Search Results (1,807)

Although estrogen has been identified to play crucial roles in the development of melasma, the exact mechanism of estrogen’s effect on pigmentation is incompletely elucidated. Recent studies have highlighted the pivotal role of immune cells in melasma. Interestingly, infiltrated macrophages are significantly enhanced in melasma lesions. Estrogen could facilitate M2 polarization. However, whether estrogen could stimulate melanogenesis via skewing M2 phenotype remains unknown. This study attempted to determine the significance and molecular mechanism of estrogen-induced M2 phenotype in melasma. We found that M2 infiltration was significantly increased in melasma lesions compared with perilesional skin. Arginase 1 was identified as the hub gene, and its expression was positively correlated with that of microphthalmia-associated transcription factor and tyrosinase-related protein 1 in melasma through transcriptome analysis. Moreover, β-estradiol (E2) was confirmed to promote M2 skewing while inhibiting M1 polarization via activating STAT6 signaling. Importantly, E2-induced M2 polarization robustly increased melanogenesis by increasing tyrosinase activity and expression of microphthalmia-associated transcription factor and tyrosinase in melanocytes, which were profoundly inhibited by VEGF knockdown or antagonism both in vitro and in ex vivo skin. Furthermore, VEGF was revealed to enhance melanogenesis through activating p38 MAPK and ERK1/2 signaling pathways in melanocytes. Additionally, dermal VEGF was significantly increased, and most of it colocalized with M2 macrophages in melasma lesions. Crucially, E2 administration potently reversed ovariectomy-decreased M2 skewing and subsequently promoted dermal VEGF expression and epidermal melanogenesis in the mouse tail skin, which were significantly suppressed by macrophage depletion. These findings suggest that estrogen may stimulate melanogenesis in melasma through increasing M2 skewing and VEGF expression and secretion in macrophages. Full article

This narrative review examines perimenopause as a critical transitional phase in women’s lives, often accompanied by elevated vulnerability to anxiety and depression. Dysfunction of the gut–brain axis is one of the key factors contributing to perimenopausal mood disorders and is currently receiving extensive attention. GBA dysfunction can trigger neurotransmitter metabolic imbalance, intestinal barrier impairment, and neuroinflammatory responses. Tryptophan (Trp) and γ-aminobutyric acid (GABA) serve as essential precursors and direct modulators of key neurotransmitters, and the dysregulation of their metabolic pathways has been implicated in perimenopausal anxiety and depression in animal models and limited clinical observations. Trp influences 5-hydroxytryptamine (5-HT) by affecting emotional states. GABA is the primary inhibitory neurotransmitter in the central nervous system and is closely associated with anxiety and depression. Fluctuations in estrogen levels during perimenopause significantly alter the composition and metabolic activity of the gut microbiota, which in turn affects Trp metabolism and GABA synthesis through increased intestinal permeability, activation of immune-inflammatory responses, and disruption of hypothalamic–pituitary–adrenal (HPA) axis function. Although traditional hormone replacement therapy and pharmacological treatments are effective, they are associated with some side effects. Preliminary evidence from in vitro and animal studies suggests that nutritional interventions targeting Trp and GABA metabolism within the gut–brain axis may offer a novel research direction, though their efficacy in perimenopausal women remains to be established. Potential nutritional strategies, including supplementation with Trp and its precursors, inhibition of the kynurenine pathway (KP), and supplementation with probiotics and prebiotics, can modulate Trp and GABA metabolism. This review focuses on Trp and GABA metabolic regulation via the gut–brain axis to explore pathogenesis of perimenopausal anxiety and depression and summarize potential nutritional intervention targets, thereby providing a scientific basis for emotional management in perimenopausal women. Full article

