Journal of Pineal Research最新文献

{"title":"Light and Temperature Coordinately Regulate Phytomelatonin Synthesis to Maintain Plant Morphogenesis via the COP1-HY5 Module","authors":"Zhi-Xin Xiang,&nbsp;Ying-Rui Li,&nbsp;Ning-Xin Zhang,&nbsp;Ya-Xuan Zhang,&nbsp;Ting-Ting Yuan","doi":"10.1111/jpi.70059","DOIUrl":"https://doi.org/10.1111/jpi.70059","url":null,"abstract":"<div>\u0000 \u0000 <p>Light and temperature change constantly under natural conditions and play vital roles in coordinating plant morphogenesis. However, how these two signals are integrated with endogenous signals to fine-tune plant morphology requires further investigation. Given that phytomelatonin is a multifunctional regulator connecting environmental signals and plant development, here we propose that phytomelatonin is involved in the integration of light and temperature signals. When co-treated with darkness and warm ambient temperature, the light–temperature signal showed synergistic upregulation of phytomelatonin synthesis and thus hypocotyl growth. Phytomelatonin synthesis gene <i>SEROTONIN N-ACETYLTRANSFERASE</i> (<i>SNAT</i>) was induced under constant darkness or warm temperature, reaching its peak level under the combined treatment. The <i>snat</i> mutant, with reduced phytomelatonin content and hypocotyl length, was less sensitive to darkness and warm temperature, whereas <i>35S::SNAT-GFP</i> had more phytomelatonin and longer hypocotyls than the wild type, indicating that <i>SNAT</i> is needed for light–temperature morphogenesis. Furthermore, <i>SNAT</i> expression and phytomelatonin content were reduced in <i>cop1</i> but increased in <i>hy5</i>. HY5 inhibits <i>SNAT</i> expression by binding to its promoter. The <i>hy5 snat</i> seedlings had less phytomelatonin and shorter hypocotyls than the <i>hy5</i> seedlings, along with the <i>SNAT</i> mutation in <i>35S::COP1 snat</i> seedlings reversed the phenotype of <i>35S::COP1</i>, further verifying that <i>SNAT</i> acts downstream of COP1-HY5 module. Moreover, RNA-Seq revealed that phytomelatonin is associated with light–temperature signal in controlling hypocotyl elongation-related genes. Taken together, our results showed that the light–temperature signal regulates <i>SNAT</i>-mediated phytomelatonin synthesis through COP1-HY5 module to coordinate plant morphogenesis.</p>\u0000 </div>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"77 3","pages":""},"PeriodicalIF":8.3,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143949792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exercise as a Synchronizer: Effects on Circadian Re-Entrainment of Core Body Temperature and Metabolism Following Light–Dark Cycle Inversion in Mice","authors":"Andrea Michele Ciorciari,&nbsp;Emanuel Irizarry,&nbsp;Angela Montaruli,&nbsp;Katja A. Lamia","doi":"10.1111/jpi.70057","DOIUrl":"https://doi.org/10.1111/jpi.70057","url":null,"abstract":"<p>Core body temperature (CBT) is a crucial marker of circadian synchrony, reflecting behavioral, metabolic, and environmental adaptations. Disruptions to CBT rhythms, as seen in shift workers or jetlag, indicate desynchronization and can lead to significant health consequences. Exercise is a potent non-photic zeitgeber that may help align circadian rhythms with external cues, but its role in re-entrainment following abrupt phase shifts remains unclear. This study investigated whether voluntary exercise accelerates the re-entrainment of CBT and metabolic rhythms in mice subjected to a 12-h light-dark cycle inversion (LDI). Fifteen C57BL/6 J mice underwent LDI and were divided into two groups. Mice in the control (CTRL) group remained sedentary throughout the experiment while mice in the other group were provided running wheels for 2 weeks after LDI. CBT was continuously monitored using implanted telemetric capsules and metabolic parameters were assessed before and 2 weeks after LDI. Mice that had access to running wheels (RW mice) initially displayed a greater disruption of CBT rhythmicity following LDI, suggesting unstructured physical activity may temporarily exacerbate misalignment, acting as a conflicting signal. Despite this, exercise accelerated recovery, as the phase of the CBT rhythm in RW mice re-aligned to the new light-dark cycle faster than that of the CTRL mice did. The phase of VO₂ rhythms in RW mice also showed trends toward faster realignment. These findings highlight the dual role of exercise as a zeitgeber, capable of both disrupting and accelerating circadian realignment depending on timing. Voluntary exercise may thus serve as an effective intervention to restore circadian synchrony and metabolic homeostasis in individuals experiencing circadian disruptions.