Periostin (POSTN), a non-structural extracellular matrix protein, plays a critical role in promoting tumor cell invasion, metastasis, and disease progression. We previously reported that POSTN mRNA and protein levels are markedly upregulated in the synovium of patients with rheumatoid arthritis (RA); however, its specific functions and underlying mechanisms remain unclear. In this study, we investigated the roles of POSTN in fibroblast-like synoviocytes (FLSs) and collagen-induced arthritis (CIA) model mice. POSTN mRNA and protein levels were markedly upregulated in primary RA-FLSs and closely associated with synovial fibrosis and angiogenesis. POSTN knockdown markedly reduced the cellular invasion, profibrotic phenotype, and vascular endothelial growth factor A secretion in RA-FLSs, whereas its overexpression exerted the opposite effects. Mechanistically, POSTN interacted with and regulated integrin αvβ3 (ITGαvβ3), leading to activation of the transforming growth factor (TGF)-β1/SMAD signaling pathway. Rescue experiments confirmed that POSTN played a critical role in promoting disease progression by regulating the ITGαvβ3/TGFβ1/SMAD axis. Moreover, adeno-associated virus 9-mediated POSTN knockdown alleviated joint destruction, synovial hyperplasia, fibrosis, and angiogenesis in CIA model mice. Collectively, our results suggest that POSTN drives RA progression by modulating the ITGαvβ3/TGFβ1/SMAD signaling pathway, highlighting its potential as a novel therapeutic target for RA.

Periodontitis serves as a model for chronic inflammatory diseases, offering critical insights into immune regulatory mechanisms at the microbe-host interface. By integrating structural immunity theory with single-cell transcriptomics and multi-omics analyses, we investigated the microbial-epithelial-immune crosstalk in periodontitis. Single-cell transcriptomic analysis revealed robust interactions between immune cells and sulcular and junctional keratinocytes (SK/JKs) in the periodontitis epithelium. SK/JKs, being directly exposed to dental plaque biofilm, exhibit significant activation of endoplasmic reticulum stress (ERS), oxidative stress, and the integrated stress response (ISR) during periodontitis. Weighted gene co-expression network analysis (WGCNA) emphasized the central role of ISR in coordinating stress pathways and immune effector functions. Experimental validation demonstrated that Porphyromonas gingivalis (P. gingivalis) infection induces epithelial ISR, triggering an inflammatory cascade, while inhibition of ISR significantly reduces cytokine production. Mechanistically, ISR activation in SK and JK cells upregulates key inflammatory mediators (CXCL1, CXCL8, CXCL16, IL-6), promoting infiltration of plasma cells and neutrophils, and reshaping the local immune microenvironment, ultimately driving alveolar bone destruction in periodontitis. Our findings uncover an ISR-mediated structural immunity axis in SK/JKs during periodontitis, enhancing our understanding of the mechanisms underlying chronic inflammatory diseases.

Gliomas are a group of highly invasive and recurrent tumors originating from neural stem cells or glial progenitor cells. According to data from the Central Brain Tumor Registry of the United States published in 2023, the global incidence of gliomas is estimated at approximately 2.53 per 100,000 individuals(Ostrom et al., 2023. Although surgical resection remains the primary treatment strategy, the 2021 WHO Classification of Tumors of the Central Nervous System reports that the five-year survival rate for gliomas typically ranges from 80 % to 90 %, whereas low-grade gliomas with IDH-wildtype mutations have a five-year survival rate of approximately 50 % to 60 %(Louis et al., 2021. Therefore, IDH1/2 mutations are widely considered favorable prognostic markers in gliomas. However, recent studies have indicated that, compared to IDH-wildtype gliomas, IDH1/2-mutant gliomas often exhibit a significant reduction in survival time and a marked deterioration in prognosis following progression or recurrence. This suggests that, even for molecular subtypes with initially favorable prognoses, progression to a higher-grade state, their biological behavior may rapidly shift toward that of more aggressive gliomas, and may be accompanied by varying degrees of blood-brain barrier (BBB) disruption. This review aims to comprehensively examine the association between IDH1/2 mutations and BBB disruption, elucidating how IDH1/2-mutant gliomas alter tumor-associated metabolic and epigenetic pathways, which subsequently influence microglial activation and polarization, contributing to BBB impairment. Furthermore, we propose that microglia-mediated BBB disruption may be one of the underlying mechanisms contributing to complications in IDH1/2-mutant gliomas, such as vasogenic edema and immune-mediated encephalopathy, both of which are closely associated with BBB breakdown.

