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The ovary, as the primary organ responsible for reproduction and new life, plays a central role in female development, maturation, and health. Neoplasms arising from the ovary and its associated tissues exhibit substantial heterogeneity in their histopathological and molecular profiles, many of which remain poorly understood. This review aims to summarize recent advances in the understanding of genetic alterations underlying ovarian neoplasms and to explore therapeutic strategies informed by molecular biomarkers and tumor microenvironmental factors. A comprehensive literature search was performed, focusing on genomic alterations, biomarker-guided therapies, and tumor microenvironmental modulation in ovarian cancers. Emphasis was placed on studies addressing lipid mediator pathways and their roles in immune regulation and therapeutic response. Based on diagnostic classifications, recurrent alterations in TP53, MYC, PIK3CA, and KRAS are consistently observed across epithelial and germ cell ovarian tumors, whereas non-epithelial subtypes such as sex cord–stromal tumors (SCSTs) and small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT), are predominantly associated with ARID1A and SMARCA4 mutations, respectively. These findings highlight distinct pathogenic mechanisms linked to specific genetic alterations and reveal potential therapeutic vulnerabilities. Moreover, lipid metabolism has been closely implicated in immune surveillance through STING signaling cascades within innate immune cells, suggesting that lipid mediators and their associated genes may represent promising therapeutic targets in ovarian cancers (OCs). Targeting lipid mediators could be particularly effective in relapsed OCs, as modulating innate immune cells within the tumor microenvironment (TME) may enhance immune surveillance and improve antitumor responses. Integrating genetic and microenvironmental insights offers a promising direction for developing more effective and personalized therapeutic strategies in OC. Full article

Colorectal cancer (CRC) is one of the leading causes of cancer-related morbidity and mortality, with inflammation playing a pivotal role in its pathogenesis. Chronic inflammation in the intestine significantly increases the risk of CRC development. Main compounds participating in the inflammatory process are prostaglandins; bioactive lipids derived from arachidonic acid metabolism via the cyclooxygenase (COX) pathway. While it is well known that prostaglandin E₂ (PGE₂) promotes CRC tumorigenesis, other prostaglandins, such as PGD₂, PGF_2α, and prostacyclin (PGI₂), remain relatively underexplored. These prostaglandins may exert distinct or opposing effects on CRC development, but the current understanding of their functions is limited. Additionally, the impact of prostaglandins on immune regulation and the tumor microenvironment, is far from being fully understood. Addressing these knowledge gaps is crucial for identifying novel therapeutic targets and optimizing chemoprevention strategies. Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce the risk of CRC, largely by inhibiting prostaglandin producing enzymes. However, their use is limited due to their gastrointestinal and cardiovascular side effects. Therefore, understanding the intricate role of inflammation and prostaglandin signaling in CRC is critical to develop safer and more effective chemopreventive approaches. This review summarizes the current knowledge of prostaglandins, linking inflammation and CRC. It further addresses the potential of targeting prostaglandin pathways for chemoprevention. Furthermore, we discuss emerging pharmacological targets that modulate prostaglandin production, signaling or degradation, offering promise for preventing CRC development. Full article

