Journal of Pineal Research最新文献

{"title":"Time-of-Day Impacts Uterine Circadian Rhythms and Response to Oxytocin: Comparison of Uterine Function in Melatonin-Deficient C57BL/6 Versus Melatonin Proficient CBA/B6 Hybrid Mice","authors":"Thu Van-Quynh Duong,&nbsp;Alexandra M. Yaw,&nbsp;Hanne M. Hoffmann","doi":"10.1111/jpi.70112","DOIUrl":"10.1111/jpi.70112","url":null,"abstract":"<p>Reaching term gestation requires a complex interplay between the uterus and hormonal signals regulating its contractile profile. Most pregnancy-associated hormones vary in their overall level of release throughout pregnancy, but also have a circadian release pattern, including progesterone, oxytocin, and melatonin. It remains poorly understood how the circadian release of hormones impacts uterine function. To determine how time-of-day, mouse strain, and melatonin proficiency were associated with the uterotonic efficacy of oxytocin, the primary hormone promoting uterine contractions, we used melatonin-deficient C57BL/6 and melatonin-proficient CBA/C57BL/6 (CBA/B6) female mice on gestation day 18. Through RNAscope, we found that oxytocin receptor (<i>Oxtr</i>) mRNA exhibited a time-of-day variation that differed between the uterine endometrium and myometrium. This uterine layer-specific, time-of-day difference in <i>Oxtr</i> was associated with a shift in phase of the molecular clock reporter PER2::Luciferase. A strain-specific effect of PER2::Luciferase rhythms were observed in the uterus, where CBA/B6 had a shorter PER2::Luciferase period than C57BL/6. In addition, CBA/B6 uteri had lower spontaneous uterine contraction force compared to C57BL/6. Despite the difference in spontaneous contractions and circadian period, the capacity of oxytocin to induce contractions varied by time-of-day, independent of mouse strain. Together, these findings reveal that uterine responsiveness to oxytocin is gated by circadian time, with <i>Oxtr</i> expression and uterine contractions showing diurnal variation. At the same time, mouse strain was associated with PER2::Luciferase period and baseline uterine contractility. These results underscore the relevance of circadian timing in uterine physiology and that strain differences impact basal uterine function.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"78 2","pages":""},"PeriodicalIF":6.3,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12853413/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146083612","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":"Pinopsin Regulates Melatonin Production and Daily Locomotor Activity: Functional Insights From Gene-Edited Xenopus Tadpoles","authors":"Neda Heshami,&nbsp;Ricardo D. Romero,&nbsp;Flavio S. J. de Souza,&nbsp;Gabriel E. Bertolesi,&nbsp;Sarah McFarlane","doi":"10.1111/jpi.70114","DOIUrl":"10.1111/jpi.70114","url":null,"abstract":"<p>Circadian rhythm alignment depends on environmental light detection via opsins. Pinopsin, originally identified in the pineal organ of birds and later in amphibian pineal complex and eyes, may play a role in this process, though its function has not been genetically tested. Evolutionary analysis suggests pinopsin was independently lost in several vertebrate lineages, including mammals (Synapsida), some reptiles (e.g. snakes and crocodiles), and teleost fish, but retained in birds, turtles, lizards, and non-teleost Actinopterygii. We conducted a detailed genomic search of the pinopsin gene across 95 amphibian species and assessed its function in <i>Xenopus laevis</i> tadpoles using CRISPR/Cas9-mediated knockout. Our survey indicates that pinopsin is highly conserved in salamanders and most anurans, but absent in many caecilians (Gymnophiona), which have a fossorial lifestyle with limited light exposure. To investigate its biological role, we generated <i>X. laevis</i> F0 pinopsin knockout tadpoles and evaluated two light-sensitive responses: (1) day/night melatonin fluctuations inferred from skin pigmentation changes, and (2) locomotor activity over a 24-h photoperiod. We show these responses depend only on pineal light sensitivity and are independent of eye sensitivity at developmental stage 46/47. Our findings reveal: (1) Pinopsin is co-expressed with Aanat, a key enzyme in melatonin synthesis; (2) knockout tadpoles show paler skin during the light phase, suggesting pinopsin suppresses melatonin production in daylight; and (3) reduced daytime locomotor activity in F0 mutants, consistent with melatonin-induced lethargy. Overall, pinopsin emerges as a critical opsin for light-regulated circadian-associated behavior in <i>Xenopus</i>, with likely conserved roles across amphibians (anurans and salamanders in general) and other non-mammalian vertebrates, including birds, turtles, and lizards.