Obesity is currently a worldwide health problem, affecting more than 600 million people, and poses a threat to lifestyle and triggers metabolic complications. The infiltration of macrophages into adipose tissue (AT) plays a key role in inducing inflammation and multiple diseases during obesity. Therefore, comprehensive knowledge is required on the crosstalk between adipocytes with resident macrophages in AT to design therapeutic options for obesity and metabolic diseases. While we have demonstrated the role of Siglec-E in inflammation, the mechanism by which Siglec-E induces AT inflammation and adipogenesis remains unclear to date. Thus, this study describes how Siglec-E alters AT macrophages phenotypes, function, and adipogenesis using a high-fat diet (HFD)-induced model of obesity. We showed that during obesity, expression of Siglec-E orchestrated the infiltration of macrophages in the AT. Further, deletion of Siglec-E increased the frequency and expression of inflammatory markers and modulated macrophages towards M1 phenotypes to induce AT inflammation. We also noticed that interleukin (IL)-6 and monocyte chemoattractant protein 1 (MCP-1), inflammatory markers, increased in differentiated 3T3-L1 adipocytes after the inhibition of Siglec-E. Further, cultured 3T3-L1 adipocytes, treated with Siglec-E siRNA, show an increasing expression of peroxisome proliferator-activated receptor γ (PPARγ), NF-κB inducing kinase (NIK), NF-κB2, and decreasing expression of CCAAT-enhancer-binding protein-α (C/EBPα), and adiponectin, which in part suggests that Siglec-E is also associated with adipogenesis. Further, we observed that stromal vascular fractions (SVF) cells isolated from HFD-fed mice subjected to treatment with Siglec-E siRNAs exhibited decreased expression of the cell death-inducing DFA-like effector a (CIDEA), supporting the notion that Siglec-E might, in part, also play a role in AT browning. Taken together, our findings highlight new possibilities for the function of Siglec-E in obese conditions and instigate us to propose that Siglec-E might serve as a potential therapeutic for obesity-associated metabolic disease and AT inflammation.

Glioma is an immunologically evasive tumor with a lymphocyte-deficient tumor immune landscape, suggesting an unknown failure in tumor-stroma interaction. The human natural killer-1 glycan (HNK-1) is present on neurons and immune cells, suggesting a potential source of glioma-stroma interaction, cross-talk, and immune regulation. Immunohistochemical staining of a human glioma microarray showed that HNK-1 progressively decreased with increasing tumor grade. However, similar immunohistochemical staining for β-1,3-glucuronic acid transferase (B3GAT1), the predominant enzyme responsible for HNK-1 synthesis, showed no change with glioma progression, indicating that the loss of HNK-1 was not due to changes in B3GAT1 expression. However, Kaplan-Meier analysis showed that B3GAT1 levels positively correlated with survival. In the syngeneic GL261 murine glioblastoma model, HNK-1 knockdown by two B3gat1 shRNAs accelerated glioma growth and reduced mouse survival in vivo. B3gat1-knockdown tumors had increased numbers of regulatory T cells, and decreased numbers of effector CD8 T cells, which correlated with increased CD8 T-cell apoptosis. In co-cultures of CD8 T cells with B3gat1-knockdown GL261 cells, we observed reduced T-cell-induced glioma Ca signaling and intracellular perforin accumulation, along with increased perforin release into the culture medium, compared to CD8 T-cell co-culture with wild-type GL261 cells. FACS analysis showed loss of co-stimulatory CD80, an immune synapse component, following B3gat1 knockdown. These results suggest that loss of HNK-1 expression contributes to tumor immune escape through loss of immune recognition and attack via downregulation of tumor cell surface co-stimulatory molecules, leading to reduced CD8 T-cell activation and immune synapse formation, and increased T-cell apoptosis.

