Copper (Cu) supplementation for growth promotion in agriculture poses toxicological risks to animals and humans. Although Cu overload is known to trigger endoplasmic reticulum (ER) stress, the downstream cellular mechanisms driven by this stress are not fully characterized. Here, we identify the ER stress response as the primary initiator of reticulophagy (ER-phagy) in porcine liver models. Using an in vivo weaned piglet model exposed to agriculturally relevant Cu doses and an in vitro hepatocyte system, we demonstrate that Cu exposure activates UPR branches, including PERK/eIF2α phosphorylation, IRE1 and ATF6 proteins, and promotes GRP78-FAM134B association. This activation precipitated ER-phagy, evidenced by autophagosome formation, receptor upregulation, and LC3-II conversion. Pharmacological inhibition of ER stress (4-PBA) attenuated this autophagic response, whereas induction (PR-619) potentiated it. These findings suggest that the ER stress-ER-phagy axis contributes to Cu-induced hepatocellular stress, providing a mechanistic framework for reassessing Cu safety thresholds in livestock feed.

Fast-growing broilers are prone to pulmonary hypertension, which is the main cause of death in broilers with ascites syndrome (AS). The underlying mechanisms of AS and the role of metabolomics changes involved in this pathological process are still not fully understood. In this study, 180 1-day-old Arbor Acres broilers were randomly divided into the test group (injected intravenously with carboxymethyl cellulose CM-32 ion exchange suspension) and the control group (injected with the same volume of saline). A comprehensive metabolic analysis based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) on the sera of the test group and the control group was conducted to identify the metabolomics profiles. Results showed significant differences in packed cell volume (PCV), hemoglobin in blood (HGB), right ventricle wall/total ventricle (RV/TV) value, and body weight between the test group and control group. Significant variations in the levels of 29 metabolites were found between the two groups, among which 17 metabolites showed a remarkable increase and 12 metabolites significantly reduced. Metabolomics analysis showed that major alterations were related to purine metabolism, glycerol phospholipid metabolism, phenylalanine metabolism and biosynthesis of phenylalanine, tyrosine and tryptophan. The study uncovered AS pathogenesis in broilers, offering new insights for diagnostic and therapeutic targets.

Copper (Cu) exposure poses significant threats to renal health yet effective mitigation strategies remain scarce. Kaempferol (Kae) is a naturally occurring flavonoid with well-documented antioxidant and anti-apoptosis activities. Nevertheless, its protective effects in renal copper poisoning and the underlying molecular mechanisms have not been fully elucidated. This study integrated network toxicology, pharmacology, molecular docking, molecular dynamics simulation and a broiler model preliminarily revealed the mechanism of Kae alleviates Cu-induced nephrotoxicity (CuN). The potential targets of CuN scanned from Comparative Toxicogenomics Database (CTD), GeneCards database (GC) and the targets of Kae scanned from SwissTargetPrediction, PharmMapper database were used to perform GO and KEGG enrichment analysis. STRING and Cytoscape were employed to constructed PPI networks and locked on core targets. Molecular docking and dynamics simulations were used to investigate the binding affinity and stability of Kae with the core targets. A broiler model to further validate the impact of Kae on key signaling pathways. Notably, Kae effectively ameliorated histopathological damage caused by excess Cu and restored renal function (P < 0.05). Network results revealed the involvement of apoptosis and MAPK signaling pathway, with Caspase-3 (CASP3) and Mitogen-activated protein kinase 8 (MAPK8) identified as core targets. In vivo experiments demonstrated that Cu significantly up-regulated the levels of Cleaved-CASP3 and phosphorylated MAPK8 and the expression of genes and proteins involved in promoting endogenous apoptosis (P < 0.05), while Kae markedly reversed these effects and reduced TUNEL staining positive rate from 43.83% to approximately 12.84% (P < 0.05). In summary, our findings demonstrate that Kae alleviates CuN by targeting the apoptotic process and the MAPK/JNK signaling axis, highlighting its potential as a natural therapeutic agent against heavy metal-induced nephrotoxicity in agricultural settings.