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"78 2","pages":""},"PeriodicalIF":6.3,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12836464/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146049849","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":"Comprehensive Genome-Wide Identification and Expression Analysis of the N6-Methyladenosine (m6A) Regulatory Network Influences Rapid Stress Adaptation With Exogenous Melatonin in Rice","authors":"Hira Khanzada,&nbsp;Ghulam Mustafa Wassan,&nbsp;Ping Wang,&nbsp;Saba Khanzada,&nbsp;Xiaoning Wang,&nbsp;Zhihui Xia","doi":"10.1111/jpi.70109","DOIUrl":"10.1111/jpi.70109","url":null,"abstract":"<p>Exogenous melatonin has emerged as a pivotal multifunctional signaling molecule, recognized for its critical role in enhancing stress tolerance and improving crop productivity. N6-methyladenosine (m6A) is the most prevalent internal modification found in eukaryotic mRNA and plays a crucial role in regulating plant growth, development, and stress responses. Despite its importance, the regulatory mechanisms of the m6A pathway in rice exposed to exogenous melatonin remain inadequately investigated. This study investigates systematic analysis of m6A-regulatory gene families in rice. We identified a total of 124 genes, which include 7 writers, 22 readers, and 95 erasers. The distribution of these genes is uneven across the 11 chromosomes of the rice genome. Analysis of conserved domains revealed structural signatures that are specific to each gene family. Phylogenetic relationships with dicot and monocot species offered insights into evolutionary trajectories. Notably, gene structure and motif analyses revealed functional divergence within and between gene families. Cis-element analysis identified abundance motifs associated with stress adaptation, hormonal signaling, and TFs, including ABRE, DRE, and MYB. Furthermore, synteny analysis unveiled both conserved regions and lineage-specific expansions, particularly within the YTH and ALKBH families. The protein interaction network revealed robust connections among subgroups and identified 10 hub genes. GO and KEGG analyses indicated significant enrichment in stress-related pathways, including secondary metabolite biosynthesis, flavonoid biosynthesis, and cysteine and methionine metabolism. RT-qPCR validates that melatonin Osm6As significantly influences the expression of targeted genes, with melatonin upregulations exhibiting a time-dependent pattern. Furthermore, GFP tagging of OsECT2 revealed that protoplasts are evenly distributed, suggesting robust nuclear enrichment of fluorescence. This study offers new insights into the epitranscriptomic regulatory responses of the m6A-modifier.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"78 1","pages":""},"PeriodicalIF":6.3,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jpi.70109","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145958361","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 Influences Bmi1+ Intestinal Stem Cell Fate Through Metabolic Regulation After Irradiation","authors":"Xudan Lei,&nbsp;Zhenni Xu,&nbsp;Xiangjun Liu,&nbsp;Chao Yang,&nbsp;Lingxiao Huang,&nbsp;Yujun Huang,&nbsp;Meihua Chen,&nbsp;Yongxia Zhu,&nbsp;Jinyi Lang,&nbsp;Dengqun Liu","doi":"10.1111/jpi.70110","DOIUrl":"10.1111/jpi.70110","url":null,"abstract":"<div>\u0000 \u0000 <p>Radiation-induced intestinal injury involves catastrophic loss of intestinal stem cells (ISCs), but the mechanisms enabling their rescue remain elusive. Here, we demonstrated that melatonin, a potent mitigator of mitochondrial oxidative stress, robustly promoted the regeneration of intestinal crypts and organoids following irradiation. Using in vivo lineage tracing with <i>Lgr5</i>^CreERT2;<i>Rosa26</i>-tdTomato, <i>Mist1</i>^CreERT2;<i>Rosa26</i>-tdTomato, and <i>Bmi1</i>^CreER;<i>Rosa26</i>-tdTomato models, we pinpointed <i>Bmi1</i>⁺ cells as the source of the melatonin-induced proliferating cells responsible for regeneration. Genetic