Invasive species are a recurring global problem, and the water hyacinth (Pontederia crassipes) is a well-known example. Various strategies have been explored to manage its spread, including its use as an agricultural amendment. However, when P. crassipes biomass is incorporated into soil and undergoes degradation, it may increase soil conductivity and promote metal leaching, potentially affecting soil biota, particularly microbiota. Saprophytic fungi play a key role in the decomposition and renewal of organic matter, and their resilience to stressors is crucial for maintaining soil function. Thus, the aim of this study was to evaluate the effects of P. crassipes biomass extracts on the saprophytic fungus Trametes versicolor by evaluating fungal growth and metabolic changes [including sugar content, phosphatase enzymatic activity, and reactive oxygen species (ROS) production]. The fungus was exposed for 8 days to a dilution series of extracts (100%—undiluted, to 3.13%) prepared from P. crassipes biomass collected at five locations in Portuguese wetlands. Two sites were in the south, within a Mediterranean climate (Sorraia and Estação Experimental António Teixeira), and three were in the north, within an Atlantic climate (São João de Loure, Pateira de Fermentelos, and Vila Valente), representing both agricultural-runoff–impacted areas and recreational zones. Extracts were used to simulate a worst-case scenario. All extracts have shown high conductivity (≥15.4 mS/cm), and several elements have shown a high soluble fraction (e.g., K, P, As, or Ba), indicating substantial leaching from the biomass to the extracts. Despite this, T. versicolor growth rates were generally not inhibited, except for exposure to the São João de Loure extract, where an EC₅₀ of 45.3% (extract dilution) was determined and a significant sugar content decrease was observed at extract concentrations ≥25%. Possibly due to the high phosphorous leachability, both acid and alkaline phosphatase activities increased significantly at the highest percentages tested (50% and 100%). Furthermore, ROS levels increased with increasing extract concentrations, yet marginal changes were observed in growth rates, suggesting that T. versicolor may efficiently regulate its intracellular redox balance under stress conditions. Overall, these findings indicate that the degradation of P. crassipes biomass in soils, while altering chemical properties and releasing soluble elements, may not impair and could even boost microbiota, namely saprophytic fungi. This resilience highlights the potential ecological benefit of saprophytic fungi in accelerating the decomposition of invasive plant residues and contribution to soil nutrient cycling and ecosystem recovery. Full article

Background: Liver transplantation is a life-saving procedure for patients with end-stage liver disease, yet the immunological consequences of surgical trauma in these patients are not fully understood. The liver plays a central role in immune regulation, and its dysfunction in HBV-related chronic liver disease may alter the systemic stress response to surgery. Aim: This study aims to evaluate the stress response to surgical trauma of patients undergoing living donor liver transplantation (LDLT) for HBV-related chronic liver disease in comparison to living liver donors (LLDs). Methods: This prospective study included 20 LDLT recipients with HBV infection and 20 LLDs who underwent living donor hepatectomy between August 2020 and February 2021. Specific biochemical markers (IL-1, IL-4, IL-6, IL-22, IFN-γ, TNF-α, TGF-β, GM-CSF, GLDH, and GalactB) were measured at designated intervals: preoperative day 0 (Preop), immediately after incision (Incision), post-hepatectomy (Hepatectomy), postoperative day 0 (POD0), POD1, and POD3 using enzyme-linked immunosorbent assay (ELISA). Routine hematological and biochemical parameters (WBC, HGB, PLT, RDW, MPV, PDW, AST, ALT, ALP, GGT, albumin, total bilirubin, plateletcrit, phosphorus, fibrinogen, and INR) were measured regularly at five predetermined times: Preop, POD0, POD1, POD2, and POD3. Results: Prior to LDLT, LDLT recipients had significantly lower levels of pro-inflammatory cytokines (IL-1, IL-6, TNF-α, IFN-γ) compared to LLDs (p < 0.05). However, following liver implantation, these cytokine levels increased significantly at POD0, POD1, and POD3 (p < 0.001). Specifically, IL-1 levels elevated from 0 in the preop period to 21.5 (97.5) in POD3, and IL-6 elevated from 0 in the preop period to 28.3 at POD3 (p = 0.056). Similarly, TNF-α and IFN-γ levels exhibited significant upward trends (p < 0.05). In contrast, cytokine levels in LLDs remained stable throughout the perioperative period, revealing no statistically significant variations (p > 0.05). Routine hematological and biochemical parameters demonstrated significant postoperative fluctuations in LDLT recipients, reflecting the metabolic and immune restoration process. Conclusions: These findings indicate that patients with HBV-related chronic liver disease exhibit a diminished stress response to trauma due to underlying immune dysregulation caused by chronic hepatic dysfunction. However, after LDLT, the stress response gradually normalizes, suggesting that liver transplantation not only restores hepatic function but also reestablishes immune homeostasis, potentially reducing infection risks and improving postoperative recovery. These findings emphasize the crucial role of the liver in regulating the body’s stress response to trauma and highlight the immunological benefits of LDLT in restoring immune homeostasis. Full article