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"77 3","pages":""},"PeriodicalIF":8.3,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jpi.70057","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143939308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IAT4, a New Indolamine N-Acetyltransferase in Saccharomyces cerevisiae Involved in Melatonin Biosynthesis","authors":"Andrés Planells-Cárcel,&nbsp;Sandra Sánchez-Martí,&nbsp;Sara Muñiz-Calvo,&nbsp;José Manuel Guillamon","doi":"10.1111/jpi.70053","DOIUrl":"https://doi.org/10.1111/jpi.70053","url":null,"abstract":"<p>Melatonin synthesis by yeast has been described on several occasions, mainly in a fermentative context. However, the genetic determinants involved in its synthesis remain undefined. Understanding melatonin synthesis in yeast is important because it can provide insights into the broader mechanisms of indolamine production, which has implications for both basic biological research and industrial applications. Although two genes with <i>N</i>-acetyltransferase (NAT) activity (<i>PAA1</i> and <i>HPA2</i>) have been identified in <i>Saccharomyces cerevisiae</i>, these genes do not seem to be major contributors to the production of melatonin and other indolamines in yeast in vivo. In this study, we identified the uncharacterized gene YDR391C as the gene encoding a protein with NAT activity, herein named <i>IAT4</i>. By comparing different substrates using the purified Iat4, we found that the <i>K</i>_<i>m</i> values were 353, 356, and 930 µM towards 5-methoxytryptamine, tryptamine, and serotonin, respectively. The substrate affinity of Iat4 towards serotonin was approximately five times higher than that reported for the previous homolog of the melatonin enzyme arylalkylamine <i>N</i>-acetyltransferase (<i>PAA1</i>), suggesting that <i>IAT4</i> could play a more significant role in melatonin biosynthesis. This enhanced affinity could lead to more efficient production of <i>N</i>-acetylserotonin, potentially improving yields in biotechnological applications. Finally, we demonstrate the conversion of serotonin into microbially-produced <i>N</i>-acetylserotonin by overexpressing <i>IAT4</i> in a serotonin-overproducing yeast strain at a titer of 14.5 mg/L. These findings represent the first steps towards the development of yeast strains optimized for the biological production of <i>N</i>-acetylserotonin and related compounds, which might aid in studying the regulatory mechanisms and functions related to melatonin biosynthesis in <i>S. cerevisiae</i> and other yeast species.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"77 3","pages":""},"PeriodicalIF":8.3,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jpi.70053","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143925806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Melatonin Supplementation Alleviates Bone Mineral Density Decline and Circulating Oxidative Stress in Iron-Overloaded Thalassemia Patients","authors":"Pokpong Piriyakhuntorn,&nbsp;Adisak Tantiworawit,&nbsp;Mattabhorn Phimphilai,&nbsp;Tawika Kaewchur,&nbsp;Piangrawee Niprapan,&nbsp;Bhumrapee Srivichit,&nbsp;Nattayaporn Apaijai,&nbsp;Krekwit Shinlapawittayatorn,&nbsp;Nipon Chattipakorn,&nbsp;Siriporn C. Chattipakorn","doi":"10.1111/jpi.70055","DOIUrl":"https://doi.org/10.1111/jpi.70055","url":null,"abstract":"<div>\u0000 \u0000 <p>Thalassemia patients often exhibit low bone mineral density (BMD). The iron overload associated with thalassemia elevates oxidative stress levels, leading to reduced BMD. Melatonin improves BMD in postmenopausal osteopenia, however, its effect on BMD in thalassemia patients with iron overload has not been investigated. A randomized controlled study was conducted at Hematology Clinic, Faculty of Medicine, Chiang Mai University. Thalassemia patients with osteopenia and iron overloaded condition, as indicated by BMD Z-score &lt;−2 at <span>l</span>-spine, femoral neck, or total hip, and serum ferritin level &gt; 500 μg/L were recruited in this study. Patients were randomized to receive either melatonin 20 mg/day or placebo at bedtime for 12 months. BMD was re-evaluated 12 