Search Results (664)

Background: Histone deacetylase inhibitors (HDACis) such as Trichostatin A (TSA) have emerged as promising epigenetic modulators of addiction-related behaviors. TSA treatment has been previously shown to decrease alcohol (ethanol) consumption with dose and sex differences. However, molecular mechanisms underlying TSA’s effects on ethanol consumption remain poorly understood. Method: We collected the nucleus accumbens shell (NAcSh) of HAD1 rats, which has been used to investigate the impact of TSA treatment on ethanol consumption. RNA-seq profiling of NAcSh followed by IPA and GSEA analysis were conducted. Results: Gene profiling identified differentially expressed genes (DEGs) with sex- and dose-specific effects, with some genes demonstrating high fold change (FC). Males showed significantly increased Oxt and decreased Ttr expression following 1 mg/kg TSA treatment. In females, Pmch expression significantly decreased following 1 mg/kg TSA treatment, whereas Tmem179 expression increased following 2 mg/kg TSA treatment. Pathways centered on Hdac and Fkbp5 in males, and Bdnf and estrogen receptor in females were significantly enriched following TSA treatment, with distinct pathways identified at the 1 mg/kg and 2 mg/kg doses. IL1β and β-estradiol are common upstream regulators among all groups. Unexpectedly, some common DEGs between male and female comparisons have opposite responses to the same dose of TSA. GSEA analysis has identified additional gene sets, hallmark genes and microRNAs, and functions including immune response, metabolism, and estrogen response significantly associated with TSA treatment. Conclusions: This study successfully identified gene expression evidence that TSA treatment is sex- and dose-specific, underscoring the importance of considering both variables in the development of HDAC-targeted therapies for alcohol use disorders. Full article

Triple-negative breast cancer (TNBC) lacks effective targeted therapeutic strategies, and cisplatin resistance remains a major challenge in clinical treatment. This study aimed to investigate whether inorganic phosphate (Pi) influences cellular responses to cisplatin and to explore the potential molecular mechanisms involving RB1–E2F signaling, DNA repair regulation, and oxidative stress. Clinical associations between serum biochemical parameters and tumor histologic grade were evaluated in 246 patients with invasive ductal carcinoma. Triple-negative breast cancer cell line (MDA-MB-231), estrogen receptor-positive breast cancer cell line (MCF-7), and non-tumorigenic breast epithelial cell line (MCF-10A) were treated with control, Pi, cisplatin, or Pi combined with cisplatin.. Cellular proliferation, cell-cycle distribution, DNA damage, intracellular reactive oxygen species (ROS), inflammatory responses, and transcriptomic alterations were assessed using functional assays and RNA sequencing-based analyses. Pi levels showed an inverse association with tumor grade. In MDA-MB-231 cells, Pi combined with cisplatin resulted in enhanced growth inhibition, increased DNA damage accumulation, elevated cellular ROS production, and activation of inflammatory responses compared with cisplatin alone. Transcriptomic analyses revealed alterations in RB1–E2F-related transcriptional programs and reduced expression of DNA repair-associated gene sets. TCGA-BRCA analysis further indicated that elevated DNA repair pathway activity was associated with unfavorable survival outcomes. These findings suggest that Pi may modulate cisplatin responses through coordinated regulation of RB1–E2F signaling, DNA repair capacity, and oxidative stress responses, providing a potential mechanistic basis for further investigation of phosphate-associated therapeutic strategies in TNBC. Full article