Background: Bronchoscopic thermal ablation has emerged as a minimally invasive therapeutic option for managing pulmonary nodules in patients unsuitable for surgery or radiotherapy. Robotic-assisted bronchoscopy (RAB) offers enhanced stability and precise navigation, potentially improving the safety and accuracy of bronchoscopic ablation. However, clinical data on RAB-guided microwave ablation (MWA) remains limited. Therefore, further evidence is needed to evaluate its feasibility, safety, and early therapeutic performance. Methods: We conducted a single-center retrospective feasibility study of shape-sensing RAB-guided MWA (ssRAB-MWA) for pulmonary nodules between October 2024 and September 2025. Eligible lesions (≤3.0 cm) included both primary lung cancers and metastatic nodules. All procedures were performed under general anesthesia using the ssRAB system integrated with cone-beam CT for intra-procedural confirmation. Technical success, safety outcomes, and short-term efficacy were assessed. Results: Nine patients (with 11 lesions: 3 primary, 8 metastatic) underwent ssRAB-MWA with 100% technical success. The median ablation time per nodule was 10 min (range, 1–26). One patient developed post-ablation pneumonia requiring hospitalization; no pneumothorax, major bleeding, or airway injury occurred. All lesions exhibited a transient increase in size immediately following MWA, followed by gradual reduction or stabilization over time. PET-CT evaluation demonstrated metabolic remission in primary lesions, with one patient achieving pathologic complete response after surgery. Conclusions: ssRAB-MWA appears to be a feasible and safe navigation-guided technique for small pulmonary lesions, offering encouraging early local control in both primary and metastatic lung cancers. This platform may expand the therapeutic spectrum of interventional pulmonology, bridging diagnosis and local therapy. Larger multicenter studies are warranted to validate long-term outcomes. Full article

Background/Objectives: Insulin resistance (IR) is a key feature of metabolic disorders and a major precursor of type 2 diabetes and cardiovascular disease. The triglyceride–glucose (TyG) index and TyG-based indices—including TyG–body mass index (TyG–BMI), TyG–waist circumference (TyG–WC), and TyG–waist-to-height ratio (TyG–WHtR), have been proposed as simple, cost-effective surrogate markers of IR. However, population-based data from Türkiye are limited. To evaluate the association between TyG-based indices, triglycerides/high-density lipoprotein cholesterol (TG/HDL-C) ratio, and IR defined by Homeostasis Model Assessment–IR (HOMA-IR) in adults from the TEKHAP study—a province-wide, population-based survey in Tokat, Türkiye. Methods: A total of 1854 adults (≥20 years) were included in the analysis. Physiologically implausible HOMA-IR outliers were identified using statistical criteria and excluded. IR was defined as HOMA-IR ≥ 2.46, previously validated in this population. TyG and its derivatives were calculated from fasting triglyceride, glucose, and anthropometric measurements. Group comparisons between IR and non-IR individuals, correlation analyses, receiver operating characteristic (ROC) curves, and multivariate logistic regression models were conducted to evaluate the diagnostic and independent associations of these surrogate markers with IR. Results: IR prevalence was 27.2%. Participants with IR had significantly higher triglycerides, fasting glucose, insulin, C-peptide, BMI, and waist circumference and lower HDL-C levels (all p < 0.001). All TyG-based indices were higher in the IR group and showed weak-to-moderate positive correlations with HOMA-IR. TyG–BMI showed the highest diagnostic accuracy in ROC curve analyses (AUC = 0.765); however, this association could not be interpreted as an independent predictive effect in adjusted models because of collinearity with BMI. In multivariable logistic regression, the TyG index demonstrated the strongest independent association with IR (OR = 4.14; 95% CI: 3.32–5.18; p < 0.001), while TyG–WC and the TG/HDL-C ratio also retained significant independent predictive value. Conclusions: The TyG index showed the strongest independent association with IR, while the TG/HDL-C ratio and TyG–WC also demonstrated significant independent predictive value. TyG-based indices may represent practical, low-cost surrogate markers for early metabolic risk stratification in community settings; however, their role in formal screening strategies requires external validation and calibration in independent populations. Full article