months after interventions. Bone turnover markers (BTM), malondialdehyde (MDA as an oxidative stress marker), and pain scores were assessed at baseline, 6, and 12 months. The outcomes, including BMD, BTM, MDA, and pain scores, were evaluated in all patients. Forty-one thalassemia patients (18 males) were enrolled in the study and randomly assigned to either the melatonin group (<i>n</i> = 21) or the placebo group (<i>n</i> = 20). Characteristics of patients were not differences between groups. Mean age was 30.8 ± 6.2 years old. Thirty-three patients (80.4%) were transfusion-dependent patients. At 12 months, mean BMD at <span>l</span>-spine in melatonin group was not significantly different from placebo group (<i>p</i> = 0.069). However, <span>l</span>-spine BMD at 12 months in the melatonin group was significantly greater than baseline (<i>p</i> = 0.029). Serum levels of P1NP and MDA were significantly reduced at 6 months compared to baseline following melatonin treatment. The melatonin group experienced a notable decrease in back pain scores after 12 months compared to the initial measurements. 20 mg daily melatonin supplementation for 12 months alleviated <span>l</span>-spine BMD loss in iron-overloaded thalassemia with low BMD. Melatonin also significantly reduced circulating oxidative stress and mitigated back pain in these patients.</p>\u0000 </div>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"77 3","pages":""},"PeriodicalIF":8.3,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143914579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluating Melatonin's Effects on Hepatocyte Lipidome: A Critique of Analytical Methods","authors":"Yoshiyasu Takefuji","doi":"10.1111/jpi.70054","DOIUrl":"https://doi.org/10.1111/jpi.70054","url":null,"abstract":"","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"77 3","pages":""},"PeriodicalIF":8.3,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143904964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EXPRESSION OF CONCERN: Adipocyte Differentiation Is Inhibited by Melatonin Through the Regulation of C/EBPβ Transcriptional Activity","authors":"","doi":"10.1111/jpi.70050","DOIUrl":"https://doi.org/10.1111/jpi.70050","url":null,"abstract":"<p><b>EXPRESSION OF CONCERN</b>: M. I. C. Alonso-Vale, S. B. Peres, C. Vernochet, S. R. Farmer and F. B. Lima, “Adipocyte Differentiation Is Inhibited by Melatonin Through the Regulation of C/EBPβ Transcriptional Activity,” <i>Journal of Pineal Research</i> 47, no. 3 (2009): 221-227, https://doi.org/10.1111/j.1600-079X.2009.00705.x.</p><p>This Expression of Concern is for the above article, published online on 03 September 2009 in Wiley Online Library (wileyonlinelibrary.com), and has been issued by agreement between the journal Editor-in-Chief, Gianluca Tosini; and John Wiley &amp; Sons Ltd. The Expression of Concern has been agreed due to concerns regarding the C/EBPα panel of the western blot shown in Figure 1 and the Perilipin panel in Figure 2. The authors provided an explanation and some data but this was not sufficient to resolve the issue. Therefore, the journal has decided to issue an Expression of Concern to inform and alert the readers about potential data inconsistencies in Figures 1 and 2.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"77 3","pages":""},"PeriodicalIF":8.3,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jpi.70050","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Melatonin and Exercise Restore Myogenesis and Mitochondrial Dynamics Deficits Associated With Sarcopenia in iMS-Bmal1−/− Mice","authors":"Yolanda Ramírez-Casas,&nbsp;José Fernández-Martínez,&nbsp;María Martín-Estebané,&nbsp;Paula Aranda-Martínez,&nbsp;Alba López-Rodríguez,&nbsp;Sergio Esquivel-Ruiz,&nbsp;Yang Yang,&nbsp;Germaine Escames,&nbsp;Darío Acuña-Castroviejo","doi":"10.1111/jpi.70049","DOIUrl":"https://doi.org/10.1111/jpi.70049","url":null,"abstract":"<div>\u0000 \u0000 <p>Sarcopenia, a condition associated with aging, involves progressive loss of muscle mass, strength, and function, leading to impaired mobility, health, and increased mortality. The underlying mechanisms remain unclear, which limits the development of effective therapeutic interventions. Emerging evidence implicates chronodisruption as a key contributor to sarcopenia, emphasizing the role of <i>Bmal1</i>, a circadian clock gene critical for muscle integrity and mitochondrial function. In