Prostaglandins & other lipid mediators最新文献

{"title":"The Dual Role of 25-Hydroxycholesterol in Atherosclerosis: From Homeostatic Regulation to Plaque Instability.","authors":"Reyhane Ghayour Vatanparast, Sahar Ghoflchi, Mahdieh Aliyari, Hadiseh Mohammadi, Mahla Palizkaran Yazdi, Hossein Hosseini","doi":"10.1016/j.prostaglandins.2026.107065","DOIUrl":"https://doi.org/10.1016/j.prostaglandins.2026.107065","url":null,"abstract":"<p><strong>Background: </strong>Atherosclerosis is a chronic inflammatory pathology driven by lipid accumulation and immune activation. 25-Hydroxycholesterol (25-HC), an oxysterol synthesized by cholesterol 25-hydroxylase (CH25H) in response to inflammatory stimuli, has emerged as a potent bioactive lipid mediator at the nexus of cholesterol homeostasis and innate immunity.</p><p><strong>Objective: </strong>Unlike broader reviews on oxysterols, this article synthesizes the multifaceted and context-dependent roles of 25-HC in atherogenesis. We aim to elucidate its specific mechanistic actions across endothelial cells, macrophages, and vascular smooth muscle cells (VSMCs), emphasizing its dual nature and potential as a therapeutic target.</p><p><strong>Methods: </strong>We conducted a comprehensive review of the literature to integrate mechanistic insights into 25-HC signaling pathways, their regulation by specific transcription factors, and their impact on vascular pathology.</p><p><strong>Results: </strong>25-HC exhibits a distinct biphasic dose-response. At physiological concentrations, it maintains lipid homeostasis through suppression of SREBP processing and activation of LXR signaling. However, supraphysiological accumulation induces oxidative stress, mitochondrial dysfunction, and a coordinated activation of apoptosis and autophagy, ultimately precipitating cytotoxicity. Mechanistically, 25-HC disrupts membrane lipid rafts and activates the RIG-I/MAVS axis to drive pro-inflammatory cytokine secretion (e.g., IL-8). Within the plaque microenvironment, it impairs macrophage efferocytosis by downregulating MerTK and promotes VSMC proliferation and migration via PI3K/AKT pathways. Conversely, the transcription factor KLF4 and enzymatic sulfation by SULT2B1b act as critical protective checkpoints against 25-HC-mediated toxicity.</p><p><strong>Conclusion: </strong>25-HC is not merely a biochemical byproduct but a functional determinant of plaque instability. Its impact is strictly governed by local concentration gradients and metabolic regulation. Future therapeutic strategies should focus on modulating the CH25H/KLF4 axis and promoting oxysterol sulfation to mitigate vascular inflammation and prevent atherosclerosis progression.</p>","PeriodicalId":21161,"journal":{"name":"Prostaglandins & other lipid mediators","volume":" ","pages":"107065"},"PeriodicalIF":2.5,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147373244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The evolving landscape of lipid mediator research: Emerging findings and observations from the 19th Winter Eicosanoid conference","authors":"Victor Garcia,&nbsp;Danielle Diegisser,&nbsp;Alexandra Wolf,&nbsp;Jonathan V. Pascale,&nbsp;Michal L. Schwartzman","doi":"10.1016/j.prostaglandins.2026.107062","DOIUrl":"10.1016/j.prostaglandins.2026.107062","url":null,"abstract":"","PeriodicalId":21161,"journal":{"name":"Prostaglandins & other lipid mediators","volume":"183 ","pages":"Article 107062"},"PeriodicalIF":2.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146197913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Wulingsan alleviates metabolic dysfunction-associated steatotic liver disease through regulating gut microbiota-bile acid axis","authors":"Junyu Luo ,&nbsp;Xiaowen Jin ,&nbsp;Mingyue Cui ,&nbsp;Hanyu He ,&nbsp;Jiabao Liao ,&nbsp;Weibo Wen ,&nbsp;Wenting Li ,&nbsp;Yongjun Cao","doi":"10.1016/j.prostaglandins.2026.107067","DOIUrl":"10.1016/j.prostaglandins.2026.107067","url":null,"abstract":"<div><h3>Background</h3><div>Metabolic dysfunction-associated Steatotic Liver Disease (MASLD) is closely linked to gut microbiota disorders and bile acid imbalance. Wulingsan (WLS) have shown promise in regulating these pathways, but its mechanism of action unclear. This study aimed to evaluate the therapeutic effect of WLS on the rat MASLD model from the perspectives of intestinal microbiota composition and bile acid homeostasis.