Severe acute pancreatitis (SAP) is a life-threatening inflammatory disease without effective therapeutic interventions. Moscatilin (Mos), a bioactive biphenyl compound derived from Dendrobium, exhibits notable anti-tumor and anti-inflammatory properties; however, its potential application in the treatment of SAP remains unexplored. This study aimed to investigate the protective effects of Mos against SAP and its underlying mechanism. In the caerulein/LPS-induced SAP mouse model and in vitro SAP model, using hematoxylin-eosin (H&E) staining, ELISA and other detection, we demonstrate that Mos significantly attenuated pancreatic injury, decreased serum amylase and lipase levels, and inhibited the production of pro-inflammatory cytokines, including IL-1β, IL-6 and TNF-α. Western blot showed that Mos up-regulated the expression of GPX4 and SLC7A11 and down-regulated ACSL4. Meanwhile, Mos inhibited lipid peroxidation and attenuated ferroptosis as measured by glutathione (GSH), malondialdehyde (MDA) and Fe concentrations. Co-IP assay showed that Mos directly binds KEAP1, disrupting its interaction with NRF2, preventing NRF2 ubiquitination and degradation, and activating the NRF2/HO-1 signaling pathway to exert its protective effect. These beneficial effects were effectively reversed by the use of the NRF2 inhibitor ML385 in rescue experiments. In conclusion, our findings demonstrate that Mos mitigates SAP progression by inhibiting ferroptosis and inflammatory responses via targeting KEAP1, blocking NRF2 degradation, and activating the NRF2/HO-1 pathway. This study provides novel insights into ferroptosis-targeted therapeutic strategies for SAP and offers experimental evidence supporting the use of dendrobium-derived compounds in the treatment of acute pancreatitis.

Emerging evidence highlights RNA N6-methyladenosine (m6A) modifications as pivotal regulators of tumorigenesis, yet the synergistic roles of m6A readers in the pathogenesis and prognosis of acute myeloid leukemia (AML) remains unclear. By leveraging multiomics data from 2680 AML patients, we systematically mapped the dysregulated m6A reader network, revealing the coordinated upregulation of readers and their associations with aggressive AML subtypes. We devised a m6A reader activity score (m6ARS), and an elevated m6ARS is associated with excessive proliferation, impaired CD8+ T cell infiltration, and PD-L1-mediated immune evasion. A machine learning-derived 28-gene prognostic model demonstrated robust performance across 10 independent cohorts and outperformed traditional clinicopathological factors in multivariate analysis. High-risk patients exhibited heightened sensitivity to targeted therapies (e.g., dasatinib and olaparib), suggesting actionable therapeutic vulnerabilities. Functional studies identified YTHDF3 as a novel oncogenic driver that is significantly overexpressed in AML, where its knockdown suppressed proliferation, induced apoptosis, and stabilized leukemogenic transcripts (ZZZ3, KLHL11) via the regulation of mRNA stability. This integrative study reveals the m6A reader network as a central orchestrator of AML progression, provides a validated prognostic framework for risk-adapted therapy, and positions YTHDF3 as a potential diagnostic and therapeutic target, bridging RNA epigenetics with clinical translation in AML.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovitis and joint destruction. While GTPase-activating protein SH3 domain-binding protein 2 (G3BP2) plays important roles in tumors and other diseases, its function in RA remains unclear. Our study demonstrated significant upregulation of G3BP2 in fibroblast-like synoviocytes (FLSs) from RA patients, which was further enhanced by TNF-α stimulation. Both G3BP2 knockdown using siRNA and pharmacological inhibition with compound C108 effectively suppressed TNF-α-induced RA-FLS migration, invasion, and reduced the secretion of IL-1β and VEGF-A as well as the expression of N-cadherin. RNA sequencing analysis revealed that compound C108 modulates the p53 signaling pathway. Mechanistically, both G3BP2 silencing and C108 treatment enhanced p53 expression by reducing its ubiquitination, thereby activating p53 signaling. Importantly, the p53 inhibitor PFT-α reversed the inhibitory effects of C108 on TNF-α-induced RA-FLS migration, invasion, and cytokine expression. In adjuvant-induced arthritis (AA) rat models, intra-articular injection of compound C108 (4 and 8 μM) significantly alleviated arthritis symptoms, reduced synovial hyperplasia, downregulated G3BP2, N-cadherin, IL-1β, and MMP3 expression, while promoting p53 expression in FLSs of AA rats. Our findings demonstrate that G3BP2 promotes abnormal activation of RA-FLSs by suppressing p53 signaling, suggesting G3BP2 as a promising therapeutic target for RA treatment.