Copper (Cu) is an essential mineral nutrient in animal, however, excess Cu causes mitochondrial homeostasis imbalance and multiple regulated cell death. This study explored how Cu overload disrupts the SAM50-MICOS-ATAD3-mtDNA axis and further activates cGAS-STING-NLRP3-mediated pyroptosis in pig liver via in vivo feeding model and in vitro hepatocyte with Cu chelator TTM, SAM50 overexpression and H₂O₂ positive control. We verified that excess dietary Cu triggers hepatic lipid metabolic disorder and impairs mitochondrial respiratory activity. Mechanistically, Cu weakens bidirectional protein interactions within the SAM50-MICOS-ATAD3 complex without altering total protein abundance of these subunits, thus breaking mtDNA retention homeostasis. Therefore, Cu exposure significantly increased the mtDNA (D-LOOP, mtATP6, mtCO1, mtND1, mtCO2 and mtND2) released to cytoplasm and plasma compared with that in the control group and raised the level of IFN-β (P < 0.05). Additionally, Cu exposure significantly increased the mRNA and protein expression of cGAS-STING pathway and NLRP3 dependent pyroptosis compared with the control group, while obviously decreased the mRNA and protein expressions of TFAM. Immunohistochemistry and immunofluorescence validated elevated GSDMD and NLRP3 as well as reduced TFAM in Cu stressed liver tissue. Notably, SAM50 overexpression effectively restored the disrupted complex, curtailed mtDNA egress, and attenuated downstream inflammatory activation, phenocopying the protective effects of TTM chelation. Collectively, our findings demonstrated Cu overload destroyed the stability of SAM50-MICOS-ATAD3-mtDNA axis, promotes mtDNA released and triggered the cGAS-STING and NLRP3 pathways in pig hepatocytes.

Copper (Cu) is widely used as a growth-promoting trace element in swine feed, but excessive Cu causes liver toxicity and modulates innate immunity, with unclear molecular mechanisms. In this study, dietary Cu overload in pigs led to Cu accumulation and liver injury, elevated levels of reactive oxygen species (ROS), and decreased mitochondrial membrane potential (MMP). These changes were accompanied by increased VDAC oligomerization in the mitochondrial membrane and mitochondrial DNA (mtDNA) release, which activates the NLRP3 inflammasome and triggers hepatocyte pyroptosis. Mechanistically, the VDAC inhibitor VBIT-4 reduced Cu-induced VDAC oligomerization and mtDNA release. Furthermore, NLRP3 is essential for Cu-mediated pyroptosis. Combined VBIT-4 and the MCC950 (NLRP3 inhibitor) treatment further attenuated VDAC oligomerization, mtDNA release, and pyroptosis. Collectively, our results reveal that Cu exposure promotes VDAC oligomerization and mitochondrial membrane pore formation, leading to mtDNA release, NLRP3 inflammasome activation, and pyroptosis in hepatocytes. These findings provide new insights into Cu-induced hepatotoxicity.

Copper (Cu), an environmental metallic pollutant, is closely associated with hepatic injury and inflammation, yet its molecular mechanisms remain incompletely understood. Although kaempferol (KAE) exhibits anti-inflammatory properties, its role in Cu exposure-induced hepatotoxicity, which is not fully clarified. In this study, we integrated animal experiments with network pharmacology and molecular docking to explore KAE's protective effects in a chicken model of Cu exposureinduced liver injury. Histopathological analysis revealed that Cu exposure induced inflammatory infiltration, hemorrhage, and collagen deposition, which were alleviated by KAE. Network pharmacology identified insulin (INS) as a key target, supported by strong binding affinity in molecular docking. Consequently, Cu exposure elevated blood glucose and upregulated INS and p38-MAPK expression, effects reversed by KAE. Further, the results showed that copper activated the p38MAPK/NF-kappa B pathway, promoting NLRP3 inflammasome assembly and caspase-1dependent pyroptosis, as evidenced by increased levels of NLRP3, ASC, caspase-1, GSDMD, N-GSDMD, IL-1 beta, and IL-18. Immunostaining confirmed upregulation of NLRP3 and N-GSDMD after Cu exposure, which KAE treatment suppressed. These findings elucidate a novel mechanism of Cu exposure-induced liver injury and highlight KAE's potential as a therapeutic agent for metal overload-related hepatotoxicity.