</div></div><div><h3>Methods</h3><div>The MASLD model was induced by a high-fat diet (HFD) and treated with different doses of WLS. Body weight and serum lipid profiles were monitored, inflammation were assessed to ELISA and RT-qPCR. H&amp;E staining to evaluate histopathological changes. The 16S rRNA sequencing and LC-MS/MS analysis of gut microbiota composition and bile acid profiles. The fecal microbiota transplantation (FMT) experiment verified the effect of WLS on the gut microbiota.</div></div><div><h3>Results</h3><div>WLS treatment reduces the body weight of MASLD rats, improves lipid indicators, and inhibits inflammation and liver damage. The results of the FMT experiment indicated that transplantation of fecal microbiota from WLS-treated donors regulated the gut microbial composition and restored bile acid metabolic homeostasis in recipient rats.</div></div><div><h3>Discussion</h3><div>This study demonstrates that WLS treats MASLD by modulating multiple pathological pathways. Its effects in improving lipid metabolism and reducing hepatic inflammation align with the pathophysiological mechanisms of MASLD, indicating direct hepatoprotective actions. WLS intervention significantly restored gut microbiota diversity, increased the proportion of beneficial bacteria, suppressed potentially harmful bacterial genera, and corrected dysbiosis. FMT experiments further confirmed that gut microbes play a crucial role in mediating the therapeutic benefits of WLS. When microbiota from WLS-treated donors were transplanted into recipient rats, significant improvements were observed in metabolic markers, hepatic histopathology, and bile acid homeostasis. Collectively, the data support that WLS improves MASLD through a multi-targeted strategy centered on the gut-liver axis.</div></div><div><h3>Conclusion</h3><div>WLS has an effective therapeutic effect on MASLD by improving lipid metabolism, reducing liver inflammation, reshaping the intestinal microbiota and normalizing bile acid homeostasis.</div></div>","PeriodicalId":21161,"journal":{"name":"Prostaglandins & other lipid mediators","volume":"183 ","pages":"Article 107067"},"PeriodicalIF":2.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147390934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Resveratrol inhibits lipid deposition via JAML/Sirt1 pathway in podocytes","authors":"Wei Gu ,&nbsp;Xiaolong Li ,&nbsp;Kunjie Zheng ,&nbsp;Xiangtuo Wang ,&nbsp;Guangyao Song","doi":"10.1016/j.prostaglandins.2026.107061","DOIUrl":"10.1016/j.prostaglandins.2026.107061","url":null,"abstract":"<div><div>Lipid deposition plays a key role in the progression of diabetic kidney disease. We previously demonstrated that resveratrol modulates the junctional adhesion molecule-like protein (JAML)/Sirtuin 1 (Sirt1) pathway involved in lipid synthesis in the kidneys of mice under high-fat diet conditions, reducing lipid deposition. However, the specific mechanisms by which resveratrol affects palmitic acid (PA)-induced lipid accumulation and metabolism in podocytes remain unclear. In this study, we used mouse podocyte cell line 5 (MPC-5) to investigate the role of the JAML/Sirt1 pathway in <em>de novo</em> lipid synthesis. Resveratrol attenuated the abnormal expression of key components in the JAML/Sirt1 lipid synthesis pathway induced by PA in MPC-5 podocytes. Specifically, siRNA-mediated silencing of <em>JAML</em> increased Sirt1 expression in PA-treated MPC-5 podocytes, downregulating sterol regulatory element-binding protein-1, carbohydrate response element-binding protein, and adipose differentiation-related protein. In contrast, <em>JAML</em> overexpression reversed these effects. Resveratrol attenuated the metabolic abnormalities caused by <em>JAML</em> overexpression, suggesting that it inhibits intracellular lipid deposition in MPC-5 podocytes by regulating the JAML/Sirt1 pathway. Our findings provide new evidence that resveratrol improves lipid deposition in the kidneys and a new treatment strategy for renal diseases associated with lipid deposition in the kidneys.</div></div>","PeriodicalId":21161,"journal":{"name":"Prostaglandins & other lipid mediators","volume":"183 ","pages":"Article 107061"},"PeriodicalIF":2.