Background and Objectives: Endometriosis is associated with chronic inflammation, immune dysregulation, oestrogen-dependent growth, oxidative stress, altered steroid hormone metabolism, compromised epithelial barrier integrity, and the production of bioactive microbial metabolites. These interconnected alterations have been proposed to create, in principle, a permissive local microenvironment for malignant transformation. This narrative review examines whether endometriosis-associated dysregulation of the gut and reproductive tract microbiota may act as a hypothetical biological modulator linking these multi-axis changes to endometrial carcinogenesis, with attention to immunological, endocrine, metabolic, microbial–metabolite, oxidative, and barrier-related pathways. Material and Methods: We narratively integrated current evidence on gut and reproductive tract microbiota alterations relevant to endometrial homeostasis, with emphasis on the estrobolome, low-biomass uterine microbial communities, inflammatory and immune signaling, microbial metabolites, and pathways implicated in carcinogenesis. Results: Available data suggest that dysbiosis may influence endometrial carcinogenesis through interconnected endocrine, inflammatory, metabolic, and immune mechanisms. Attention has been given to loss of Lactobacillus dominance, enrichment of anaerobic and pro-inflammatory taxa, altered estrogen recirculation, progesterone resistance, Toll-like receptor activation, NF-κB/STAT3 signaling, COX-2/PGE2 activity, PI3K/AKT/mTOR pathway activation, oxidative stress, macrophage polarization, and impaired natural killer cell surveillance. These alterations may contribute to a permissive microenvironment characterized by persistent inflammation, defective immune control, and disrupted endometrial homeostasis. However, the current literature remains limited by small and heterogeneous cohorts, predominantly cross-sectional designs, contamination risk, and marked methodological variability, particularly in low-biomass uterine samples. Conclusions: Current evidence supports the view that microbiome dysregulation is a context-dependent biological modulator that intersects with endocrine, inflammatory, metabolic, immune, oxidative, and barrier-related pathways relevant to endometrial carcinogenesis. Microbiome dysbiosis should be regarded as a hypothetical contributory factor rather than as an established causal driver. Its near-term translational relevance appears greater for biomarker development and risk stratification than for immediate microbiome-directed therapy. Longitudinal, standardized, and functionally integrated studies are needed to clarify whether microbiome-associated signatures can be translated into clinically meaningful prevention and management strategies in endometrial cancer. Full article

Bisphenols (BPs) are widespread environmental endocrine disruptors, but their potential depression-related neurotoxicity has not been systematically assessed. Here, we combined machine learning (ML), network toxicology, molecular docking, and in vivo experiments to screen 26 bisphenols for depression-related neurotoxic risk. We first integrated bisphenol A (BPA)-related targets with depression-related genes to build a chemical-gene-phenotype-disease network and an adverse outcome pathway (AOP) framework. We then used nine ML algorithms to rank the predicted risk of the 26 bisphenols. Molecular docking showed that the predicted high-risk compounds had strong binding affinity for estrogen receptor 1 (ESR1). The AOP analysis further suggested the involvement of the ESR1–cAMP response element-binding protein 1 (CREB1)–glutamate ionotropic receptor N-methyl-D-aspartate type subunit 2B (GRIN2B) pathway. In vivo experiments showed that BPA exposure caused neuronal damage in the cornu ammonis 3 (CA3) region of the rat hippocampus and significantly reduced the messenger RNA (mRNA) expression of the corresponding genes Esr1, Creb1, and Grin2b in hippocampal tissue. Overall, this study screened and prioritized the model-predicted depression-related neurotoxic risk of 26 bisphenols, supports a role for the ESR1–CREB1–GRIN2B pathway in BPA-induced neurotoxicity, and provides mechanistic evidence for bisphenol risk assessment. Full article

Kaempferol is a natural flavonol compound widely present in various single-herb remedies and compound formulations used for the treatment of ocular diseases. Despite its inherent pharmaceutical limitations, accumulating evidence indicates that kaempferol exerts broad protective effects against diverse ocular disorders through multiple biological pathways, highlighting its potential as a multi-target therapeutic candidate in ophthalmology. However, current evidence regarding kaempferol-based ophthalmic applications remains fragmented across different ocular diseases and mechanistic investigations, and a comprehensive evaluation of its therapeutic potential, translational challenges, and existing limitations is still lacking. This review systematically summarizes the research progress on kaempferol in the treatment of eye diseases, encompassing its source distribution, structural characteristics, ocular delivery strategies, disease spectrum coverage, molecular mechanisms, and safety profile. By critically evaluating currently available evidence, this review further identifies unresolved issues and translational barriers that hinder the clinical application of kaempferol in ophthalmology. Regarding delivery strategies, carriers such as gelatin nanoparticles, porous bovine serum albumin membranes, platelet-derived extracellular vesicles, and polyvinylpyrrolidone-based nanocomposites have preliminarily improved ocular surface retention and corneal permeability of kaempferol in models of corneal neovascularization and alkali burns. In terms of therapeutic indications, kaempferol has demonstrated protective effects in diverse experimental models, including age-related macular degeneration (AMD), diabetic retinopathy, diabetic cataract, dry eye disease, fungal keratitis, corneal transplant rejection, acute glaucoma, and retinoblastoma. At the mechanistic level, kaempferol exerts comprehensive pharmacological actions—anti-inflammatory, antioxidant, metabolic regulation, anti-angiogenic, and immunomodulatory—by modulating multiple signaling pathways, including MAPK, NF-κB, STAT1/IRF7, Nrf2/HO-1, VEGF/PI3K/Src/Akt/ERK, aldose reductase, estrogen-related receptor alpha (ERRα), and the NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome. Available safety assessments suggest that kaempferol exhibits a generally favorable safety profile across ocular, cellular, systemic, and genetic evaluations. Despite these advances, the clinical translation of kaempferol in ophthalmology remains limited by insufficient clinical and pharmacokinetic evidence, underdeveloped targeted delivery strategies, and a lack of integrated understanding of its molecular basis in ocular protection. By systematically integrating evidence from ocular disease models, molecular mechanisms, delivery strategies, and safety evaluations, this review bridges fragmented knowledge regarding kaempferol-based ophthalmic applications and provides an integrated framework for understanding its therapeutic potential and translational prospects. Overall, this review highlights kaempferol as a promising multi-target therapeutic candidate for ocular diseases and provides insights into its future translational development. Full article