Background: Traumatic brain injury (TBI) initiates a complex sequence of inflammatory, glial, and metabolic events that evolve dynamically and contribute substantially to secondary brain injury. This study aimed to characterize the temporal serum dynamics of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), glial fibrillary acidic protein (GFAP), and insulin following severe diffuse TBI in a rat model, with the goal of delineating the coordinated progression of inflammatory, astroglial, and metabolic responses. Methods: Severe diffuse TBI was induced in adult male Sprague–Dawley rats using the Marmarou weight-drop model. Animals were randomized into five groups (sham, 1 h, 6 h, 24 h, 72 h; n = 10 per group). Serum TNF-α, IL-6, GFAP, and insulin levels were quantified using ELISA assays. Group differences were assessed using one-way ANOVA with Tukey’s post hoc test or Kruskal–Wallis analysis with Dunn’s correction where appropriate. Results were expressed as mean ± SD. Results: TNF-α demonstrated a biphasic pattern, declining at 6 h before peaking significantly at 24 h (p < 0.05) and subsequently decreasing at 72 h. IL-6 exhibited mild suppression at 6 h followed by a significant secondary elevation at 24 h (p < 0.05), with persistently elevated levels at 72 h. GFAP showed delayed kinetics, decreasing at 6 h but rising progressively to a peak at 24 h, consistent with subacute astroglial activation. Insulin levels declined at 6 h and increased significantly at 24 h and 72 h (p < 0.05), indicating evolving metabolic adaptation. Overall, cytokine activity preceded glial and endocrine changes, revealing a sequential inflammatory–glial–metabolic cascade. Conclusions: This study delineates the temporal serum profiles of TNF-α, IL-6, GFAP, and insulin after severe diffuse TBI, revealing a coordinated transition from acute inflammation to astroglial activation and metabolic adaptation. These results support the utility of multimodal biomarker panels for phase-specific characterization of secondary injury and identify GFAP and IL-6 as promising subacute markers with translational relevance. The findings should be interpreted as descriptive temporal patterns rather than mechanistic evidence, pending confirmation with complementary molecular analyses. Full article

Silymarin, a polyphenolic flavonolignan complex extracted from Silybum marianum (milk thistle), has long been recognized for its hepatoprotective, antioxidant, anti-inflammatory, and anticancer properties. Among its constituents, silybin is the most pharmacologically active and has been extensively studied in both preclinical and clinical settings. However, the clinical application of silymarin-based therapies remains limited by poor aqueous solubility, low oral bioavailability, rapid metabolism, and physicochemical instability. This review systematically outlines the pharmacokinetic challenges of silymarin and highlights recent advancements in formulation strategies designed to overcome these barriers. Key innovations include nanotechnology-enabled delivery systems, lipid-based carriers, water-soluble derivatives, bioavailability enhancers, parenteral and transdermal formulations, as well as controlled and synchronous release technologies. These approaches significantly improve tissue targeting, intracellular uptake, and pharmacological efficacy. Additionally, this review evaluates currently marketed silymarin formulations and recent clinical/preclinical evidence, revealing a persistent gap between laboratory advances and commercially available products. By synthesizing the mechanistic, regulatory, and manufacturability barriers that hinder translation, we delineate the key challenges that must be addressed to enable clinically deployable next-generation silymarin products. Collectively, these insights illustrate a paradigm shift in the modernization of phytomedicine, positioning silymarin as a model compound for the transformation of traditional herbal remedies into precision therapeutics through interdisciplinary drug delivery innovations. Full article