Mutations in a specific protein called calcium-activated nucleotidase 1 (Cant1) cause skeletal deformities, but the role of Cant1 in these deformities remains unclear. This study shows how Cant1 acts as a key regulator of bone and cartilage health. We found that Cant1 binds to and stabilizes a protein called Wnt/β-Catenin. Wnt/β-Catenin then enters the cell nucleus to activate specific genes. One of these genes, CHSY1, is turned on to produce building blocks such as collagen and sugars that form the extracellular matrix (ECM), which acts as the scaffolding of cartilage. When Cant1 and Wnt/β-Catenin expression are suppressed, there is a reduction in glycosaminoglycans (GAGs; mucopolysaccharides) and proteoglycans (like ACAN), which create a hydrated, gel-like matrix by binding with hyaluronan and link proteins to make cartilage resistant to compression. Additionally, there is a decrease in the α-1 chain of type II collagen (COL2α1), which forms the structural mesh or framework that gives tissue its tensile strength. In summary, we identified a conserved signaling pathway, the Cant1/β-Catenin/transcription factor 4 (TCF4)–CHSY1 axis, that regulates ECM homeostasis during skeletal development. Dysfunction of this pathway is a core cause of skeletal disorders. These findings not only provide mechanistic insights into human Cant1-related skeletal diseases but also highlight potential new targets for broad-spectrum therapies aimed at correcting deficiencies in ECM biosynthesis.

Tibetan pigs are a vital source of income and meat for local residents. P. multocida is a main pathogen in pig respiratory diseases, seriously threatening Tibetan pig industry. However, few studies explored the pathogenicity of P. multocida isolated from Tibetan pigs. Thus, this study aims to investigate the pathogenicity P. multocida isolated from Tibetan pigs. Results indicated that P. multocida could cause organic damage, including the heart, spleen, liver, lungs, and kidneys. Furthermore, P. multocida dramatically increased the protein expression of IL-11 and IL-4, while decreasing the TNF-alpha level in the lungs. In the liver, the levels of IL-11 and IL-4 were dramatically increased during P. multocida infection. Importantly, we also found a significant increase in the expression of APAF1, Bax, and Cyt-c in the lungs, whereas the levels of Bcl2 and Caspase8 were dramatically decreased during P. multocida infection. Similarly, the levels of APAF1 and Caspase3 dramatically increased, whereas the Caspase9 was dramatically decreased in the liver during P. multocida infection. In the lungs, the levels of ATG5, mTOR, Beclin1, and LC3b increased significantly, while p62 showed an opposite trend. Likewise, P. multocida infection also decreased the levels of Beclin1 and p62 in the liver. In summary, this research investigated the effects of P. multocida on mice health. Results indicated that P. multocida infection can induce inflammatory responses and organic damage. In addition, excessive activation of apoptosis and autophagy may be one of the potential pathways for P. multocida to affect host health.

Copper (Cu) is an essential trace element but also an agricultural pollutant with hepatotoxic risks. This study investigated the relationship among UPRmt, the Sirt3/FOXO3a pathway, and oxidative stress in chicken hepatocytes under Cu exposure. Here, broilers were fed diets containing 11, 110, 220, or 330 mg/kg Cu for 49 days, and primary hepatocytes were treated with Cu combined with OTC overexpression, Sirt3 agonist ADTL-SA1215, Sirt3 inhibitor 3-TYP, and FOXO3a overexpression or silencing. Cu exposure causes liver injury and activates UPRmt (upregulated HSP60 and LonP1) and was associated with Sirt3/FOXO3a inhibition. OTC-overexpression-induced UPRmt activation further correlated with Sirt3/FOXO3a inhibition, decreased antioxidant enzymes (GPX4 and SOD2), increased oxidative markers (8-OhdG and LPO), and aggravated liver injury. Pharmacological and genetic modulation confirmed Sirt3/FOXO3a as a key downstream mediator. These results suggest that Cu-induced UPRmt activation, association with Sirt3/FOXO3a inhibition, may disrupt the redox balance and promote hepatocyte injury, providing new insights into Cu hepatotoxicity.

Arsenic is one of the important pollutants in the environment. As the main target organ of arsenic exposure, the liver contains a large number of lysosomes, which play an important role in liver injury induced by arsenic. The involvement of lysosomes in arsenic-induced hepatic damage among avian species, specifically chickens, has yet to be documented. Therefore, in this study, we established animal models of chickens and primary chicken hepatocyte models with different concentrations of arsenic trioxide (ATO) and further explored the hepatotoxic mechanism of arsenic from the perspective of lysosome damage. Our study confirmed that ATO affected the growth and development of chickens; caused substantial liver damage with decreased antioxidant capacity. Our study also found that exposure to ATO leads to lysosomal damage. This leads to the leakage of tissue protease B (CTSB) within lysosomes and triggers the Gal-3-dependent lysosomal phagocytosis mechanism to eliminate the damaged lysosomes.Moreover, we also found that lysosome damage and lysophagy induced by ATO were associated with intracellular Ca2+ disturbance. Taken together, the results show that ATO can induce lysosome damage and activate Gal-3 mediated lysophagy.