Background: Endometriosis and lipedema are chronic female-predominant disorders characterized by persistent pain that is frequently disproportionate to anatomical lesion burden. Although traditionally interpreted within distinct lesion-centered frameworks, both conditions exhibit striking clinical and epidemiological parallels, including hormonally modulated symptom dynamics, overlap with central pain syndromes, weak correlation between structural disease severity and pain intensity, and symptom clustering during reproductive transitions such as puberty, pregnancy, and menopause. Methods: This study aims to synthesize clinical, molecular, neuroimmune, and endocrine evidence on the interrelationship between endometriosis and lipedema, and to propose a hypothesis-generating neuroimmune framework linking both conditions. This integrative narrative review conducted a non-systematic literature search in PubMed/MEDLINE, Scopus, and Web of Science, focusing on mechanisms related to chronic pain, mast cell biology, TRPV1 signaling, CGRP-mediated neurogenic inflammation, intracrine steroidogenesis, and peripheral and central sensitization. Results: The review identifies convergent biological characteristics between the two diseases, including mast cell activation, macrophage polarization, endothelial dysfunction, fibrosis, angiogenesis, intracrine estrogen metabolism, and persistent inflammatory signaling. In endometriosis, direct evidence demonstrates increased sensory innervation, nerve growth factor expression, TRPV1 sensitization, CGRP-positive fibers, and mast cell-nerve interactions. In lipedema, convergent upstream mechanisms, including mast cell infiltration, elevated histamine levels, adipose tissue inflammation, and local estrogen activation, support the plausibility of a functionally analogous neuroimmune organization, despite incomplete direct neural characterization. In this context, the mast cell-TRPV1-CGRP axis is proposed as a biologically plausible framework, directly supported in endometriosis and currently hypothetical in lipedema, connecting peripheral sensitization, neurogenic inflammation, hormonal chronodependence, and central nociceptive amplification. The model further conceptualizes pain crises as transient events of instability within a sensitized neuroimmune network and proposes mechanistic phenotypes that integrate gastrointestinal, inflammatory, central, and hormonal triggers. Conclusion: Endometriosis and lipedema may represent topographically distinct manifestations of a shared neuroimmune process operating within hormone-sensitive tissues. Although the evidentiary basis remains asymmetric, with stronger mechanistic support in endometriosis than in lipedema, this framework provides a biologically plausible and experimentally testable model integrating endocrine, immune, neural, and vascular contributors to chronic pain amplification. This perspective supports coordinated translational investigation across reproductive biology, endocrinology, and pain medicine and may contribute to future mechanism-based stratification and therapeutic development. This work is hypothesis-generating and is not intended to establish causality or to provide clinical recommendations; all proposed mechanistic and therapeutic inferences require prospective experimental validation. Full article

Background/Objectives: Estrogen deficiency is associated with metabolic disturbances and impaired glucose homeostasis. Morin, a natural flavonol, has shown promising hypoglycemic and antioxidant properties, but its effects under hypoestrogenic diabetic conditions remain poorly understood. The aim of this study was to evaluate the effects of morin on body weight, fasting blood glucose, glucose tolerance, and selected serum biochemical markers in an experimental model of diabetes under estrogen-deficient conditions (ovariectomized diabetic female mice). Methods: Female CD1 mice underwent sham surgery or ovariectomy (OVX), and each surgical condition was further divided into non-diabetic and diabetic subgroups treated with vehicle, glibenclamide (10 mg/kg), or morin (30 mg/kg). Body weight and fasting blood glucose were monitored over a 15-day treatment period. Oral glucose tolerance was assessed on day 15, and serum biochemical markers, including glucose, cholesterol, triglycerides, uric acid, blood urea nitrogen, creatinine, ALT, and AST, were measured thereafter. Results: Ovariectomy aggravated diabetes-associated hyperglycemia, impaired glucose tolerance, and triglyceride elevation. Morin treatment reduced fasting blood glucose and improved glucose tolerance in diabetic mice, including ovariectomized animals. Morin also attenuated the increase in serum triglycerides and blood urea nitrogen in ovariectomized diabetic mice, although it did not significantly improve cholesterol, uric acid, creatinine, ALT, or AST levels. Compared with glibenclamide, morin showed relevant glucose-lowering activity but had a more limited effect on the overall biochemical profile. Conclusions: These findings suggest that morin may partially improve glycemic control and selected metabolic alterations in experimental diabetes associated with estrogen deficiency. Further studies are required to clarify its mechanisms of action, long-term efficacy, and translational relevance. Full article