Background: Osteoblast senescence constitutes one of the major mechanisms in bone degeneration and is under tight regulation by metabolism and oxidative stress. While hypoxia has recently emerged as an important microenvironmental factor influencing the function of bone cells, its role in osteoblast senescence and metabolic regulation has yet to be defined. Methods: The present work entails hypoxia-modulated osteoblast senescence at one level, transcriptomic and metabolomic sequencing, and two levels, in vitro MC3T3-E1 and in vivo AAV-shAtp6v1a mouse models. In transcriptome profiling, hypoxia-responsive genes were identified, whereas non-targeted metabolomics was used to uncover metabolic alterations induced by ATP6V1A knockdown. Oxidative stress and mitochondrial function were assessed by qRT-PCR, Western blotting, SA-β-Gal staining, ROS detection, JC-1 mitochondrial potential, and immunofluorescence. Micro-CT, H&E, Masson, and immunohistochemistry studies were performed to investigate bone structure and protein expression in vivo. Results: Hypoxia markedly mitigated osteoblast senescence, decreasing p53 and p21 expressions and the number of SA-β-Gal-positive cells. It reduced intracellular ROS levels and increased HK2 and LDH expression, decreased ATP, and increased lactate, hinting at a shift toward glycolysis. Transcriptome analysis identified ATP6V1A as one of the major hypoxia-downregulated genes. Knockdown of ATP6V1A reduced ROS levels, inhibited p21 expression, improved mitochondrial function. Metabolomics disclosed remapping pathways in glycolysis, lipid, and amino acid metabolism. Conclusion: This study identifies a “Hypoxia–ATP6V1A–Oxidative Stress–Metabolic Remodeling–Anti-Senescence” axis, demonstrating that hypoxia delays osteoblast senescence by downregulating ATP6V1A, suppressing oxidative stress, and reprogramming metabolism, providing new insights and potential therapeutic targets for bone degenerative diseases. Full article

Background: Insect metamorphosis is one of the most fascinating developmental processes in the natural world. Complete metamorphosis requires the breakdown and reorganisation of larval tissues and the coordinated construction and development of adult structures. The molecular events that achieve this transformation are, however, incompletely understood, and there is a particular shortage of data describing changes in protein abundance that occur during the process. Methods: Here, using a label-free quantitative bottom-up approach, we perform a novel whole-organism proteomic analysis of consecutive developmental stages of male Bicyclus anynana butterflies as they develop from caterpillars into adults via pupation. Results: Our analysis generated a dynamic reference dataset representing 2749 detected proteins. Statistical analysis identified 90 proteins changing significantly in abundance during metamorphosis, and functional interpretation highlights cuticle formation, apoptosis and autophagy during the pupal stages, and the up-regulation of respiration and energy metabolism upon completion of the fully formed adult. A preliminary search for potential peptide phosphorylation modifications identified 15 candidates, including three proteins with roles in muscle function. Conclusions: The study provides a basis for future protein-level analysis of butterfly metamorphosis and suggests the importance of dissecting the post-translational regulation associated with this fascinating developmental transformation. Full article

