory effect on Th17 cells, while sphingosine-1-phosphate (S1P) and its receptors (S1PRs) modulate Th17/Treg balance and inflammation, with S1PR modulators approved for UC. ATX can catalyze sphingosylphosphorylcholine (SPC) to produce S1P; however, the relationship between ATX and S1P/S1PRs in UC is unclear. Understanding the role of ATX-S1P/S1PRs in intestinal immunity can provide new treatment strategies for intestinal inflammatory diseases. Both UC patients and DSS-induced colitic mice showed significantly increased levels of ATX and S1P compared with healthy controls. ATX inhibitor PF8380 treatment led to reduced levels of S1P/S1PRs in colitic mice. Consistent with this, the S1PR antagonist etrasimod was able to alleviate ATX-induced intestinal inflammation, as well as partially restore ATX-induced Th17/Treg imbalance in MLNs and the spleen. In HT-29 and Raw246.7 cells, ATX treatment led to enhanced expression of S1P/S1PRs, with S1PR1 being the most significant. Furthermore, S1PR1 mediates the effect of ATX on Th17/Treg cell differentiation and function in vivo. Therefore, ATX affects the differentiation and function of Th17/Treg cells through S1P/S1PR1 signaling, increased ATX expression leading to Th17/Treg cell imbalance, intestinal mucosal immune dysfunction, and exacerbating intestinal inflammation. Full article

Retinal vein occlusion (RVO) is a common vascular disease that leads to vision loss due to macular edema (ME). This study investigated the role of autotaxin (ATX), a lysophospholipase D, in the pathogenesis of RVO. In mice, RVO was induced by intravenous administration of rose bengal followed by laser irradiation of retinal veins. ATX expression in the retina was evaluated using immunohistochemistry. Intravitreal ATX was administered, and retinal changes were assessed using fluorescence angiography and optical coherence tomography (OCT). In human retinal microvascular endothelial cells (HRMECs), intercellular barrier function was evaluated using transepithelial electrical resistance (TEER). In the murine RVO model, the ATX inhibitor HA130 was administered intravitreally, and retinal thickness was measured and compared using OCT. ATX expression was increased in retinal vessels in the RVO model. Intravitreal administration of ATX induced retinal edema and serous retinal detachment (SRD). ATX significantly disrupted the barrier integrity of HRMECs and promoted the expression of vascular endothelial growth factor (VEGF), which was ameliorated by HA130. Intravitreal administration of HA130 significantly reduced retinal thickening caused by retinal edema secondary to RVO and the elevated expression of intercellular adhesion molecule (ICAM)-1 in the retina. These findings suggest that ATX plays a critical role in RVO-induced ME by disrupting endothelial barrier integrity, potentially through the upregulation of VEGF in retinal endothelial cells and subsequent ICAM-1 upregulation in the retina. Full article

Kidney transplantation (KTx) corrects many uremia-related metabolic disturbances; however, dyslipidemia remains common in kidney transplant recipients and contributes to persistent cardiovascular risk. Lipoprotein(a) [Lp(a)] is a largely genetically determined proatherogenic lipoprotein that increases in advanced chronic kidney disease (CKD) and may decrease after restoration of renal function. Autotaxin (ATX), an enzyme involved in proinflammatory lipid signaling through the ATX–lysophosphatidic acid axis, has also been implicated in cardiovascular pathology, but its early post-transplant dynamics remain poorly characterized. In addition to quantitative lipid abnormalities, CKD is associated with high-density lipoprotein (HDL) dysfunction and reduced paraoxonase-1 (PON-1) activity; however, data on early post-transplant changes in PON-1 activity are limited. In this prospective observational study, lipid profile parameters, Lp(a) concentration, ATX activity, and PON-1 activity were assessed in 55 Caucasian patients with CKD stage 5, most of whom were dialysis-dependent, before and 2–3 weeks after KTx. All recipients received tacrolimus-based maintenance immunosuppression with corticosteroids and mycophenolate mofetil. After KTx, Lp(a) levels decreased by a median of 21% and ATX activity by 28% (both p < 0.001). Lp(a) and ATX showed no cross-sectional or longitudinal association either before or after transplantation, and their percentage changes were not correlated. In contrast, conventional lipid fractions increased significantly, including total cholesterol (+22%), LDL cholesterol (+27%), HDL cholesterol (+24%), and triglycerides (+55%) (all p < 0.001). PON-1 activity increased by approximately 13% after KTx (p < 0.001), and its percentage change correlated positively with the increase in HDL cholesterol. In exploratory analyses, the magnitude of Lp(a) reduction was associated with early graft function: patients with eGFR <45 mL/min/1.73 m² exhibited a significantly smaller decline in Lp(a) than those with better graft function (−4.8% vs. −26.7%, p = 0.009). Multivariable analysis showed that demographic characteristics, body mass index, tacrolimus exposure, and post-transplant eGFR did not independently predict the magnitude of Lp(a) reduction. Tacrolimus trough concentrations and cumulative corticosteroid exposure were not associated with lipid parameters or their changes, except for a single subgroup difference in PON-1 activity of uncertain clinical significance. In summary, in the early period after KTx under tacrolimus-based immunosuppression, Lp(a) concentration and ATX activity decrease, whereas conventional lipid fractions increase and PON-1 activity improves. These changes were not associated with tacrolimus exposure or cumulative corticosteroid dose. The reduction in Lp(a) was associated with early graft function in exploratory analyses, suggesting that recovery of renal function may contribute to early post-transplant Lp(a) dynamics; however, no independent causal relationship was established, and the findings should be interpreted cautiously given the limited sample size and exploratory design. The clinical significance of these changes for long-term cardiovascular and graft outcomes requires further investigation. Full article