ablation of <i>Bmi1</i>⁺ lineages abolished the regenerative benefits of melatonin. Mechanistically, melatonin was associated with a shift in mitochondrial metabolism in <i>Bmi1</i>⁺ ISCs, in part through the suppression of Ca²⁺/CaMKⅡ-driven phosphorylation of DRP1, which contributed to reduced reactive oxygen species (ROS) production. This attenuation of oxidative stress subsequently reduced DNA damage and cell cycle arrest, while enhancing mitochondrial oxidative phosphorylation. Crucially, pharmacological inhibition of p-DRP1 phenocopied the effects of melatonin, promoting <i>Bmi1</i>⁺ ISC-mediated regeneration. In conclusion, our work revealed that melatonin acts as a guardian of <i>Bmi1</i>⁺ ISCs and promotes regeneration by imposing a critical checkpoint on CaMKII/DRP1-dependent metabolic dysfunction. Targeting this pathway with melatonin or specific p-DRP1 inhibitors represents a novel and highly promising therapeutic strategy for radiation-induced intestinal injury.</p></div>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"78 1","pages":""},"PeriodicalIF":6.3,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145958383","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":"Manipulation of the Expression of SNAT1 Enhances Melatonin Biosynthesis, Promotes Plant Growth, and Improves Salt Stress Tolerance in Kiwifruit","authors":"Xinling Liu,&nbsp;Xinbo Tian,&nbsp;Xiaowei Yan,&nbsp;Fan Tang,&nbsp;Wenjie Jiang,&nbsp;Dan Xu,&nbsp;Xiaoli Zhang,&nbsp;Yuxing Li,&nbsp;Dong Liang,&nbsp;Hui Xia","doi":"10.1111/jpi.70107","DOIUrl":"10.1111/jpi.70107","url":null,"abstract":"<div>\u0000 \u0000 <p>Kiwifruit is susceptible to salt stress due to its shallow root system. Melatonin has been demonstrated to play a crucial role in responding to abiotic stresses, particularly salinity stress. In this study, we isolated a key melatonin biosynthesis gene, <i>PavSNAT1</i>, from sweet cherry and generated transgenic kiwifruit plants overexpressing <i>PavSNAT1</i>. The transgenic plants exhibited increased melatonin and cytokinin levels, accompanied by improved growth performance. Under salt stress conditions, transgenic plants demonstrated enhanced tolerance by alleviating ROS accumulation and chlorophyll degradation and increasing free amino acid content. Furthermore, three salt-responsive transcription factors, AcMYB60, AcBZIP11, and AcERF8, were highly upregulated under salt stress in transgenic plants. Transient overexpression of these genes resulted in enhanced salt tolerance in kiwifruit. Collectively, our findings demonstrate that heterologous expression of <i>PavSNAT1</i> enhances plant growth and salt stress resistance in kiwifruit, revealing a promising strategy for improving crop resilience under adverse environmental conditions.</p></div>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"78 1","pages":""},"PeriodicalIF":6.3,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145931753","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":"Corrigendum to Melatonin Attenuates D-Galactose-Induced Memory Impairment, Neuroinflammation and Neurodegeneration via Rage/Nf-KB/Jnk Signaling Pathway in Aging Mouse Model","authors":"","doi":"10.1111/jpi.70106","DOIUrl":"10.1111/jpi.70106","url":null,"abstract":"<p>Ali, T., Badshah, H., Kim, T.H., &amp; Kim, M.O. (2015). Melatonin attenuates <span>d</span>-galactose-induced memory impairment, neuroinflammation and neurodegeneration via RAGE/NF-KB/JNK signaling pathway in aging mouse model. <i>Journal of Pineal Research</i>, <i>58</i> (1), 71-85.</p><p>In Figure 3B the results of the 8-oxoG hippocampal CA1 region of the control group was unfortunately overlapped with the CA1 region of <span>d</span>-Gal+M. The corrected image of both the control and <span>d</span>-Gal+M are included in corrected figure below.</p><p>We apologize for the error.