Background/Objectives: Benzimidazole and hydrazone scaffolds are widely investigated in anticancer drug discovery because of their structural versatility and capacity to interact with multiple cancer-related targets. This study aimed to synthesize a series of trifluoromethyl-substituted benzimidazole-hydrazone derivatives, evaluate their antiproliferative activity and cancer-cell selectivity, and explore their potential interactions with breast cancer-associated molecular targets. Methods: A series of benzimidazole-hydrazone derivatives were prepared through a four-step synthetic route using both conventional and microwave-assisted procedures. The structures of the synthesized compounds were characterized using spectroscopic and analytical methods. Antiproliferative activity was evaluated in estrogen receptor-positive MCF-7 human breast cancer cells using the MTT assay after 48 h of exposure. Selected active compounds were additionally tested against non-tumorigenic hTERT cells to determine their selectivity indices. In silico analyses were performed against estrogen receptor alpha in antagonist and selective estrogen receptor degrader conformations, bromodomain-containing protein 4, and the mTOR kinase domain. Results: Microwave irradiation substantially reduced reaction times from 12–24 h to 4–6 min and increased isolated yields by 7–24 percentage points compared with conventional conditions. Compounds 4, 7, 9, and 11 reduced MCF-7 cell viability below 50% at 20 μM. Compound 7 showed the highest antiproliferative activity, with an IC₅₀ value of 7.5 ± 0.8 μM, and the greatest selectivity toward MCF-7 cells over hTERT cells, with a selectivity index of 12.66. Molecular docking, MD simulation, and MM/GBSA calculations predicted that compound 7 would effectively bind to the investigated targets, particularly estrogen receptor alpha, as well as the BRD4 and mTOR kinase domains. Conclusions: Compound 7 represents a selective, mid-micromolar benzimidazole-hydrazone lead against MCF-7 breast cancer cells. Its predicted molecular interactions warrant further target-based, mechanistic, pharmacokinetic, and in vivo evaluation. Full article

Ovarian function is essential for fertility in dairy cattle, yet the cellular and molecular features associated with physiological ovarian states and ovarian dysfunction remain incompletely characterized. In this study, serum and follicular-fluid hormone measurements showed distinct endocrine profiles among ovarian states, and the follicular-fluid estrogen to progesterone was highest during the follicular phase and lowest in luteal and luteal cystic ovaries. Then, single-nucleus RNA sequencing was performed on ovarian tissues from 18 Holstein cows representing follicular, luteal, mid-gestation pregnancy, inactive, and luteal cystic states. After quality control, 154,054 nuclei were retained for cell-type annotation, granulosa cell (GC) subclustering, trajectory inference, co-expression analysis, ligand-receptor and ligand-target prediction, and transcriptome-based metabolic flux estimation. Twenty-seven ovarian cell clusters and five GC subtypes were identified, with state-associated variation in relative nuclear composition and transcriptional profiles. Luteal cystic ovaries showed a higher relative representation of immune cells and enrichment of inflammation-related transcriptional signatures, whereas inactive ovaries exhibited lower levels of predicted intercellular communication. GC analyses indicated differences among ovarian states in transcriptional programs related to proliferation, steroidogenesis, extracellular-matrix organization, inflammation, and metabolism. Transcriptome-based metabolic inference further suggested subtype-associated variation in tricarboxylic acid cycle, lipid, polyamine, phosphoinositide, and gamma-aminobutyric acid-related pathways. This study provides a multi-state single-nucleus transcriptomic resource for bovine ovarian research and identifies candidate cell populations and molecular features for future experimental validation. Full article