Background Aflatoxin B1 (AFB1) is a highly toxic mycotoxin that poses significant risks to poultry health, causing neurotoxicity and economic losses. However, the precise mechanisms underlying AFB1-induced brain injury, particularly regarding the role of PANoptosis—a coordinated cell death pathway—remain largely unexplored. Aim This study aimed to investigate the mechanisms of AFB1-induced neurotoxicity in ducks, focusing on the inflammatory response and PANoptosis, and to evaluate the potential neuroprotective effects of curcumin. Methodology A duck model of AFB1 intoxication was established. Ducks were divided into four groups: Control, Curcumin (Cur), AFB1, and AFB1+Cur. We assessed body weight, brain coefficients, and histopathological changes. Oxidative stress was measured via SOD activity and MDA content. The integrity of the blood-brain barrier (BBB) and the expression of genes and proteins related to the TLR4/NF-κB signaling pathway and PANoptosis were analyzed using Western blot, RT-qPCR, and immunofluorescence. Results AFB1 exposure resulted in significant growth retardation, degenerative brain damage (such as neuronal necrosis, cytoplasmic vacuolization, and nuclear shrinkage), reduced SOD activity by approximately 53%, and MDA levels increased by approximately 1.88-fold. It also compromised the BBB by downregulating ZO-1 and Occludin expression. Furthermore, AFB1 significantly upregulated the TLR4/NF-κB signaling pathway and key PANoptosis markers (ZBP1, RIPK1/3, Caspase-8, NLRP3, GSDMD). Curcumin attenuated the pathological damage of AFB1-intoxicated duck brain and was able to mitigate AFB1-induced neurotoxicity by inhibiting the phosphorylation of NF-κB and IκB, preventing IκB degradation, and downregulating the expression of key PANoptosis mediators. Conclusion AFB1 could trigger PANoptosis and activate the TLR4/NF-κB signaling pathway, leading to brain damage in ducks. Curcumin exerted a significant protective effect by inhibiting these pathways, suggesting its potential as a therapeutic agent for alleviating mycotoxin-induced neurological damage.

Hexavalent chromium (Cr[VI]) is a significant environmental contaminant that poses substantial risks to agricultural safety and public health. Although Cr(VI)-induced hepatic injury is associated with oxidative stress and organelle dysfunction, the crosstalk between ionic homeostasis disruption and organelle-specific pathophysiology remains incompletely elucidated. Herein, we identified significant suppression of peroxiredoxin 1 (PRDX1) following Cr(VI) exposure, concomitant with intracellular calcium depletion, mitochondrial lipid peroxidation, endoplasmic reticulum (ER) stress, and ferroptosis. Mechanistically, Cr(VI)-driven PRDX1 deficiency initiates calcium-mediated mitochondrial oxidative damage and ER stress, synergistically triggering the ferroptosis cascade that culminates in hepatic injury. These findings establish PRDX1 as the master regulator of Cr(VI) hepatotoxicity and uncover a novel calcium-dependent axis that converges mitochondrial redox imbalance with ER proteotoxic stress to drive ferroptotic cell death. This study provides fundamental insights into the toxicological role of PRDX1 in Cr(VI) exposure and advances theoretical frameworks for understanding chromium-associated pathophysiological mechanisms.

Copper (Cu) is an essential trace element in animal organisms, participating in numerous vital processes. However, excessive intake can cause poisonous damage to organs such as the intestines. This study aims to elucidate the role of miR-206 in copper-induced pyroptosis in porcine jejunal epithelial cells and its molecular mechanism. In this study, we found that high-dose copper exposure induces pyroptosis in jejunal epithelial cells, while miR-206 expression was significantly reduced to 0.60 and 0.64 times that of the control group in vivo (Fed a diet containing 250 mg/kg of copper) and in vitro (treatment of IPEC-J2 cells with 400 μM CuSO₄), respectively (P < 0.05). Upregulation of miR-206 significantly reduced the expression of copper-induced pyroptosis-related proteins, with the expression levels of NLRP3, IL-18, and IL-1β downregulated to 0.28-, 0.47-, and 0.42-fold, respectively, compared to the group treated with copper alone (all P < 0.05). At the same time, it markedly alleviated copper-induced cell membrane rupture. Bioinformatics analysis and dual luciferase reporter assays confirmed that Caspase-1 is a direct target of miR-206. Overexpression of Caspase-1 significantly reversed the protective effect of miR-206 against copper-induced pyroptosis, whereas RNA interference of Caspase-1 produced the opposite effect. Therefore, our study reveals the molecular mechanism by which miR-206 alleviates copper-induced pyroptosis in porcine jejunal epithelial cells by suppressing Caspase-1 expression. This provides a novel perspective for investigating the molecular pathology of copper toxicity and lays a theoretical foundation for developing early diagnostic and therapeutic targets for copper toxicity.