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"78 1","pages":""},"PeriodicalIF":6.3,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jpi.70106","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145909648","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":"Sleep Deprivation Exacerbates High-Fat Diet-Induced Obesity and MAFLD Through Melatonin Reduction Mediated NF-κB Activation","authors":"Renjiao Liu,&nbsp;Yiping Zhou,&nbsp;Chongyang Wei,&nbsp;Xincheng Wang,&nbsp;Huiyu Hao,&nbsp;Lifeng Wang,&nbsp;Yakun Ma,&nbsp;Yi Wang,&nbsp;Chunjun Li,&nbsp;Dongyan Chen","doi":"10.1111/jpi.70108","DOIUrl":"10.1111/jpi.70108","url":null,"abstract":"<div>\u0000 \u0000 <p>The rising prevalence of unhealthy lifestyles characterized by chronic sleep deprivation (SD) combined with a high-fat diet (HFD), represents a significant health concern. However, the synergistic effects of these factors on metabolic disorders remain poorly understood. To address this, we developed a model of ‘Unhealthy Lifestyles Zebrafish’ (UHL) to investigate the interaction between chronic SD and HFD. We demonstrated that SD synergistically exacerbated HFD-induced obesity, lipid accumulation, and the progression of Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD). Compared to zebrafish exposed to HFD alone, the UHL zebrafish exhibited more severe metabolic dysregulation, including elevated cholesterol levels, metabolic inflammation, and bile acid imbalance. Mechanistically, this synergy was driven by melatonin deficiency resulting from SD, which triggered NF-κB activation. This activation led to the upregulation of pro-inflammatory cytokines (<i>TNF-α</i>, <i>IL-6</i>, <i>IL-1β</i>). Crucially, exogenous melatonin supplementation reversed these detrimental effects by inhibiting NF-κB activation and restoring metabolic homeostasis. Conversely, pharmacological activation of NF-κB antagonized melatonin's protective effects. This study confirms the critical role of the melatonin/NF-κB axis in mediating the synergistic impact of sleep deprivation and a high-fat diet on obesity and MAFLD. These findings advocate for integrated lifestyle interventions targeting both sleep quality and dietary habits in metabolic health management.</p>\u0000 </div>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"78 1","pages":""},"PeriodicalIF":6.3,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145909630","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 Enhances Peanut Productivity by Enriching Root-Associated Nitrogen-Fixing Bacteria","authors":"Ali Muhammad,&nbsp;Xiangjun Kong,&nbsp;Lijie Li,&nbsp;Muhammad Hafeez Ullah Khan,&nbsp;Peipei Jia,&nbsp;Chen Miao,&nbsp;Zhiyong Zhang","doi":"10.1111/jpi.70105","DOIUrl":"10.1111/jpi.70105","url":null,"abstract":"<div>\u0000 \u0000 <p>Melatonin, a pleiotropic phytohormone, is widely recognized as a promising bio-stimulant, yet its integrative effects on root development, yield gain, and microbiome assembly in legumes remain underexplored. In this study, we investigated the effects of melatonin seed treatment across three peanut genotypes, focusing on plant productivity and the composition and structure of bacterial communities in root, rhizosphere, and bulk soil compartments. Melatonin treatment substantially improved root biomass, nodulation, nitrogen balance index, and yield-related traits, with the highest response observed in the genotype Xinbaihua 16. Amplicon sequencing revealed that melatonin induced distinct genotype and compartment specific shifts in bacterial community composition, with the root bacteria showing the increased remodeling, including a 45.9% increase in unique amplicon sequence variants (ASVs). Melatonin selectively enriched key Proteobacteria taxa such as <i>Rhizobium</i>, <i>Sphingomonas</i>, and <i>Enterobacter hormaechei</i>, known for their plant-growth promoting and biocontrol capabilities. Notably, melatonin-enriched taxa also included widely recognized nitrogen-fixing symbionts such as <i>Pararhizobium</i> and <i>Ensifer</i>, underscoring a direct link between melatonin-induced microbiome shifts and enhanced nitrogen acquisition capacity. Co-occurrence network analysis indicated that melatonin-treated roots harbored more complex bacterial networks, and Modules 3 and 4, dominated by melatonin-induced Proteobacteria, were strongly correlated with most plant traits. Collectively these findings highlight melatonin dual role as a bio-stimulant and microbiome modulator, promoting a functionally enriched and responsive bacteria that support enhanced plant performance. This study provides novel insights into the melatonin-mediated coordination of plant performance and bacterial assembly, offering a foundation for microbiome-informed crop improvement strategies.