This study investigates the role of calreticulin (CRT) in intervertebral disc degeneration (IVDD) and elucidates its underlying mechanisms. CRT expression was markedly reduced in degenerated disc tissues, implicating its involvement in IVDD pathogenesis. Both in vitro and in vivo experiments were conducted to assess the effects of CRT on nucleus pulposus cell (NPC) pyroptosis, apoptosis, and mitochondrial function. Functional analyses demonstrated that CRT overexpression alleviated disc degeneration, inhibited pyroptotic cell death, and preserved mitochondrial integrity. Mechanistically, CRT promoted the clearance of damaged mitochondria through PINK1/Parkin-mediated mitophagy, restoring mitochondrial homeostasis and suppressing ROS accumulation and NLRP3 inflammasome activation. In vivo studies using an IVDD animal model further validated these protective effects, showing reduced disc degeneration and maintenance of extracellular matrix integrity. Recent studies have demonstrated the protective effect of CRT in IVDD. This study builds on these findings and investigates a novel mechanism through which CRT mediates its protective effects in IVDD. Specifically, our study identifies the involvement of PINK1/Parkin-mediated mitophagy in CRT's ability to preserve mitochondrial function and mitigate inflammation in NPCs, offering new insights into the molecular pathways underlying CRT's protective role in IVDD.

Many studies have elucidated the pivotal significance of the gut microbiota in the pathogenesis of numerous diseases. Research has demonstrated that administering high-grain diets (HGDs) to ruminants to enhance growth performance results in subacute ruminal acidosis (SARA), which subsequently triggers rumen microbial dysbiosis. This dysregulation can result in inflammation within the gastrointestinal tract, disruption of the gastrointestinal barrier, and an increased risk of disease. Nevertheless, the precise underlying mechanism that governs the contribution of the ruminal microbiota to the development of gastrointestinal inflammation remains elusive. The objective of this study was to investigate the role and potential mechanisms of microbial dysbiosis in the context of gastrointestinal inflammation. An HGD was used to induce SARA in dairy goats, thus establishing a model of ruminal microbial dysbiosis. The findings of this study indicate that dairy goats with SARA exhibit significant gastrointestinal and systemic inflammation, which is associated with ruminal microbial dysbiosis. The transplantation of ruminal microbiota from SARA dairy goats in mice has been demonstrated to induce gastrointestinal inflammation and disrupt the gastrointestinal barrier, thereby leading to a systemic inflammatory response. Furthermore, ruminal microbial dysbiosis is involved in gastrointestinal inflammation through the promotion of ferritinophagy-ferroptosis via activation of the NCOA4/FTH signalling pathway. However, this process can be reversed following pretreatment with Fer-1. These findings suggest that the modulation of the ruminal microbiota could be a potential strategy to prevent inflammation in the gastrointestinal tract and even systemic inflammatory responses. Importance. SARA is a common nutritional metabolic disease in ruminants and has significant implications for animal welfare and performance. Research has shown a strong link between SARA-induced rumen flora disorders in ruminants and inflammatory diseases such as hepatitis, mastitis and endometritis. The results of the present study demonstrate that disorders of the rumen flora can disrupt the gastrointestinal barrier through the ferritinophagy-ferroptosis pathway, leading to the movement of harmful substances and the development of systemic inflammation and other related inflammatory diseases. This study offers a new theoretical basis for treating inflammatory diseases in ruminants.

Allicin has been identified as a potential drug for colorectal cancer (CRC) therapy, whether it plays an anti-tumor effect via regulating immunity has not yet been explored. We investigated the mechanism by which allicin combated tumors in the treatment of CRC. Flow cytometry was utilized to analyze the infiltration of immune cells and the functionality of CD8 T cells after treating with allicin in tumor-loaded C57BL/6 mice. To assess the unique effect of allicin on T cells, we employed male OT-I mice for the analysis. RNA-seq and WB were utilized to determine the mechanism of allicin on T cells. The proliferation and migration of HCT116 and HT29 cells were evaluated using CCK-8, cloning, and transwell assays. BALB/c-nude mice were utilized to test the anti-tumor efficacy of allicin. Allicin could significantly inhibit the tumor growth, with an inhibition rate of 72.2 %. Moreover, allicin promoted the CD8T cells infiltration from 18.44 % to 47.01 % in vivo. Moreover, allicin enhanced the function of CD8T cells via promoting the secretion of IL-2, TNF-α and IFN-γ, differentiation of effector T cells as well as decreasing the expression of TIM-3 in vitro. Ovalbumin-specific CD8T cells were obviously increased after treating with allicin from 41.96 % to 58.40 % in vivo. Mechanically, allicin could enhance the anti-CRC function through targeting STAT3 in CD8T cells and tumor cells, with an inhibition rate of 80.3 % and 53.6 %, which suggests that allicin is a promising candidate for CRC treatment.