a skeletal muscle-specific and inducible <i>Bmal1</i> knockout model (iMS-<i>Bmal1</i>^−/−), we observed hallmark features of sarcopenia, including disrupted rhythms, impaired muscle function, and mitochondrial dysfunction. Exercise and melatonin treatment reversed these deficits independently of <i>Bmal1</i>. Building on these findings, the present study elucidates several mechanisms underlying these changes and the pathways by which melatonin and exercise exert their beneficial effects. Our findings indicate that iMS-<i>Bmal1</i>^−/− mice exhibit reduced expression of satellite cell and muscle regulatory factors, indicating impaired muscle regeneration. While mitochondrial respiration remained unchanged, notable alterations in mitochondrial dynamics disrupted mitochondria in skeletal muscle. In addition, these mice showed alterations in muscle energy metabolism, compromised antioxidant defense, and inflammatory response. Remarkably, exercise and/or melatonin successfully mitigated these deficits, restoring muscle health in <i>Bmal1</i>-deficient mice. These findings position exercise and melatonin as promising therapeutic candidates for combating sarcopenia and emphasize the need to elucidate the molecular pathways underlying their protective effects.</p></div>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"77 3","pages":""},"PeriodicalIF":8.3,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143840889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell-Type-Specific mRNA N6-Methyladenosine Landscape and Regulatory Mechanisms Underlying Immune Dysregulation of Sleep-Deprived","authors":"Yakun Liu,&nbsp;Zhe Wang,&nbsp;Sha Liu,&nbsp;Xinrong Li,&nbsp;Denggao Wang,&nbsp;Dan Wang,&nbsp;Ying Li,&nbsp;Chaojie Liu,&nbsp;Yong Xu","doi":"10.1111/jpi.70046","DOIUrl":"https://doi.org/10.1111/jpi.70046","url":null,"abstract":"<div>\u0000 \u0000 <p>Sleep deprivation impairs daytime cognitive functioning and is a risk factor for various diseases related to immune dysregulation. N⁶-methyladenosine (m⁶A) is a common epigenetic RNA modification with essential roles in regulating neurogenesis and circadian rhythms. m⁶A dysregulation resulting in immune imbalance has received much attention. In this study, we elucidated the landscape and specific mechanisms of m⁶A regulators in the peripheral blood of patients with sleep deprivation through RNA sequencing and single-cell transcriptomics data sets. We observed that m⁶A regulator upregulation aggravated sleep loss and immune disorders. Women were more sensitive to sleep deprivation. Notably, m⁶A regulator <i>ALKBH5</i> was downregulated in peripheral blood mononuclear cells (PBMC) of patients with sleep deprivation at the transcriptome level. However, <i>ALKBH5</i> was cell-type specific upregulated in T cells (TC), B cells (BC), and natural killer (NK) cells, involving the dysregulation of acquired immune mechanisms by aberrant cell–cell communication that mediated ligand–receptor interactions across diverse cell types. Furthermore, the immune dysregulation of sleep loss could be regulated by a potential pathway between ALKBH5 and CD99 in SH-SY5Y and HT22 cells. Sleep deprivation group CD3⁺/CD45⁺ T cells had higher levels of <i>ALKBH5</i> mRNA than the control group. This study demonstrated that abnormal m⁶A modification patterns caused by m⁶A regulators play a key role in the dysregulation of innate and acquired immunity in sleep deprivation.</p></div>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"77 3","pages":""},"PeriodicalIF":8.3,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143818640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circadian Rhythm Disruption in Triple-Negative Breast Cancer: Molecular Insights and Treatment Strategies","authors":"Li-Hua He,&nbsp;Xin-Yi Sui,&nbsp;Yu-Ling Xiao,&nbsp;Peng Ji,&nbsp;Yue Gong","doi":"10.1111/jpi.70042","DOIUrl":"https://doi.org/10.1111/jpi.70042","url":null,"abstract":"<div>\u0000 \u0000 <p>Disruption of the circadian clock has been closely linked to the initiation, development, and progression of cancer. This study aims to explore the impact of circadian rhythm disruption (CRD) on triple-negative breast cancer (TNBC). We analyzed bulk and single-cell RNA sequencing data to assess circadian rhythm status in TNBC using multiple bioinformatic tools, alongside metabolomic profiles and tumor microenvironment evaluations to understand the influence of