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146202501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell metabolomics to reveal the mechanism of saponins and alkaloids on prostate inflammation via COX and LOX pathways","authors":"Lili Liu ,&nbsp;Lijuan Xue ,&nbsp;Guiyue Hou ,&nbsp;Jingxuan Zhang ,&nbsp;Ling Tian ,&nbsp;Xueqin Wang ,&nbsp;Ronghua Dai","doi":"10.1016/j.prostaglandins.2026.107066","DOIUrl":"10.1016/j.prostaglandins.2026.107066","url":null,"abstract":"<div><div>Inflammation initiates and progresses due to overexpression of the arachidonic acid cascade mediators. Cyclooxygenase (COX) and lipoxygenase (LOX) are considered to be the primary targets, and the aim of this study was to assess the anti- inflammatory activity of several herbal compounds as dual COX-LOX inhibitors on prostatic diseases. Compounds Timosaponin AⅡ, timosaponin AⅢ, berberine and demethyleneberberine were selected according to our previous studies. Human prostate cancer cells (PC-3) were cultured and the cell viability was detected by CCK-8 method at different concentrations. Ultra high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was applied to monitor the changes of AA metabolites after treatment. Western blot and qPCR were used to detect COX-2 and LOX-5 at protein and mRNA levels, respectively. Additionally, the levels of inflammatory factors (IL-6, IL-1β, TNF-α) in each group were detected by ELISA. After drug interference, 13 altered metabolites associated with the COX/LOX pathway, including PGE₂, 5-HETE, LTB₄, etc. were identified in cell medium. Quantitative metabolomics analysis showed that the candidate compounds could significantly decreased the concentrations of dual target related metabolites to varying degrees (<em>P</em> &lt; 0.01). These compounds could also suppressed COX-2 and LOX-5 expression at the protein and mRNA levels simultaneously. Moreover, the levels of cytokine IL-6, IL-1β and TNF-α were also significantly reduced in the treated group compared to controls (<em>P</em> &lt; 0.05 or <em>P</em> &lt; 0.01). Our findings revealed the four active compounds were potential COX/LOX dual-target inhibitors, which inhibited a range of inflammatory responses by interfering with AA metabolism and down-regulating the levels of COX and LOX metabolites.</div></div>","PeriodicalId":21161,"journal":{"name":"Prostaglandins & other lipid mediators","volume":"183 ","pages":"Article 107066"},"PeriodicalIF":2.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147390931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Resolvin E1 and Resolvin E2 suppress cyclooxygenase-2 expression through ubiquitin-proteasome-mediated degradation in human macrophage-like U937 cells","authors":"Ayaka Hamaguchi ,&nbsp;Hayato Fukuda ,&nbsp;Mizuki Watanabe ,&nbsp;Koichi Fujiwara ,&nbsp;Keijo Fukushima ,&nbsp;Satoshi Shuto ,&nbsp;Hiromichi Fujino","doi":"10.1016/j.prostaglandins.2026.107064","DOIUrl":"10.1016/j.prostaglandins.2026.107064","url":null,"abstract":"<div><div>Inflammatory responses comprise a crucial defense mechanism against infection and injury. Prostanoids, including prostaglandin E₂ (PGE₂), are well-known to play important roles in the generation of inflammatory responses. However, their excessive or prolonged activation can cause tissue damage and drive the development of diseases. Resolvin E-series (RvEs), including RvE1, RvE2, and RvE3, are specialized pro-resolving mediators that actively promote the resolution of inflammation. Here, using human macrophage-like U937 cells, we show that RvE1 and RvE2, but not RvE3, suppressed protein expression of cyclooxygenase (COX)-2, an essential and inducible enzyme involved in prostanoid synthesis during the onset of inflammatory responses. Furthermore, the suppression of COX-2 protein expression by RvE1 and RvE2 was suggested to involve enhanced ubiquitin-proteasome-dependent degradation, resulting in the rapid reduction of PGE₂ production by decreasing functional COX-2. This is the first reported evidence that RvEs exert pro-resolving effects on macrophage-associated COX-2/PGE₂ signaling. Importantly, RvEs reduced COX-2 expression at the low concentration of 10 nM without affecting COX-1 expression. Thus, they may represent promising candidates for novel anti-inflammatory drugs with potentially fewer gastrointestinal side effects than exhibited by many nonsteroidal anti-inflammatory drugs.</div></div>","PeriodicalId":21161,"journal":{"name":"Prostaglandins & other lipid mediators","volume":"183 ","pages":"Article 107064"},"PeriodicalIF":2.