</p>\u0000 </div>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"78 1","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145699336","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 Circadian Phase Timing and Stability: Associations With Mood Symptoms Among a Clinically-Enriched Sample of Young Adults With Mood Disorders","authors":"Rachel F. L. Walsh,&nbsp;Mackenzie A. Maddox,&nbsp;Joshua Klugman,&nbsp;Namni Goel,&nbsp;Lauren B. Alloy","doi":"10.1111/jpi.70104","DOIUrl":"10.1111/jpi.70104","url":null,"abstract":"<div>\u0000 \u0000 <p>Circadian rhythms regulate many aspects of human health, and disruptions in these rhythms have been implicated in mood disorders. Dim light melatonin onset (DLMO) provides a gold standard measure of circadian timing, yet few studies have examined its stability or relation to mood symptoms in psychiatric populations. This study examined DLMO across three time points over 20 days in a clinically-enriched sample of 124 young adults with and without mood disorders. Participants also reported mood symptom levels three times daily via ecological momentary assessments (EMA). Circadian timing and stability were quantified and their associations with mood symptoms and diurnal mood patterns were assessed. Overall, DLMO demonstrated substantial stability, and did not differ by diagnostic group. The mood disorder group had earlier circadian timing than healthy controls. Hypomanic, but not depressive, symptoms were consistently associated with later DLMO in both cross-sectional and prospective analyses. Moreover, hypomanic symptoms exhibited a diurnal pattern that differed for participants with earlier and later circadian timing. Future work should examine endogenous circadian rhythms in relation to mood disorder subtypes and mood episodes to determine whether circadian timing changes can be used to predict or intervene on psychiatric symptoms.</p>\u0000 </div>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"78 1","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145699374","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":"Therapeutic Potential of Melatonin in Gastrointestinal Cancers: Molecular Mechanisms, Preclinical Evidence and Clinical Implications","authors":"Maciej Gonciarz,&nbsp;Benita Wiatrak,&nbsp;Iga Lombard,&nbsp;Łukasz Konecki,&nbsp;Joanna Sarbinowska","doi":"10.1111/jpi.70101","DOIUrl":"10.1111/jpi.70101","url":null,"abstract":"<p>Gastrointestinal (GI) cancers remain a leading cause of global morbidity and mortality, necessitating novel therapeutic strategies. Melatonin (MEL), an indoleamine with pleiotropic biological activities, has emerged as a promising adjuvant in oncology due to its antiproliferative, proapoptotic, and antioxidant properties. This review synthesizes current evidence on MEL's molecular mechanisms in GI carcinogenesis, including modulation of NF-κB, PI3K/AKT, and Wnt/β-catenin pathways, suppression of reactive oxygen species (ROS), and regulation of circadian rhythm-related genes (e.g., CLOCK, BMAL1). Preclinical studies demonstrate that MEL enhances chemoradiotherapy efficacy-reducing tumor volume by 70% in murine colorectal models and decreasing 5-fluorouracil (5-FU) resistance via miR-532-3p/β-catenin axis modulation. Clinical trials report a 23%–41% risk reduction in colorectal cancer among shift workers with MEL supplementation and a 53% decrease in radiotherapy-induced oral mucositis. Despite promising data, limitations persist: fewer than 15% of clinical trials focus on GI cancers, dosing remains unstandardized (10–40 mg/day), and molecular heterogeneity (e.g., KRAS mutations in pancreatic cancer) may limit therapeutic responses. Future research must prioritize phase III trials, chronotherapy optimization, and biomarker-driven approaches, including MT1/MT2 receptor expression and microbiome profiling. Given its low toxicity and putative synergy with immunotherapies, MEL should be regarded as an adjunct under investigation rather than an established option; to date, no GI-specific phase III randomized trials exist, and clinical signals come primarily from small, heterogeneous cohorts. Dosing is unstandardized and limited by low oral bioavailability (first-pass) and possible pharmacogenomic variability.</p>","PeriodicalId":198,"journal":{"name":"Journal of Pineal Research","volume":"78 1","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12676935/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145666441","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}