CRD on metabolic reprogramming and immune evasion. The results indicate that TNBC experiences profound CRD. Patients with a higher CRDscore exhibit significantly poorer relapse-free survival compared to those with a lower CRDscore. Cyclic ordering by periodic structure (CYCLOPS) identified significant changes in rhythmic gene expression patterns between TNBC and normal tissues, with TNBC showing a “rush hour” effect, where peak expression times are concentrated within specific time windows. Transcripts with disrupted circadian rhythms in TNBC were found to be involved in key pathways related to cell cycle regulation, metabolism, and immune response. Metabolomic analysis further revealed that TNBCs with high CRDscore are enriched in carbohydrate and amino acid metabolism pathways, notably showing upregulation of tryptophan metabolism. High CRDscore was also linked to an immunosuppressive tumor microenvironment, characterized by reduced immune cell infiltration, exhausted CD8⁺ T cells, and a diminished response to immune checkpoint blockade therapy. These findings suggest that the disrupted molecular clock in TNBC may activate tryptophan metabolism, thereby promoting immune evasion and potentially reducing the effectiveness of immunotherapy.</p>\u0000 </div>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"77 3","pages":""},"PeriodicalIF":8.3,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Melatonin Repairs the Lipidome of Human Hepatocytes Exposed to Cd and Free Fatty Acid-Induced Lipotoxicity","authors":"Anna Migni,&nbsp;Desirée Bartolini,&nbsp;Giada Marcantonini,&nbsp;Roccaldo Sardella,&nbsp;Mario Rende,&nbsp;Alessia Tognoloni,&nbsp;Maria Rachele Ceccarini,&nbsp;Francesco Galli","doi":"10.1111/jpi.70047","DOIUrl":"https://doi.org/10.1111/jpi.70047","url":null,"abstract":"<p>Hepatocyte lipotoxicity is central to the aetiology of nonalcoholic fatty liver disease (NAFLD), a leading cause of liver failure and transplantation worldwide. Long-lasting toxic pollutants have increasingly been considered as environmental risk factors of NAFLD. These include cadmium (Cd), a metal that synergizes with other cellular toxicants and metabolic stimuli to induce fat build-up and lipotoxicity. Recent studies demonstrated that melatonin (MLT) holds great potential as repairing agent in this form of hepatocyte lipotoxicity. In this study, the molecular hints of this MLT effect were investigated by lipidomics analysis in undifferentiated HepaRG cells, a human pre-hepatocyte cell line, exposed to Cd toxicity either alone or combined with prototypical free fatty acids (FFA), namely the saturated species palmitic acid and the monounsaturated oleic acid (OA and PA, respectively), to simulate the cellular lipotoxicity conditions of fatty liver disease. Cd exposure synergized with FFAs to induce cellular steatosis, and PA produced higher levels of lipotoxicity compared to OA by leading to increased levels of H₂O₂ production and apoptotic death. These effects were associated with changes of the cellular lipidome, which approximate those of NAFLD liver, with differentially expressed lipids in different classes that included triacylglycerols (TG), di- and mono-acylglycerols, phospholipids (PL), sphingolipids, acylcarnitines and FA; characteristic differences were observed in all these classes comparing the combinations of Cd exposure with PA or OA treatments. MLT significantly reduced the effects of either individual or combinatorial treatments of Cd and FFAs on lipotoxicity hallmarks, also repairing most of the alterations of the cellular lipidome, including those of the chain length and number of double bonds of acyl residues esterified to TG and PL classes. These findings and their bioinformatics interpretation suggest a role for the earliest acyl elongase and desaturase steps of FA metabolism in this repairing effect of MLT; biochemistry studies validated such interpretation identifying a specific role for SCD1 activity. This lipidomics study shed light on the cytoprotective mechanism of MLT in Cd and FFA-induced hepatocyte lipotoxicity, highlighting a repairing effect of this molecule on the cellular lipidome, which may hold therapeutic potential in fatty liver diseases.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"77 3","pages":""},"PeriodicalIF":8.3,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jpi.70047","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}