Background: High body mass index (BMI) is a causal risk factor for endometrial cancer, but the tumor molecular mechanisms affected by adiposity remain poorly understood. Here, we characterize the tumor multi-omic landscape of endometrial cancers that have developed on a background of lifelong germline genetic liability to elevated BMI. Methods: We built a polygenic score (PGS) for BMI in women using data on independent, genome-wide significant variants associated with adult BMI in 434,794 women. We performed germline (blood) genotype quality control and imputation on data from 354 endometrial cancer cases from The Cancer Genome Atlas (TCGA). We assigned each case in this TCGA cohort their genetically predicted BMI based on the BMI PGS. Multivariable generalized linear models adjusted for age, stage, microsatellite status and genetic principal components were used to test for associations between the BMI germline PGS and endometrial cancer tumor genome-wide genomic, transcriptomic, proteomic, epigenomic and immune traits in TCGA. Results: High BMI germline PGS was associated with (i) upregulated tumor gene expression in IL6-JAK-STAT3 signaling (FDR = 4.2 × 10⁻⁷) and in other immune/inflammatory pathways; (ii) increased estimated intra-tumor activated mast cell infiltration (FDR = 0.008); and (iii) increased single base substitution (SBS) mutational signature 1 (FDR = 0.03), implicating age-related mutagenesis. In contrast, BMI at diagnosis associated with elevated progesterone receptor expression and alterations in estrogen and androgen signaling. Conclusions: Thus, we integrated germline, somatic and clinical data to identify associations between genetically predicted lifelong liability to higher BMI and endometrial cancer tumor molecular features. These associations inform our understanding of how high BMI may influence the development of this cancer, shaping endometrial tumor biology differentially over the long term. Full article

Background: Breast cancer is the most common malignancy among women and a leading cause of cancer-related deaths globally. Its development involves hormonal, genetic, environmental and inflammatory factors. Among environmental contributors, cadmium (Cd²⁺), a metalloestrogen known to induce redox imbalance, as well as estrogen metabolites, may exert divergent biological effects. Methods: This study investigated the effects of 17β-estradiol (E2) and its metabolites—2-methoxyestradiol (2-MeOE2) and 4-hydroxyestradiol (4-OHE2)—administered alone or in combination with CdCl₂, on estrogen receptor–-positive MCF-7 breast cancer cells and their doxorubicin-resistant cells (MCF-7/DOX). We evaluated cytotoxicity, interaction profiles (synergism/antagonism), and redox-related enzymes associated with drug resistance, including superoxide dismutase 1 (SOD1) and glutathione S-transferase pi (GST-pi). There are no known examples of these types of interactions, especially those involving estrogen metabolites with opposing biological activities—anticancer 2-MeOE2 and procarcinogenic—4-OHE2 in combination with cadmium. Cell viability was assessed after 48 h exposure to individual and combined treatments of CdCl₂. Interaction types (synergism/antagonism) were determined via the combination index method. Antioxidative enzymes were evaluated by quantitative and immunocytochemical analysis of SOD1, GST and GST-pi expression. Results: All tested compounds reduced cell viability in a concentration-dependent manner, with CdCl₂ showing the highest cytotoxicity. MCF-7 cell lines were generally more sensitive to CdCl₂, E2, and 2-MeOE2, whereas MCF-7/DOX cell lines exhibited greater sensitivity to 4-OHE2. Combination studies revealed predominantly antagonistic interactions, particularly for CdCl₂ + 2-MeOE2, suggesting a protective redox-modulating effect of this metabolite. Resistant cells consistently displayed higher SOD1 activity and GST-pi expression, indicating enhanced adaptive responses to oxidative stress. Conclusions: Our study underscores the importance of concentration-dependent interactions between environmental Cd²⁺ and pathways regulated by 17β-estradiol and its metabolites, particularly in the context of cytotoxicity and redox imbalance relevant to breast cancer progression and therapy resistance. Full article

Purpose: Obesity is a chronic multifactorial disease whose increasing prevalence cannot be fully explained by excessive caloric intake and sedentary behaviour alone. This review aimed to synthesize current evidence on the role of endocrine-disrupting chemicals (EDCs), particularly obesogenic EDCs, as potential environmental contributors to obesity-related phenotypes, with emphasis on their main classes, etiopathogenetic mechanisms and clinical implications. Methods: A structured literature analysis was conducted using PubMed, Web of Science and additional relevant scientific reports and governmental publications. Eligible sources included original research articles, systematic reviews, meta-analyses and authoritative reports addressing endocrine disruption, obesogens, obesity, metabolic dysfunction and related molecular mechanisms. Results: The review identified several major classes of obesogenic EDCs, including organotins, bisphenols, phthalates and persistent organic pollutants. These compounds have been linked to obesity-related phenotypes through overlapping mechanisms, including disruption of adipogenesis via estrogen receptor-dependent and independent pathways, PPARγ/RXR activation, altered adipokine signalling, neuroendocrine dysregulation across developmental stages, oxidative stress and pro-inflammatory activation, genetic and epigenetic alterations, gut microbiota-mediated effects and impaired thermoregulation through brown and beige adipose tissue dysfunction. EDC-associated obesity may contribute to metabolic, endocrine, cardiovascular, hepatic and reproductive complications. Conclusion: Obesogenic EDCs should be regarded as environmental contributors to obesity that act through interconnected molecular, cellular and systemic pathways. Their biological effects support the need for further mechanistic and epidemiological research, preventive strategies, public education and regulatory measures aimed at reducing exposure. Full article