Aflatoxin B1 (AFB1), the most toxic and widely distributed aflatoxin, poses considerable health hazards to both animals and humans. Following oral intake, the gastrointestinal tract is the primary site of contact. Our study shows that AFB1 exposure markedly alters the gut microbiota composition, mainly by reducing the population of beneficial bacteria. It also increases PTEN expression and suppresses the downstream PI3K/AKT signaling pathway both in jejunal and IPEC-J2 cells, promoting apoptosis and necroptosis. In addition, AFB1 impaired intestinal barrier function by decreasing expression of ZO-1 and Occludin. Notably, the PTEN-specific inhibitor VO-Ohpic can effectively alleviate the above changes induced by AFB1, confirming PTEN's key role. Our study has first elucidated the mechanism by which AFB1 induces intestinal damage through disrupting gut microbiota structure and the "PTEN/PI3K/AKT─epithelial barrier" axis, providing new targets and theoretical basis for the prevention and treatment of AFB1 poisoning.

[This corrects the article DOI: 10.34133/research.1227.].

Nano-copper (nanoCu), a nanoscale form of copper (Cu), has been widely applied in the animal husbandry industry. However, it is of great concern that the Cu exposure to humans and animals can cause toxic damage to multiple organs. Hesperidin (Hes), a flavonoid found in citrus fruits, has shown mitigating effects on various organ damages. In our study, we aimed to investigate the toxic effects of nanoCu exposure on the kidneys of chickens and the therapeutic efficacy of Hes in nanoCu-induced renal injury. Our results indicated that Hes could alleviate endoplasmic reticulum stress (ERS) caused by nanoCu exposure. Intriguingly, nanoCu significantly disrupted endoplasmic reticulum (ER) homeostasis, which manifested as increased levels of key proteins such as GRP78, PERK, and CHOP, as well as elevated H2O2 levels. But Hes treatment exhibited an opposite trend. Furthermore, nanoCu significantly induced autophagy in renal cells, which was accompanied by the activation of the AMPK-AKT/mTOR pathway and a concurrent increase in the protein levels of ATG5, Beclin 1, LC3 II/LC3 I, and ULK1, along with a decrease in the level of p62. However, it can be reversed by Hes treatment. These findings suggest that Hes could mitigate ER homeostasis disruption and autophagy caused by nanoCu exposure, providing new insights into the pharmacological treatment of Hes in related health issues.

Mn2O3 nanometer particles(Mn2O3 NPs), a new material, is widely used in medicine, electrochemical sensing and energy storage fields. The widespread use of Mn2O3 NPs has caused health concerns, and it is necessary to clarify the toxic mechanism of Mn2O3 NPs exposure. Our findings showed that Mn2O3 NPs exposure could lead to liver histological abnormalities, mitochondrial dysfunction in liver, as well as mitochondrial-mediated apoptosis, autophagy and mitochondrial dynamics disorder, and eventually lead to liver injury. At the same time, the ileal epithelium suffered physiological damage and inflammation after Mn2O3 NPs exposure, and the expression levels of genes and proteins related to intestinal barrier function (MUC1 ZO-1 Claudin1 and Occludin) were significantly down-regulated. Meanwhile, 16s sequencing analysis of intestinal bacteria showed that Mn2O3 NPs exposure caused significant changes in intestinal flora abundance. The Firmicutes/Bacteroidetes ratio increased, and the abundance of probiotics (Bacteroides, Bifidobacterium, Faecalibacterium) decreased, while the abundance of harmful bacteria (Streptococcus, Enterococcus, Pseudomonas) increased. The changes in these microflorae may potentially impact the development of liver injury. Altogether, these results provide novel insights into the potential mechanism of Mn2O3 NPs related hepatotoxicity induced by gut microbiota via the gut-liver axis, and contribute to a better interpretation of the health impact of Mn2O3 NPs.