Lipid metabolism-associated disorders are pathological states characterized by abnormal levels of lipids and their metabolites, which serve as key drivers of metabolic diseases such as atherosclerosis and diabetes. The endoplasmic reticulum (ER) is primarily recognized for its roles in protein folding and lipid synthesis, and maintaining its homeostasis is crucial for proper cellular function. Emerging evidence indicates that lipid metabolism-associated disorders can disrupt ER homeostasis through multiple mechanisms, leading to ER stress. Persistent ER stress triggers chronic inflammatory responses, thereby accelerating the development of diseases associated with lipid metabolism. Recent studies have demonstrated that chronic inflammation and metabolic dysfunction may be linked to persistent activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway. Moreover, crosstalk between ER stress and the cGAS-STING signaling pathway has been observed in various metabolic diseases. In this review, we summarize the molecular mechanisms by which lipid metabolism-associated disorders induce ER stress and discuss the regulatory role of ER stress in modulating the STING signaling pathway. Our aim is to provide novel insights into the potential of targeting the ER stress-STING axis for the treatment of metabolic diseases.

Deep vein thrombosis (DVT) is a vascular complication with a high incidence after trauma and surgery, and its pathogenesis is closely related to vascular endothelial dysfunction. Recent studies have found that M1 macrophage polarization participates in thrombosis through exosome-mediated miRNA delivery, but the specific mechanism has not yet been clarified. This study focuses on the regulatory role of miR-126-5p in M1 macrophage exosomes and its downstream splicing factor SRSF11 in endothelial senescence and DVT.

Ulcerative colitis (UC) is one of the most common intestinal disorders. Its pathological mechanisms are complex and involve multiple cellular signaling pathways. Among these, NF-κB and Nrf2 signaling pathways play significant roles in the pathogenesis of UC. Currently, there are not many types of medications available for the treatment of UC. Although traditional therapeutic agents have anti-inflammatory effects, they also have many adverse reactions. Therefore, there is an urgent need for new research drugs to treat UC. This study aims to investigate the effects of a novel hydrogen sulfide-releasing small molecule compounds, DXFD-1, on UC and its potential mechanisms. In vitro experiments were conducted to establish an inflammation model using LPS-stimulated RAW264.7 cells. In vivo model of UC in mice was established using dextran sulfate sodium (DSS). The results of in vivo and in vitro experiments indicated that DXFD-1 could inhibit oxidative stress by activating the Nrf2 signaling, increasing the levels of SOD and GSH-PX, and reducing the levels of ROS, MPO, and MDA. Meanwhile, DXFD-1 significantly decreased the expression of TNF-α, IL-6, and IL-1β, downregulating the NF-κB signaling. These results demonstrate that DXFD-1 exhibits potent anti-inflammatory and anti-oxidative stress effects, and its potential mechanism related to the inhibition of the NF-κB signaling and the activation of the Nrf2 signaling. Therefore, DXFD-1 is expected to become a lead compound for the clinical treatment of UC.

Depression is a frequent neuropsychiatric complication of diabetes mellitus, but the underlying molecular mechanisms of diabetes-associated depression remain poorly understood. Asprosin, a recently identified fasting-induced glucogenic adipokine, is significantly elevated in diabetes. Pyroptosis, a form of inflammatory programmed cell death, can induce robust neuroinflammation, which also disrupts the kynurenine pathway (KP) of tryptophan metabolism, implying a potential cascade of pyroptosis-neuroinflammation-KP disorder relevant to depression pathogenesis. Therefore, this study aimed to elucidate whether hippocampal Asprosin contributes to the development of diabetes-associated depression by modulating this cascade. A rat model of diabetes-associated depression was established using a high-fat diet and streptozotocin (HFD/STZ). Results showed that diabetic rats exhibited increased depression-like behaviors, accompanied by elevated hippocampal Asprosin levels. Hippocampal Asprosin knockdown significantly alleviated depression-like behaviors, notably without affecting systemic glucose metabolism in diabetic rats, whereas hippocampal Asprosin overexpression induced depression-like behaviors. Mechanistically, Asprosin knockdown attenuated hippocampal neuroinflammation, suppressed astrocyte/microglial activation, and inhibited pyroptosis. Furthermore, Asprosin knockdown also restored KP homeostasis by reducing levels of neurotoxic metabolites (KYN, 3-HK, 3-HAA, QA) and increasing NAD levels in the hippocampus of diabetic rats. Conversely, Asprosin overexpression exacerbated hippocampal neuroinflammation, pyroptosis, and KP disorder. These findings suggest that hippocampal Asprosin may contribute to diabetes-associated depression, possibly by provoking the cascade of pyroptosis-neuroinflammation-KP disorder.