Background: Caffeine is one of the most widely consumed bioactive compounds worldwide. The available data regarding its effects on bone metabolism and skeletal health remain inconsistent. The aim of this study was to review experimental studies on the effects of caffeine on the skeletal system. Methods: A literature search was conducted using PubMed to identify original experimental studies investigating the effects of caffeine on the skeletal system published up to December 2025. The reviewed studies included in vivo studies on different animal models and in vitro studies on bone-related cells. Due to data heterogeneity, a narrative analysis was performed. Results: Fifty-three studies on caffeine effects were included in the review. The findings indicate that the effects of caffeine are dose-dependent and bidirectional. Low-to-moderate doses in vivo generally exerted neutral or sometimes beneficial effects on the skeletal system, whereas higher doses were associated with impaired bone development, reduced mineralization, and increased bone loss. In estrogen-deficient animals, moderate doses showed potential protective effects, while high doses exacerbated bone loss. In vitro studies demonstrated concentration-dependent effects, with high concentrations often reducing cell viability and osteogenic activity. Conclusions: The effects of caffeine on the skeletal system are complex and context-dependent. While high exposure may adversely affect bone, low-to-moderate intake appears to be safe and may exert beneficial effects under specific conditions. Full article

Improvement in the in vitro maturation (IVM) of oocyte quality is a gateway to enhancing the efficiency of in vitro embryo production. The anti-Müllerian hormone (AMH) is a crucial hormone secreted by granulosa cells that effectively suppresses primordial follicle recruitment and regulates follicular growth and development. This study was designed to investigate the role of AMH on the IVM of sheep oocytes. In this current study, oocytes in vitro were cultured in media supplemented with AMH. We comprehensively analyzed the impact of AMH on various developmental parameters of sheep oocytes, such as cellular activity, cortical granules (CGs) migration, cytoskeleton and mitochondrial function of oocytes. Furthermore, Smart-seq2 single-cell RNA sequencing (scRNA-seq) was employed to elucidate the oocytes’ development. The results showed that treatment with 100 ng/mL improved the maturation rate of the oocytes, the normal distribution rate of cortical granules and mitochondrial function, while reducing the rate of spindle abnormalities in oocytes. A total of 741 differentially expressed genes (DEGs) were observed between the FSH_12 h and AMH_12 h groups, and 746 DEGs were observed between the FSH_24 h and A+F groups. KEGG pathway analysis revealed that the FSH_12 h and AMH_12 h groups significant enrichment in DEGs were associated with p53, MAPK, PI3K-Akt and TGF-beta signaling pathways, and the FSH_12 h and AMH_24 h groups significant enrichment in DEGs were associated with cAMP, AMPK, Hedgehog and estrogen signaling pathways. These findings suggest that AMH may regulates oocytes IVM via several candidate signaling pathways. Our results provide preliminary clues for exploring the regulatory mechanism of sheep oocyte maturation and optimizing relevant culture systems. Full article

Endometriosis is increasingly recognized as a chronic systemic disorder extending beyond the classical estrogen-dependent paradigm, integrating metabolic, immune, fibrotic, and nociceptive pathways that sustain lesion persistence and refractory pelvic pain. We propose a mechanistic, translational hypothesis in which tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, may modulate four interconnected pathological axes of refractory endometriosis—Warburg-type metabolic reprogramming with lactate accumulation, peritoneal immune dysfunction, NF-κB/NLRP3/TGF-β1-driven inflammatory–fibrotic remodeling, and persistent nociceptive sensitization—through three convergent molecular nodes: AMPK-associated signaling, GLP-1 receptor activity in peritoneal macrophages and spinal microglia, and the NF-κB/NLRP3/TGF-β1 axis. Particular emphasis is placed on the concept of “peritoneal incretin deficiency”, characterized by reduced peritoneal GLP-1 concentrations and increased expression of incretin-degrading proteases. This concept currently rests on a single, non-replicated case–control study, and the broader mechanistic chain is supported largely by indirect evidence extrapolated from adjacent inflammatory, metabolic, and neuroimmune disease models rather than by endometriosis-specific data. Direct experimental or clinical validation in endometriosis-specific models is currently absent. Accordingly, this article represents a hypothesis-generating framework rather than evidence of established efficacy, or a clinical treatment recommendation, intended to guide future mechanistic and prospective clinical investigation of incretin-based modulation as a potential adjunctive strategy in refractory endometriosis. Full article