Scientific evidence supports the role of the autotaxin-lysophosphatidic acid (ATX-LPA) pathway in obesity and liver damage. The present study aim is to investigate variations in serum ATX and LPA levels across different BMI categories in a subcohort of subjects with MASLD. The study sample comprises 199 patients with liver steatosis from the most recent follow-up of the MICOL study, a prospective cohort study established in 1985, based on a random sample of the population of Castellana Grotte. In adjusted model, a positive association of BMI with ATX was observed when modeled as both a continuous (β = 0.018, p < 0.001, 0.012 to 0.024 95% C.I.) and categorical variable β = 0.170, p < 0.001, 0.111 to 0.228 95% C.I.). Conversely, a negative association was observed for LPA alone (β = −0.083, p = 0.020, −0.152 to −0.013 95% C.I.) and for the BMI and LPA interaction term (β = −0.109, p = 0.002, −0.176 to −0.042 95% C.I.). A positive association between ATX levels and BMI was found, whereas LPA levels tended to decrease with increasing BMI. Within the obese subgroup, ATX concentrations were notably higher in female compared to male participants. These findings suggest that elevated ATX in MASLD may reflect obesity-related metabolic and inflammatory alterations rather than adiposity alone, possibly involving altered LPA feedback and metabolism. Full article

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a frequent manifestation of obesity and other metabolic diseases. Autotaxin (ATX), an enzyme involved in the generation of lysophosphatidic acid (LPA), has recently emerged as a potential biomarker of metabolic inflammation and liver disease progression. Vegetable-based dietary interventions have been shown to reduce liver steatosis, but evidence of the impact of this dietary approach on ATX levels remains limited. Objectives: To evaluate the short-term effects of a bioactive vegetable-enriched diet from the Brassicaceae and Asteraceae families on serum ATX levels and liver-related parameters in individuals with obesity and MASLD, with a specific focus on sex differences. Methods: In this two-month pilot study, 44 obese adults (BMI > 30 kg/m²) underwent clinical and instrumental assessments at baseline (T0) and after the dietary intervention (T1). Results: After the intervention, serum ATX levels significantly decreased (from 206.3 ± 52.8 to 191.7 ± 45.7 ng/mL, p < 0.001), and there were improvements in metabolic parameters (BMI, waist circumference, blood pressure, fat mass, insulin, HOMA-IR, triglycerides, total and LDL cholesterol) and liver indices (CAP, ALT, AST, γGT). The multivariate GEE model confirmed a significant reduction in ATX, independent of age, sex, FFM, LPA, LSM, Hemoglobin A1c, and PAI-1 (β = −9.87, p < 0.001). When stratified by sex, women exhibited a more pronounced reduction in ATX levels (β = −12.24; p = 0.005) compared to men (β = −9.43; p = 0.014). Conclusions: A short-term, vegetable-enriched dietary intervention can significantly reduce serum ATX levels and improve metabolic and liver-related parameters in individuals with MASLD. Sex-specific analysis reveals a greater ATX-lowering effect in women, suggesting potential sex-based differences in ATX metabolism or dietary responsiveness. These findings suggest that ATX may serve as a modifiable biomarker responsive to nutritional intervention and a potential therapeutic target in metabolic liver disease. Full article