Acetaminophen (APAP) overdose causes severe hepatotoxicity, yet how mitochondrial injury in hepatocytes amplifies innate immune activation remains unclear. This study investigated whether extracellular vesicles released from APAP-injured hepatocytes (APAP-EVs) deliver damaged mitochondrial components to neutrophils, promoting NETs formation and worsening liver injury.

People are more likely to get infections, cancer, and other long-term illnesses as they age due to immunosenescence, which is a decrease in immune function. This loss is marked by less adaptive immunity and chronic inflammation. Although several lifestyle changes can slow this decrease, one non-pharmacological technique that has shown considerable promise is regular exercise. The effects of immunosenescence on inflammatory, infectious, and cancerous disorders are explored in this article. It is predicated on a thorough literature search of data from 2000 to 2025 in PubMed, Web of Science, Scopus, and ClinicalTrials.gov. We assess the data, which show that physical activity improves immunological responses and reduces immunosenescence alterations in these specific clinical settings. To enhance clinical outcomes and delay immunological decline, our synthesis confirms that physical exercise is a promising option. We conclude by providing an in-depth analysis of the benefits and drawbacks of exercise therapies for improving immunological function in older people.

Osteopontin (OPN), a multifunctional bioactive protein, has been shown to be elevated in the serum and bronchoalveolar lavage fluid (BALF) of. individuals with asthma and modulate the airway smooth muscle cells (ASMCs) proliferation and migration, yet its underlying molecular mechanisms are not completely understood. The aim of the present study is to address this issue.

Osteoporosis is a widespread metabolic bone disorder characterized by reduced bone mass and increased fracture risk, particularly in postmenopausal women due to estrogen deficiency. This hormonal decline enhances osteoclast activity, leading to excessive bone resorption. Current therapies are limited by long-term safety concerns, necessitating alternative treatments. Methylnissolin (Astrapterocarpan), a bioactive flavonoid from Astragalus membranaceus, has known anti-inflammatory and antioxidant properties, but its role in bone metabolism remains poorly defined.

Excessive osteoclast-mediated bone resorption is central to osteoporosis pathogenesis. We initially observed that Acyl-CoA Cholesterol Acyltransferase-1 (ACAT1) is significantly upregulated during receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastogenesis, and its knockdown potently inhibited osteoclastogenesis. This prompted us to investigate the therapeutic potential of Avasimibe (AVA), a specific ACAT1 inhibitor, originally developed for atherosclerosis due to its suppression of cholesterol esterification and anti-inflammatory effects, for osteoporosis treatment. In vitro, AVA markedly suppressed RANKL-induced osteoclastogenesis without cytotoxicity, as demonstrated by tartrate-resistant acid phosphatase (TRAP) staining, immunofluorescence, quantitative real-time PCR (qRT-PCR), and western blot analysis. In vivo, AVA administration effectively attenuated bone loss in ovariectomized (OVX) mice, significantly improving bone mineral density, preserving trabecular microarchitecture. Mechanistically, RNA sequencing (RNA-seq) and bioinformatic analysis revealed that AVA downregulates creatine kinase B (CKB), a key mediator identified as upregulated during osteoclastogenesis, consequently inhibiting the phosphatidylinositol 3-kinase-protein kinase B (PI3K-AKT) signaling pathway. Critically, the inhibitory effects of AVA on osteoclast differentiation and PI3K-AKT activation were reversed by exogenous phosphocreatine (PCr). Collectively, our data demonstrate that AVA attenuates osteoclastogenesis and bone resorption by targeting the CKB/PI3K-AKT axis, identifying it as a promising novel therapeutic candidate for osteoporosis.