Endometriosis is a long-term gynecological condition marked by the growth of endometrial-like tissue outside the uterus, which undergoes proliferation, bleeding, and regeneration. This disease is associated with disrupted steroid hormone signaling, notably progesterone (P4) resistance and estradiol (E2) dominance. P4 resistance has been associated with impaired activation of the progesterone receptor (PR) and reduced transcription of P4 target genes, while elevated E2 levels induce estrogen receptor (ER)-mediated signaling, enhancing estrogen-dependent lesion growth. This hormonal imbalance contributes to a pro-inflammatory microenvironment, chronic pelvic pain, infertility, and enhanced neuroangiogenesis. Emerging evidence indicates that the coordinated regulation of neurotrophins and sex hormones promotes nerve fibers and blood vessel growth and invasion within endometriotic lesions. P4 and E2 have been shown to modulate the expression of key neurotrophins, including nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). This review presents current evidence on the interplay between neurotrophins and ovarian steroids in endometriosis, with a specific focus on their contribution to neuroangiogenesis and pain pathophysiology. The review includes articles in English containing the Medical Subject Headings (MeSH) terms: “endometriosis”, “neurotrophins”, “nerve growth factor”, “brain-derived neurotrophic factor”, “neuroangiogenesis”, “progesterone”, and “estradiol”, found in the PubMed database published between 2000 and 24 May 2026. This review included a range of original research articles, systematic reviews, meta-analyses, prospective observational studies, case–control studies, and review papers, for a total of 122 articles. Full article

Background: Selective estrogen receptor modulators (SERMs) are widely used for postmenopausal osteoporosis, yet whether treatment response attenuates with aging in routine practice remains unclear. We examined age- and site-specific responses to SERM therapy. Methods: We retrospectively analyzed postmenopausal women with primary osteoporosis treated with a SERM for 1 year (2017–2021). Participants were stratified by age (50–64, 65–74, and ≥75 years). We evaluated changes in bone mineral density (BMD) at the lumbar spine (L2–4) and femoral neck and changes in urinary NTX and serum BAP. Multivariable linear regression modeled BMD change ratios (1-year/baseline) adjusting for baseline site-specific BMD, estimated glomerular filtration rate (eGFR), and active vitamin D co-therapy (none, alfacalcidol, or eldecalcitol). The primary endpoint was the 1-year change in lumbar spine BMD; secondary endpoints included femoral neck BMD and bone turnover markers. Results: Lumbar spine BMD increased significantly across all age groups, whereas femoral neck BMD increased significantly only in women aged 50–64 years. However, BMD change ratios did not differ among age groups at either site. In adjusted models, age was not independently associated with BMD change at the lumbar spine or femoral neck. Lower baseline BMD predicted larger relative gains at both sites, and eldecalcitol co-therapy was independently associated with femoral neck BMD response. Conclusions: In real-world practice, BMD changes observed during SERM treatment were site-specific rather than clearly age-dependent. Lumbar spine BMD improved across age groups, whereas femoral neck changes were smaller and less consistent. Full article

Dietary factors, including the consumption of isoflavones-rich foods of plant origin, may contribute to the reduced incidence of prostate cancer. Isoflavones, natural phytoestrogens often found in legumes, can modulate estrogen and androgen receptor signaling. This study aimed to evaluate the biological potential of isoflavone-rich extracts obtained from twelve species from the Fabaceae family, targeting prostate cancer cell viability, proliferation, inflammatory markers, prostate-specific antigen secretion, and 5α-reductase activity. The tested extracts showed moderate cytotoxic activity against prostate cancer cell lines, apart from highly susceptible PC3 cells, and only weak toxicity to normal prostate epithelial cells. Significant antiproliferative activity was observed, especially for Cytisus scoparius, Ononis arvensis, and Genista tinctoria, while most extracts reduced prostate-specific antigen (PSA) secretion in normal prostate cells. Furthermore, the extracts showed anti-inflammatory properties by reducing the pro-inflammatory cytokine interleukin 6 (IL-6) and improving cytokine balance indices. Multivariate analyses revealed correlations between total isoflavone content and antiproliferative activity. Full article