Conventional ultrasound (US) has long been central to hepatocellular carcinoma (HCC) surveillance in cirrhotic patients, due to its low cost, wide availability, non-invasiveness, and adequate sensitivity for detecting small nodules. However, its specificity in distinguishing HCC from other lesions is limited. Contrast-enhanced ultrasound (CEUS) has significantly improved the characterization of nodules first identified on conventional US. Yet, when CEUS is performed using sulfur hexafluoride (SonoVue)—the only contrast agent available in Western countries—assessment remains restricted to a single nodule per examination, and enhanced CT or MRI is still required for full characterization and staging. In clinical settings, such as hepatology, internal medicine, infectious diseases, and surgery, CEUS offers the advantage of immediate availability, enabling rapid characterization of suspicious nodules in cirrhotic livers and facilitating timely therapeutic decisions. Although the introduction of direct-acting antivirals (DAAs) has substantially reduced HCV-related HCC, HCC incidence is increasingly driven by metabolic dysfunction-associated steatohepatitis (MASH). Evidence on surveillance strategies for MASH patients remains limited, and current EASL guidelines recommend monitoring only patients with >F2 fibrosis. Additionally, the effectiveness of US in obese or diabetic/obese populations is under ongoing investigation; abbreviated non-contrast MRI has been proposed as an alternative surveillance tool, but its adoption would entail significant economic implications for healthcare systems. HCC arising from MASH—sometimes even without cirrhosis—exhibits different sonographic and pathological features. Instead of small, hypoechoic nodules, typically seen in HCV-related cirrhosis, clinicians increasingly encounter larger or multiple lesions, often accompanied by macrovascular invasion, limiting access to curative treatments. Furthermore, typical CEUS LI-RADS patterns are less frequently observed. This review summarizes the evolving US findings in the era of MASH-related HCC and underscores the continued importance of US as the primary imaging tool in routine clinical practice. Full article

Seed germination of celery (Apium graveolens L.) is notoriously slow and asynchronous, which severely constrains uniform seedling establishment and crop yield. Seed priming is an effective technique to improve germination, and acidic electrolyzed water, characterized by low pH and high oxidation–reduction potential, has emerged as a novel priming agent. However, the effect of acid electrolyzed water priming (EWP) on celery seed germination and the underlying mechanisms still need to be explored. The present study aimed to investigate the physiological and molecular mechanisms by which EWP promotes celery seed germination, with a focus on the roles of the phenylpropane metabolism and the antioxidant enzyme system. Celery seeds were treated with EWP, hydro-priming (HYD), and untreated (CK). It was found that the EWP treatment significantly enhanced germination characteristics compared to both CK and HYD. Transcriptome analysis revealed that EWP triggered more extensive transcriptional reprogramming than HYD, and EWP specifically enriched “Phenylpropanoid biosynthesis” and “Flavonoid biosynthesis” pathways, downregulating upstream genes (PAL, 4CL) while upregulating downstream genes (CCR, CHI, F3H) in the phenylpropane pathway. Physiologically, EWP significantly increased CHI activity and the contents of total phenols and flavonoids at all sampling time points, and enhanced the activities of SOD, POD, CAT, and APX. Consequently, the DPPH and FRAP free radical scavenging capacities were significantly strengthened in EWP-treated seeds. In conclusion, it is believed that EWP activation promotes celery seed germination by coordinating the phenylpropane pathway and antioxidant enzyme system, ensuring effective radical scavenging activities and cell protection. These findings provide a theoretical basis for the application of EWP and highlight the potential as a novel priming technology for celery and other horticultural crops. Full article

Nonylphenol (NP) bioremediation is constrained by the scarcity of efficient and non-pathogenic degrading strains. To clarify the role of acetyl-CoA C-acetyltransferase (AtoB) in NP degradation, we generated an atoB-overexpressed strain (LY-OE) from the environmentally tolerant Bacillus cereus LY and compared its degradation rate with the wild type using HPLC. Untargeted lipidomics was conducted to characterize metabolic responses under NP stress, and key differential lipid metabolites (DELMs) were further validated by ELISA. Additionally, AtoB concentration and ATP content were quantified using commercial assay kits in Bacillus cereus. LY-OE showed a markedly higher NP degradation rate (96%) than LY (85%). Lipidomic analysis identified 34 significant DELMs (VIP > 1, p < 0.05), including elevated cardiolipin (CL) and phosphatidylglycerol (PG), and reduced phosphatidylcholine (PC) and triglycerides (TG). ELISA confirmed these changes (p < 0.01 or p < 0.001), consistent with lipidomic findings. LY-OE showed significantly higher AtoB concentration during the logarithmic growth phase and exhibited higher ATP content during NP degradation. These findings suggest that atoB overexpression enhances NP degradation by both boosting energy supply and remodeling lipid metabolism. This work identifies atoB as a key factor for NP biodegradation and provides a promising strategy for developing high-performance bioremediation strains. Full article