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146220980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiscale analysis of resolvin D1 biosynthesis and its neuroprotective role in intracerebral hemorrhage","authors":"Lv Xiaoyu ,&nbsp;Zhang Ziyou ,&nbsp;Liu Zhenlin ,&nbsp;Li Zhuang ,&nbsp;Sun Kai ,&nbsp;Wang Siqi ,&nbsp;Li Tong ,&nbsp;Li Yunfei ,&nbsp;Zhou Weixiu ,&nbsp;Wang Yifan ,&nbsp;Shi Chun ,&nbsp;Zhang Bensi","doi":"10.1016/j.prostaglandins.2026.107063","DOIUrl":"10.1016/j.prostaglandins.2026.107063","url":null,"abstract":"<div><h3>Background</h3><div>Intracerebral hemorrhage (ICH) is a destructive cerebrovascular disease, whose secondary injury can trigger severe neuroinflammatory responses. Resolvin D1 (RvD1), as an endogenous specific pro-resolving mediator, has been demonstrated to possess significant anti-inflammatory effects. However, how brain networks relate to RvD1 biosynthesis and the therapeutic potential of RvD1 in post-hemorrhagic repair processes within the brain remain unclear.</div></div><div><h3>Methods</h3><div>Serum RvD1 levels were measured at admission and discharge in 40 ICH patients, and their correlation with neurological functional outcomes was analyzed. Combining neuroimaging and Mendelian randomization, we investigated the association between brain network integrity and genetically predicted plasma RvD1 levels. Network pharmacology identified key targets, and an oxyhemoglobin-induced BV2 microglial model validated RvD1’s <em>BDNF-</em>dependent anti-inflammatory and anti-apoptotic effects.</div></div><div><h3>Results</h3><div>Serum RvD1 levels decreased from admission to discharge during recovery, with significant correlation between its changes and neurological improvement. Neuroimaging and MR analysis revealed that brain network integrity is significantly associated with genetically predicted plasma RvD1 levels, partially explaining interindividual prognostic variation. Mechanistically, RvD1 modulates microglial metabolism, alleviates oxidative stress, and promotes anti-inflammatory polarization involving the <em>BDNF</em>/<em>AKT</em> signaling network.</div></div><div><h3>Conclusion</h3><div>Genetically predicted plasma RvD1 levels correlate with macro-level brain network integrity while simultaneously promoting micro-level neural repair. This approach overcomes limitations of previous single-pathway or static indicator studies, offering novel biomarkers and intervention strategies with predictive and therapeutic potential for ICH.</div></div>","PeriodicalId":21161,"journal":{"name":"Prostaglandins & other lipid mediators","volume":"183 ","pages":"Article 107063"},"PeriodicalIF":2.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146259036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Digoxin-induced gut dysbiosis: Mechanistic links to prostaglandin dysregulation and lipid metabolic imbalance","authors":"Nila Ganamurali ,&nbsp;Sarvesh Sabarathinam","doi":"10.1016/j.prostaglandins.2025.107055","DOIUrl":"10.1016/j.prostaglandins.2025.107055","url":null,"abstract":"<div><div>Digoxin, a cardiac glycoside with established roles in heart failure and arrhythmia, increasingly exemplifies drug–microbiome–host interactions. Its bioavailability and efficacy are profoundly influenced by <em>Eggerthella lenta</em>–mediated reduction, producing inactive metabolites that reshape systemic physiology. Emerging evidence demonstrates that digoxin-induced gut dysbiosis perturbs arachidonic acid metabolism, altering cyclooxygenase-driven prostaglandin production and disrupting vascular tone and inflammatory homeostasis. These changes extend to lipid regulation, where reduced short-chain fatty acid production and bile acid derangements impair hepatic lipid utilization, promoting steatosis and metabolic dysfunction. This review integrates mechanistic insights into digoxin–microbiota interactions, prostaglandin pathway perturbation, and lipid imbalance, emphasizing their clinical significance and therapeutic implications for precision medicine in cardiovascular care.</div></div>","PeriodicalId":21161,"journal":{"name":"Prostaglandins & other lipid mediators","volume":"182 ","pages":"Article 107055"},"PeriodicalIF":2.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145820433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SREBF1 maintains the contractile phenotype of vascular smooth muscle cells via PPARγ signalling","authors":"Xiaoying Chen ,&nbsp;Huiling Jin ,&nbsp;Guanyi Zheng","doi":"10.1016/j.prostaglandins.2025.107054","DOIUrl":"10.1016/j.prostaglandins.2025.107054","url":null,"abstract":"<div><h3>Background</h3><div>Atherosclerosis is a complex chronic inflammatory disease. Although SREBF1 has been implicated in the regulation of atherosclerotic progression, its precise mechanisms remain incompletely understood.