Introduction: The discharge of treated wastewater into coastal and marine environments represents a continuous source of pollutants, including pharmaceuticals and plastic additives with endocrine-disrupting (ED) potential. These compounds are of increasing concern for the European Union due to their capacity to interfere with hormonal systems and their inclusion in current environmental monitoring priorities. ED compounds may induce sublethal effects in aquatic organisms, particularly in vertebrates, where endocrine pathways are highly conserved. In this context, the use of Cyprinodon variegatus, a euryhaline fish species, provides a suitable model to assess potential risks in marine ecosystems. Despite advances in wastewater treatment technologies, the persistence of biologically active substances in treated effluents remains a concern. Objective: This study aims to evaluate whether treated effluent water still contains compounds with endocrine-disrupting activity and to assess their potential effects on marine organisms. Methodology: Larvae of C. variegatus from a laboratory stock maintained at ECIMAT (University of Vigo), one of the few available stocks of this species in Europe, were exposed for 48 h to environmentally relevant dilutions (1:10, 1:30, and 1:100) of wastewater treatment plant effluent collected after UV disinfection as the final treatment step. Pools of 10 larvae were used for each condition. Sublethal effects were assessed through gene expression analysis using quantitative PCR (qPCR), targeting biomarkers involved in endocrine regulation. Two housekeeping genes (tbp and hprt) were used for normalization. Estrogenic responses were evaluated through vtgab and zp2, while androgenic responses were assessed using 17hsd and 11hsd. Results: Preliminary results indicate significant alterations in estrogen-related gene expression, particularly in vitellogenin (vtgab) and zona pellucida (zp2), highlighting the activation of estrogenic pathways and supporting the presence of endocrine-disrupting activity in treated effluent water. Conclusions: This study highlights the relevance of assessing endocrine disrupting activity in treated effluents and supports the use of molecular biomarkers as sensitive tools for evaluating their potential impact on marine ecosystems, contributing to the improvement of wastewater monitoring and management strategies. Full article

The gut microbiota and its metabolites, as components of the gut–bone axis, play a pivotal role in regulating skeletal homeostasis through the bidirectional communication network. In this systematic review, evidence was collected from mainstream databases following standardized inclusion/exclusion criteria for screening, to comprehensively retrieve and screen eligible studies from multiple mainstream databases according to standardized inclusion and exclusion criteria, and systematically summarize current research progress on plant-derived bioactive compounds targeting the gut–bone axis for skeletal health regulation. This review systematically explores the underlying mechanisms of the gut–bone axis and critically evaluates the regulatory effects and therapeutic potential of plant-derived bioactive compounds. Particular attention is given to targeted interventions involving prebiotics, probiotics, synbiotics, and plant-rich diets or functional foods. Among these interventions, synbiotics represent the most successful strategy and show the most prominent therapeutic possibilities in bone-related disorders. Different from single prebiotics (only nourish endogenous intestinal microbes), individual probiotics (easy to be degraded in gastrointestinal tract with poor colonization) and ordinary plant-rich diets (unfixed effective dosage and weak targeting property), synbiotics combine prebiotic carriers and viable probiotic strains to produce complementary advantages, which is the core reason for its outstanding therapeutic prospect against bone diseases. Synbiotics exert synergistic effects on gut microecology, mineral absorption, and immune regulation, leading to more robust and consistent improvements in bone health than single prebiotics, probiotics, or general plant-rich diets. They have been verified in preclinical and clinical studies to ameliorate osteoporosis and related skeletal diseases via the gut–bone axis. These strategies offer novel insights into the prevention and treatment of bone metabolic disorders, such as osteoporosis, by targeting the gut–bone axis with phytochemicals. Key outcomes of this review include that synbiotics, soy isoflavones, naringin, curcumin, and resveratrol effectively improve bone mineral density, restore gut microbiota balance, and inhibit pathological bone resorption via the gut–bone axis. Collectively, the above bioactive substances realize bone protection mainly by reshaping gut flora, elevating mineral uptake and suppressing excessive osteoclast activity. Representative cases include soy isoflavones mitigating estrogen-deficient bone loss in OVX models, naringin improving the trabecular microarchitecture, and probiotic BL-11 promoting longitudinal bone growth in children. Future directions will focus on clarifying dose–response relationships, developing standardized synbiotic formulations, constructing microbiome-guided precision diets, and conducting large-sample randomized controlled trials to translate plant-derived compounds into clinical therapies. Full article