Type 2 diabetic nephropathy (T2DN) stands as a critical microvascular complication of type 2 diabetes, and current pharmacological interventions remain necessitate refinement and supplement. Through network pharmacology and preliminary screening, andrographolide (AND) emerged as a potential intervention. A canine T2DN model, established via high-fat and high-carbohydrate diet and streptozotocin, exhibited hallmark metabolic dysfunction (hyperglycemia, insulin resistance, hyperinsulinemia, glycosuria) and renal pathology (reduced Glomerular filtration capacity, fibrosis). AND administration ameliorated glycemic homeostasis, insulin sensitivity, and renal function. Integrated transcriptomic profiling revealed T2DN progression mechanistically linked to PI3K/AKT1 signaling activation, RRM2 upregulation, and hydrogen peroxide-predominant ROS response, with subsequent experimental validation confirming ROS-dependent oxeiptosis induction through PI3K/AKT1/RRM2 axis hyperactivation. Mechanistically, T2DN exacerbates renal damage via a self-amplifying loop: hyperglycemia-stimulated ROS overproduction drives PI3K/AKT1-mediated RRM2 upregulation, which in turn promotes oxeiptosis. Crucially, AND interrupts this pathogenic cascade by suppressing PI3K/AKT1/RRM2 signaling hyperactivity and inhibiting ROS-oxeiptosis crosstalk, thereby establishing its therapeutic potential as a novel multi-target supplement for T2DN management. These findings provide both translational guidance for clinical strategies targeting the PI3K/AKT1/RRM2-oxeiptosis axis and mechanistic rationale for AND-based therapeutic development.

Background: The nutritional status during the late stage of pregnancy significantly influences the survival rate, birth weight, growth performance, and immune function of piglets while also playing a pivotal role in regulating intestinal barrier function. However, it remains unclear whether supplementation with traditional Chinese medicine (TCM) can enhance offspring piglets' intestinal barrier function and immune function. Methods: 24 late-pregnancy sows (85 days pregnant) were randomly assigned to either CON group or TCM group for a 30-day feeding trial. Following parturition, 10 newborn piglets from each group were randomly selected for euthanasia, and the ileal tissues as well as cecal contents were collected for analysis. The hub active ingredients and targets of TCMs formula were analyzed using network pharmacology. Results: TCM group exhibited elongation and deepening of villi in the ileum, a significant increase in Peyer's patches, notable enhancement of intestinal immune function, and improved anti-inflammatory ability. Further, maternal TCMs supplementation might increase the abundances of Sutterella and Actinoplanes in the piglet cecum, which significantly affected chemoheterotrophy, aerobic-chemoheterotrophy, and fermentation functions. PI3KCA and PI3KCB may serve as hub genes for the 14 TCMs. Kaempferol, Quercetin, and Luteolin were identified as the top three active ingredients with potential positive effects on Neonatal piglets through modulation of MAPK signaling pathway, calcium signaling pathway, and cAMP signaling pathway. Conclusion: Incorporating Chinese herbs into the diets of sows significantly improves the Ileum barrier function and anti-inflammatory capacity of piglets, potentially attributable to active ingredients, modulation of intestinal microbial communities, and activation of diverse signaling pathways.

The bone extracellular matrix (ECM) is a dynamic scaffold crucial for skeletal integrity, and its dysregulation underpins pathologies such as achondroplasia (ACH), osteoporosis (OP), and osteoarthritis (OA). Emerging evidence reveals that the gut microbiota acts as a critical regulator of bone homeostasis via its metabolites. The key metabolites, including short-chain fatty acids (SCFAs), tryptophan derivatives (indole metabolites), bile acids (BAs), and bacterial extracellular vesicles (BEVs), modulate bone ECM homeostasis through multiple pathways, such as enhancing mineral absorption, regulating immune and endocrine signaling (e.g., GH/IGF-1, AhR/PXR, and FXR/TGR5), and influencing the differentiation and activity of bone cells. They also promote metabolite host interactions to impact critical ECM components, including collagen mineralization and non-collagenous protein expression. Although preclinical studies demonstrate the therapeutic potential of microbiota derived metabolites for skeletal disorders, significant challenges remain in elucidating precise molecular mechanisms and translating these findings into clinical applications. This review summarizes recent advances in understanding how gut microbiota derived metabolites regulate bone ECM biosynthesis and remodeling. We emphasize that targeting these metabolites presents a promising strategy for promoting bone health by orchestrating ECM homeostasis. Understanding this interaction provides a novel insight for developing innovative strategies to improve skeletal health.