</div></div><div><h3>Methods</h3><div>The study constructed an <em>in vitro</em> model of atherosclerosis by exposing vascular smooth muscle cells (VSMCs) to oxidized low-density lipoprotein. The model was validated through inverted microscopy, quantitative polymerase chain reaction, and western blotting. The effects of SREBF1 on VSMC’s functions, including proliferation, migration, and clonogenic capacity, were assessed using Cell Counting Kit-8 assays, scratch wound healing assays, and colony formation assays, and western blotting following SREBF1 knockdown or overexpression. The PPARγ signalling pathway was further examined by western blotting and dual-luciferase reporter gene assay.</div></div><div><h3>Results</h3><div>The experimental results demonstrated that knockdown of SREBF1 significantly enhanced VSMC proliferation and migration while suppressing the expression of the two contractile markers SM22α and α-SMA. Mechanistic studies revealed that SREBF1 directly upregulated PPARγ transcriptional activity, activated PPARγ expression, and inhibited phosphorylated PPARγ expression. Notably, the addition of GW9662, a specific PPARγ signalling inhibitor, partially reversed the regulatory effects of SREBF1 overexpression on VSMC proliferation, migration, and phenotype.</div></div><div><h3>Conclusion</h3><div>This research found that SREBF1 maintains the contractile phenotype of VSMCs by activating PPARγ signalling, suggesting that SREBF1 may serve as a key molecule in ameliorating atherosclerosis.</div></div>","PeriodicalId":21161,"journal":{"name":"Prostaglandins & other lipid mediators","volume":"182 ","pages":"Article 107054"},"PeriodicalIF":2.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145782692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Revealing the biochemical regulations of L-PGDS in hepatic insulin-resistance using HepG2 cells","authors":"Rhema Khairnar,&nbsp;Md Asrarul Islam,&nbsp;Kuljeet Singh,&nbsp;Divya K. Shetty,&nbsp;Anjali Yadav,&nbsp;Vikas V. Dukhande,&nbsp;Sunil Kumar","doi":"10.1016/j.prostaglandins.2025.107052","DOIUrl":"10.1016/j.prostaglandins.2025.107052","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease, and its prevalence poses a serious health threat globally. MASLD is a multifactorial hepatic disorder, but insulin resistance is a key player. Our prior <em>in vivo</em> studies revealed that the absence of lipocalin prostaglandin D₂ synthase (<span>L</span>-PGDS) leads to the development of MASLD, often coexisting with insulin resistance. Briefly, <span>L</span>-PGDS belongs to the arachidonic acid pathway and enzymatically catalyzes the conversion of prostaglandin H₂ to prostaglandin D_2, which imparts physiological effects via DP1 and DP2 receptors. <span>L</span>-PGDS plays a crucial role in MASLD; however, its mechanistic regulation remains unexplored. Therefore, we aimed to study the biochemical regulation of <span>L</span>-PGDS using a cellular model of MASLD. We successfully recapitulated the MASLD phenotype in HepG2 cells by co-treating with palmitate and insulin. Our results showed significant downregulation of <span>L</span>-PGDS and decreased PGD₂ levels in an insulin-resistant state. To study this <span>L</span>-PGDS downregulation, we employed MG132, chloroquine, cycloheximide, and immunoprecipitation to assess proteasomal degradation, autophagy, translational activity, and ubiquitination, respectively. However, the above pathways were not involved. Interestingly, gene and protein expression results revealed the clues for <span>L</span>-PGDS downregulation, showing significantly decreased transcription and subsequently protein levels. Additionally, subcellular localization results showed that insulin resistance induced the trafficking of <span>L</span>-PGDS from the cytoplasm to the nucleus. In summary, <span>L</span>-PGDS downregulation possibly involves transcription-translation and/or subcellular localization pathways. However, further studies are required to delineate the molecular mechanism of <span>L</span>-PGDS downregulation and apply this knowledge to MASLD pathogenesis and treatment.</div></div>","PeriodicalId":21161,"journal":{"name":"Prostaglandins & other lipid mediators","volume":"182 ","pages":"Article 107052"},"PeriodicalIF":2.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145712351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}