Bone marrow-derived mononuclear cells (BMMCs) have shown beneficial effects on tissue repair, largely attributed to the paracrine action of bioactive mediators such as lysophosphatidic acid (LPA). This study aimed to evaluate the effects of BMMC treatment in a rat model of renal ischemia/reperfusion (I/R) injury, focusing on LPA-related molecular pathways. Male Wistar rats were divided into three groups: control; I/R, subjected to bilateral renal artery clamping for 30 min followed by 24 h of reperfusion; and I/R + BMMC, which received 1 × 10⁶ BMMCs per kidney directly into the renal capsule post-ischemia. During reperfusion, the rats were placed in metabolic cages for urine collection, renal function and protein expression. BMMC treatment did not reverse the I/R-induced increase in urine volume or decrease in glomerular filtration rate, serum potassium, or filtered sodium load. However, it prevented proteinuria, increased blood urea nitrogen, and enhanced urinary potassium excretion. Mechanistically, BMMC treatment prevented I/R-induced upregulation of LPAR1, downregulated LPAR2 and LPAR3, restored plasma LPA levels, and reduced renal autotaxin content. These results suggest that BMMCs modulate harmful LPA-related signaling and may contribute to renal protection through paracrine mechanisms in the setting of acute I/R injury. Full article

Background: Autoimmune cholestatic liver diseases (AICLDs), including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), are characterized by progressive biliary injury and cholestasis, leading to an impaired quantity/quality of life. Pruritus affects 20–70% of patients and is often refractory to current treatments. Ileal bile acid transporter (IBAT) inhibitors reduce bile acid reabsorption and may alleviate cholestatic pruritus. This systematic review and meta-analysis evaluates their efficacy and safety in adults with AICLD. Methods: Following PRISMA guidelines, we systematically searched PubMed, Embase, and Cochrane-CENTRAL for studies assessing IBAT inhibitors in adult AICLD patients with pruritus for ≥12 weeks. The primary outcome was the change in the 5-D Pruritus Scale. Secondary outcomes included sleep quality, serum bile acids, liver biochemistry, and safety. Heterogeneity was assessed using Cochrane Q and I² statistics. Results: Three studies (n = 180) met inclusion criteria, including two RCTs and one single-arm study. Patients (78% female; 85% PBC; 77% linerixibat) showed a significant pruritus reduction (MD = −4.93, 95%CI [−6.26, −3.59], p < 0.0001), accompanied by improved sleep quality (MD = −8.12, 95%CI [−13.54, −2.70], p = 0.0033). Serum bile acids, FGF19, and autotaxin decreased significantly, with increased C4 levels. AST and GGT declined, while ALP, ALT, and bilirubin remained stable. Adverse events occurred in 89.7%, mainly diarrhea (22.7%), nausea (12.2%), and abdominal pain (18.2%); serious events were rare (2.2%). Conclusions: IBAT inhibitors significantly reduce pruritus and improve sleep in AICLD, with a favorable safety profile. These findings support their potential as a novel therapeutic option for cholestatic pruritus in adults with AICLD. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β plaques, tau hyperphosphorylation, and chronic neuroinflammation. Emerging evidence suggests a crucial role of lipid signaling pathways in AD pathogenesis, particularly those mediated by autotaxin (ATX) and lysophosphatidic acid (LPA). ATX, an enzyme responsible for LPA production, has been implicated in neuroinflammatory processes, blood–brain barrier dysfunction, and neuronal degeneration. LPA signaling, through its interaction with specific G-protein-coupled receptors, influences neuroinflammation, synaptic plasticity, and tau pathology, all of which contribute to AD progression. This review synthesizes recent findings on the ATX/LPA axis in AD, exploring its potential as a biomarker and therapeutic target. Understanding the mechanistic links between ATX, LPA, and AD pathology may open new avenues for disease-modifying strategies. Full article

Aortic stenosis (AS) is a progressive valvular heart disease characterized by fibrocalcific remodeling, inflammation, and hemodynamic disturbances. Serum biomarkers may indirectly reflect these processes. Autotaxin (ATX) and lysophosphatidic acid (LPA) have been implicated in osteogenic differentiation of valvular interstitial cells, while growth differentiation factor-15 (GDF-15) reflects cellular stress and vascular changes. Thrombomodulin (TM) indicates endothelial injury and interacts with thrombin. This study aimed to evaluate biomarkers focusing on serum ATX, LPA, GDF-15, and TM levels and flow-mediated dilatation (FMD) in patients with AS. Overall, 149 patients were included in the study: 86 consecutive patients with AS hospitalized due to qualification for invasive treatment of AS and 63 controls. The clinical characteristics, echocardiographic data, FMD, and the following biomarkers—ATX, LPA, GDF-15, and TM—were included in the analysis. AS patients presented increased serum levels of ATX, GDF-15, and TM as compared to the controls. Differences in LPA levels were not statistically significant. FMD values were significantly lower in AS patients. The biomarkers mentioned above and FMD correlated with AS severity. There were no differences in both biomarkers’ serum levels and FMD regarding the hemodynamic AS phenotype. GDF-15 serum level was a risk factor for all-cause mortality and MACCE in the 12-month follow-up. Full article