Postharvest storage and quality maintenance represent significant constrains for the marketability and long-distance exportation of button mushroom (Agaricus bisporus). Protective techniques such as arginine application has been demonstrated to extend the shelf life of button mushroom. However, the underlying mechanism by which arginine mitigates postharvest softening in button mushroom require further elucidation. In this study, comprehensive physiology, metabolomics and transcriptomics analyses of button mushroom following arginine treatment were conducted to investigate its potential mechanisms of action. Physiological analysis showed that arginine treatment (1.5 g L⁻¹) markedly alleviated the postharvest softening of button mushroom, resulting in a 23.8% increase in firmness, reduced malondialdehyde (MDA) content, suppressed activities of phenylalanine ammonia-lyase (PAL) and polyphenol oxidase (PPO), and maintained elevated superoxide dismutase (SOD) activity. Integrated transcriptomic and metabolomic analyses demonstrated that arginine application significantly altered lipid-related metabolites, including free fatty acids, lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE) and phosphatidylcholine (PC). Notably, arginine treatment increased the levels of unsaturated fatty acids (UFAs). Transcriptomic analysis further revealed that differentially expressed genes (DEGs) were predominantly enriched in lipid metabolism pathways following arginine treatment. Specifically, arginine application stimulated the lipid metabolism by upregulating genes associated with fatty acid desaturation (FAD), while downregulating genes related to phospholipases A2 (PLA2). These findings collectively demonstrate that arginine effectively mitigates postharvest softening of button mushroom by modulating lipid metabolism. Full article

Background/Objectives: Osteoporosis is highly prevalent and contributes substantially to morbidity and mortality, yet long-term concerns about pharmacologic therapies leave a major treatment gap. Soy isoflavones have been investigated as safer alternatives, but results across trials are inconsistent. A key unresolved issue is the equol-producer phenotype, the gut microbial ability to convert daidzein to S-equol, the most bioactive isoflavone metabolite, which may explain much of this variability. This narrative review synthesizes mechanistic, translational, and clinical evidence to clarify the potential skeletal relevance of S-equol. Methods: Literature was identified through PubMed and Scopus searches (January 2000–October 2025) for experimental, mechanistic, and clinical studies examining S-equol, estrogen receptor β (ERβ), and bone metabolism, with emphasis on equol-producing status, bone strength and bone microarchitecture. Results: S-equol acts as a high-affinity ERβ agonist with antioxidant and anti-inflammatory properties but lacks the carcinogenic or thrombotic risks linked to ERα activation. In estrogen-deficient rodent models, S-equol improves trabecular bone volume by 10–20%, increases trabecular number, and enhances biomechanical strength. These findings align with preclinical evidence demonstrating that S-equol preserves trabecular microarchitecture, enhances bone strength, and reduces bone turnover. A limited number of human trials show reductions in bone resorption by 20% at a daily dose of 10 mg S-equol. In contrast, trials of soy isoflavones in humans have produced inconsistent findings, partly because of substantial variability in equol-producer phenotype among participants and the reliance on dual-energy X-ray absorptiometry, which cannot distinguish trabecular from cortical compartments. Advanced bone imaging and microbiome-informed approaches enable the precise evaluation of S-equol’s skeletal effects on trabecular bone and cortical bone, separately. Conclusions: S-equol represents a promising model for “precision nutrition,” where microbiome, hormonal, and host factors converge with potential to prevent age-related bone fragility. Rigorous trials that integrate microbiome phenotyping and advanced imaging are needed to validate this approach, translate mechanistic promise into clinical benefit, and better define safety. Full article