Homer proteins (Homer1–3) are scaffold proteins that mediate protein–protein interactions in signal transduction; however, the role of Homer3 in breast cancer (BC), particularly triple-negative breast cancer (TNBC), remains poorly defined. Here, we investigated the clinical relevance and functional significance of Homer3 in BC and TNBC. Publicly available datasets from TCGA and GEO were analyzed to evaluate associations between Homer3 expression and patient outcomes using Kaplan–Meier survival analysis. Pathway enrichment analysis and gene set variation analysis (GSVA) were performed to identify signaling programs associated with Homer3 co-expressed genes. Functional roles were examined using stable TNBC cell lines with Homer3 knockdown or overexpression, followed by assays for cell proliferation, clonogenic growth, migration, invasion, and wound healing. We found that Homer3 expression was elevated in breast tumors compared with normal tissues and was associated with poor prognosis in both BC and TNBC. Homer3 expression was higher in TNBC than in non-TNBC subtypes and negatively correlated with estrogen receptor (ER) and progesterone receptor (PR) expression. Functionally, Homer3 depletion suppressed TNBC cell proliferation, clonogenic capacity, migration, invasion, and wound healing, whereas Homer3 overexpression produced reciprocal effects. Pathway analyses revealed that Homer3 co-expressed genes were enriched in cell cycle-related pathways and Hallmark MYC signaling, which were associated with adverse clinical outcomes. Consistently, Homer3 knockdown selectively reduced key proliferative cell-cycle regulators. Collectively, these findings demonstrate that Homer3 is associated with aggressive phenotypes and MYC- and cell cycle-linked proliferative programs in breast cancer, particularly in TNBC. Survival analyses are presented as exploratory findings, supporting the biological relevance of Homer3 in TNBC. These findings suggest that Homer3 may represent a potential therapeutic vulnerability. Full article

Women are particularly vulnerable to sarcopenia- a progressive, age-related condition characterized by the loss of skeletal muscle mass, strength, and physical performance- due to sex-specific hormonal and physiological changes, most notably the decline in estrogen levels after menopause. This increased risk highlights the critical importance of developing tailored, sex-specific strategies for prevention, diagnosis, and management. Among nutritional factors, vitamin D is increasingly recognized as a key regulator of skeletal muscle physiology, exerting direct effects on muscle tissue via vitamin D receptors and modulating the gene expression involved in muscle cell proliferation, protein synthesis, and mitochondrial function. This review aims to evaluate the synergistic roles of vitamin D, nutrition, and exercise in improving skeletal muscle function in women, with a specific focus on the prevention and management of sarcopenia. Vitamin D can contribute to skeletal muscle integrity by influencing fiber composition, preserving type II fibers, and preventing mass loss. Additionally, it promotes satellite cell activation, thereby supporting muscle repair and regeneration. Consequently, vitamin D supplementation can improve muscle strength, balance, and physical performance, while reducing the risk of falls, frailty, osteoporosis and sarcopenia. Recent studies suggest that vitamin D acts synergistically with diets enriched with whey protein and leucine, as well as with structured exercise programs, predominantly resistance training, to further enhance muscle function and bone health. This review critically examines the current evidence regarding these combined interventions in preserving and optimizing skeletal muscle function in older women, while also addressing the major limitations and inconsistencies in available studies. Understanding the collective impact of these strategies is crucial for developing personalized and effective strategies aimed at maintaining musculoskeletal health, physical performance, and functional independence throughout the female aging process. Full article