Patients with chronic cholestatic liver diseases often experience itch and struggle with this symptom. We discuss the mechanism of itch in patients with chronic cholestatic liver diseases, such as primary biliary cholangitis (PBC) and others, and their therapies, including ileal bile acid transporter (IBAT) inhibitors. In patients with PBC, there are high serum/plasma concentrations of multiple factors, including bile salts, bilirubin, endogenous opioids, lysophosphatidic acid (LPA), autotaxin, and histamine. Bile salts, bilirubin, LPA, and autotaxin affect itch mediators in the skin and sensory nerves, while the endogenous opioid balance affects mediators in the spinal cord. Itch is sensitized by both the peripheral and central nervous systems. Both mechanisms are involved in itch in patients with chronic cholestatic liver disease. Although IBAT inhibitors have been approved for use in pediatric cholestatic conditions, such as progressive familial intrahepatic cholestasis and Alagille syndrome, IBAT inhibition seems to be a promising treatment for chronic refractory itch in patients with PBC. A traditional non-systematic review results in this narrative review. Multidisciplinary cooperation, involving hepatologists, dermatologists, and pharmacists, could provide better treatment for PBC patients suffering from refractory itch. In conclusion, we summarized the existing knowledge on itch caused by chronic cholestatic liver diseases, especially in PBC with a focus on the mechanisms and therapies. This narrative review provides the mechanisms and therapeutic options for itch in patients with chronic cholestatic liver diseases. Full article

The autotaxin–lysophosphatidic acid receptor (ATX-LPAR) signaling axis is pivotal in various clinical conditions, including cancer and autoimmune disorders. This axis promotes tumorigenicity by interacting with the tumor microenvironment, facilitating metastasis, and conceding antitumor immunity, thereby fostering resistance to conventional cancer therapies. Recent studies highlight the promise of ATX/LPAR inhibitors in combination with conventional chemotherapeutic drugs to overcome some forms of this resistance, representing a novel therapeutic strategy. In the current study, we employed structure-based virtual screening, integrating pharmacophore modeling and molecular docking, to identify MolPort-137 as a novel ATX inhibitor with an IC₅₀ value of 1.6 ± 0.2 μM in an autotaxin enzyme inhibition assay. Molecular dynamics simulations and binding free energy calculations elucidated the binding mode of MolPort-137 and its critical amino acid interactions. Remarkably, MolPort-137 exhibited no cytotoxicity as a single agent but enhanced the effectiveness of paclitaxel in 4T1 murine breast carcinoma cells and resensitized taxol-resistant cells to paclitaxel treatment, which highlights its potential in combination therapy. Full article

Oxidative modifications of lipoproteins play a crucial role in the initiation of atherosclerotic cardiovascular diseases (ASCVDs). Nowadays, the one effective strategy for the treatment of patients with hyperlipoproteinemia(a) is lipoprotein apheresis (LA), which has a pleiotropic effect on reducing the risk of ASCVDs. The significance of oxidative susceptibility of the LDL fraction in ASCVDs has been extensively studied. Whether LA alters the susceptibility of lipoprotein(a) to oxidative modifications remains an unresolved issue. In this study, we isolated lipoprotein fractions by ultracentrifugation in patients with hyperlipoproteinemia(a) undergoing apheresis (LA group) at three time points and patients who were qualified for LA but did not consent to the procedure (non-LA group). We performed copper-mediated oxidation of Lp(a) and LDL fractions and determined autotaxin activity. After apheresis, we observed a lower susceptibility to oxidation of the Lp(a) and LDL fractions as expressed by the extended value of oxidation lag time, decreased slope of the oxidation curve, and decreased final concentration of conjugated dienes. No significant differences were found between these parameters before and 7 days after LA. Additionally, both patients undergoing and not undergoing LA had a significant correlation between autotaxin activity and all parameters characterizing susceptibility to oxidation in the Lp(a) fraction. Our results demonstrate that the pleiotropic effect of apheresis may be related to the reduced oxidative susceptibility of Lp(a) and LDL particles, which may influence the reduction in ASCVD risk in patients undergoing apheresis. The results of the rebound effect 7 days after LA will contribute to a better definition of apheresis frequency guidelines. Full article