Mentha pulegium L. is reported to contain phytochemicals known to bind to estrogen receptors and modulate estrogenic effects. A hydroethanolic leaf extract of Mentha pulegium L. (MPE) was prepared, and its effects on uterine and ovarian tissues in immature rats were investigated, focusing on transcriptional endpoint-related estrogenic activity. Female Sprague Dawley rats were treated with varying doses of MPE alone or in combination with estradiol for seven days. Gene expression analysis was performed using reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) to evaluate the effect of MPE on estrogen-responsive biomarkers: Calbindin-D9k (CaBP-9k), Progesterone receptor (Pgr), Trefoil factor 1 (pS2), Intestinal calcium-binding protein integral (Icabp), Integral membrane-associated protein-1 (Itmap1) and Complement component 3 (CC3) genes. In ovarian tissues, MPE treatment decreased CaBP-9k and Icapb expression, with CC3 showing significant decreases in the 200 mg/kg group. Treatments with MPE and estradiol significantly reduced the expression of all estrogen-responsive genes compared to estradiol treatment. In uterine tissues, 1000 mg/kg MPE increased CaBP-9k and pS2 expression significantly but decreased Icapb, CC3, pS2, and Itmap across all treatment groups significantly. Combined estradiol treatment with MPE (500 and 1000) mg/kg showed significantly low CaBP-9k and CC3 expressions. Increased expression of Icapb, Itmap, and pS2 was observed when combined estradiol treatments with MPE (500 and 1000) mg/kg were compared to estradiol treatment. MPE influenced the expression of specific genes in the uterus and ovaries and thus may exhibit endocrine-modulatory activity by multiple mechanisms of action, highlighting its potential complexity in modulating estrogenic responses. Full article

11-ketotestosterone (11-KT) has previously been shown to promote previtellogenic ovarian development and vitellogenin-related hepatic responses in sterlet (Acipenser ruthenus), but the endocrine genes involved in this process remain unclear. In this study, previtellogenic female sterlets were implanted with slow-release 11-KT strips at 5 or 25 mg/kg for 30 days, and transcriptional responses of HPG-axis-related genes, including GnRH paralogs, gonadotropins, and gonadotropin receptors, were examined in the brain-pituitary complex, liver, and ovary. In the brain-pituitary complex, 11-KT increased fsh expression in the 25 mg/kg group and upregulated fshr in both treatment groups, whereas gnrh paralogs showed limited responses. In the liver, most GnRH- and gonadotropin-related genes were not significantly altered, suggesting that hepatic expression of upstream reproductive-axis genes was not a major in vivo target of 11-KT feedback. The ovary exhibited the strongest response, with increased gnrh2 and fsh expression and reduced gnrh3, fshr, and lhr expression, especially at the higher dose. To further examine receptor-related regulation of hepatic vtg expression, liver tissue was incubated in vitro with 11-KT alone or in combination with the androgen receptor antagonist flutamide or the estrogen receptor antagonist fulvestrant. Flutamide did not abolish 11-KT-induced vtg expression, whereas high-dose fulvestrant reduced both era and vtg expression relative to 11-KT treatment alone. Overall, 11-KT elicited tissue-specific transcriptional responses in HPG-axis-related genes, particularly involving ovarian gnrh2, fsh, fshr, and lhr. The differential antagonist responses observed in liver explants provide in vitro evidence consistent with the involvement of ER-associated signaling in hepatic vtg expression, but do not establish direct receptor-mediated regulation. Full article

Early childhood exposure to bisphenol A (BPA) is closely associated with autism spectrum disorder (ASD), though the precise molecular mechanisms remain unclear. To investigate this, we employed an integrated computational approach combining network toxicology, molecular docking, and molecular dynamics simulation. Potential targets of BPA and ASD-related genes were collected from multiple databases, identifying 57 overlapping targets. Protein–protein interaction network analysis highlighted 16 core targets among them. Gene Ontology and KEGG pathway enrichment analyses indicated these targets are primarily involved in synaptic transmission, GABAergic signaling, and neuroactive ligand–receptor interactions. Molecular docking demonstrated potential binding between BPA and several core targets, including estrogen receptor 1 (ESR1), gamma-aminobutyric acid type A receptor subunit beta-2 (GABRB2), and amyloid precursor protein (APP), with binding energies below −5 kcal/mol. The stability of the BPA-ESR1 complex was further supported through 100 ns molecular dynamics simulation. These results suggest that BPA may contribute to ASD by disrupting neuroendocrine pathways and synaptic function via interactions with key targets such as ESR1. Full article

With a lifetime risk estimated to be 1 in 8 in industrialized countries, breast cancer is the most frequent type of cancer among women worldwide and the second leading cause of cancer deaths in women. More importantly, current evidence suggests that in women aged <45 years, breast cancer is unquestionably the leading cause of cancer-related deaths. Hormonal therapy has an established role in the treatment of breast cancer. Hormonal therapy aims at preventing the stimulation of mitogenic estrogen-dependent pathways. Hormonal therapy can be performed through blocking the production of estrogens or through blocking the action of estrogens upon tumor cells. The action of estrogens upon tumor cells can be blocked through selective estrogen receptor modulators (SERMs) or through selective estrogen receptor downregulators (SERDs). Estrogen receptor mutation (ESR1 mutation) is one of the common mechanisms by which breast cancer becomes resistant to additional therapies from SERMs or aromatase inhibitors. Fulvestrant, an injectable anti-estrogen, is the SERD commonly used. Fulvestrant has no agonistic activity and causes degradation of the estrogen receptor. This agent is more active in postmenopause than premenopause and is indicated in the treatment of advanced breast cancer in case of disease progression during or after tamoxifen. Oral SERDs are being rapidly developed to replace fulvestrant with the potential of higher efficacy and lower toxicities. Novel agents such as complete estrogen receptor antagonists (CERANs), proteolysis targeting chimeras (PROTACs), and selective estrogen receptor covalent antagonists (SERCAs) are also promising therapies. This manuscript focuses on recent advances in the development of drugs targeting the estrogen receptor. Full article

Background/Objectives: Estrogen is a key female hormone; however, its role in periodontitis remains poorly understood. This study investigated the effects of 17β-estradiol (E2) on experimental periodontitis using an ovariectomy (OVX) model with E2 administration. Methods: Female mice aged 8–10 weeks underwent OVX, followed by induction of ligature-induced periodontitis, and subsequent quantification of alveolar bone resorption. Additional groups received an aromatase inhibitor or E2 supplementation after OVX, with subsequent induction of periodontitis and evaluation of bone resorption. Histological analysis assessed multinucleated giant cells and tartrate-resistant acid phosphatase-positive osteoclasts on the bone surface. Gingival tissue was analyzed for gene expression related to osteoclastogenesis. The effect of E2 on osteoclast differentiation from bone marrow cells was also examined. Results: OVX significantly reduced serum E2 levels and decreased alveolar bone resorption. Aromatase inhibitor administration similarly reduced bone loss. Histological evaluation revealed a reduced number of resorbing osteoclasts in OVX mice, whereas E2 supplementation increased osteoclast numbers. No significant changes in inflammatory cytokine or receptor activator of nuclear factor-kappa B ligand (RANKL) expression were observed. E2 promoted osteoclast differentiation in vitro, and treatment with E2 prior to RANKL stimulation further increased the number of osteoclasts. This effect was suppressed by an estrogen receptor antagonist. Moreover, E2 enhanced the expression of osteoclast differentiation–associated genes in the presence of RANKL, an effect abolished by tamoxifen. Conclusions: E2 increased alveolar bone resorption in experimental periodontitis, likely by promoting osteoclast differentiation, independent of inflammatory cytokine or RANKL gene expression. Full article

Junken meat sheep exhibit a characteristic postnatal coat-color transition, in which the initially black fleece gradually fades and develops into a white-trunk phenotype; however, the transcriptional basis of this developmental change in follicular pigment output remains unclear. In this study, three Junken meat sheep lambs showing a natural postnatal black-to-white coat-color transition were sampled longitudinally at the newborn black-fleece stage and the 179-day white-trunk stage, generating three matched biological pairs for RNA-seq analysis. Representative candidate genes were further validated by RT-qPCR. Differential expression analysis identified 1657, 400, and 1086 differentially expressed genes in the C11 vs. C1, C22 vs. C2, and C33 vs. C3 comparisons, respectively. Functional enrichment analysis indicated that these genes were mainly associated with tyrosine metabolism, ECM–receptor interaction, focal adhesion, Phosphoinositide 3-kinase-Akt signaling pathway (PI3K-Akt), arachidonic acid metabolism, estrogen signaling, and immune-related pathways. Integrated analysis of shared downregulated genes and expression patterns highlighted candidate genes related to pigmentation, the ECM/follicular microenvironment, and regulatory or metabolic processes. Pigmentation-related genes, including SOX10, TYR, TYRP1, PMEL, OCA2 and SLC45A2, were generally downregulated in 179-day white-trunk-stage skin, while changes in ECM- and metabolism-related genes suggested altered follicular microenvironmental regulation. These findings identify candidate transcriptional features associated with developmental coat-color fading in Junken meat sheep and support a follicular microenvironment–melanogenesis expression axis as a transcriptome-based framework for further investigation. Full article