Pathogenic microorganisms pose significant threat to global health. In particular, conventional antibiotic treatments run the risk of exacerbating bacterial resistance. Antimicrobial sonodynamic therapy (aSDT), which combines sonosensitizers and low-intensity ultrasound (US), has opened up new avenues for treating drug-resistant bacteria. The appeal of this therapy lies in its ability to focus US energy toward the deep-seated site of bacterial infection sites, which it locally activates sonosensitizers and generates cytotoxic reactive oxygen species (ROS), and ultimately induces bacterial death. In the last decade, aSDT has been rapidly developed due to its good penetrative, biocompatibility and targeting properties. This paper highlights the recent aSDT advances in antimicrobial applications. We review aSDT mechanisms and sonosensitizers types, and propose relevant strategies to improve aSDT effects in terms of improving hypoxia and combining applications with other therapies. Furthermore, we summarize the potential obstacles and opportunities for the advancement of aSDT, and provide a deeper understanding of sonodynamic therapy (SDT) for antimicrobial applications, thereby promoting further innovation and clinical application.

Respiratory diseases pose a significant global health challenge due to their high morbidity and mortality rates. Traditional Chinese medicine (TCM), particularly the herb Epimedium, has demonstrated therapeutic potential in managing these diseases. This review systematically evaluates evidence from both in vitro and in vivo studies to assess the effects of Epimedium and its bioactive compounds, including icariin (ICA), icariside I (ICS I), icariside II (ICS II), icaritin (ICT), and others, on respiratory diseases. The synthesis of current literature reveals that these compounds exhibit anti-inflammatory, antioxidant, and immunomodulatory activities, as well as other effects crucial for the management of respiratory diseases. Further research is needed to fully understand and harness the therapeutic potential of Epimedium and its bioactive compounds in respiratory diseases.

Transforming growth factor beta (TGF-β) receptor 3 (TGFBR3), or betaglycan, is a transmembrane proteoglycan that serves as a coreceptor for TGF-β ligands, modulating TGF-β signaling in a context-dependent manner. Its extracellular domain can undergo proteolytic cleavage, yielding a 120 kDa soluble isoform (soluble transforming growth factor beta receptor 3 (sTGFBR3)) that antagonizes TGF-β signaling by sequestering ligands. Through this dual role, TGFBR3 exerts profound influence over various physiological and pathological processes, including cell survival, stemness, differentiation, cancer metastasis, chemoresistance, and fibrosis, underscoring its significance as both a biomarker and therapeutic target. Despite its significance, regulatory mechanisms, particularly tissue-specific expression, cross-talk with other pathways and post-translational modifications, remain poorly defined. A current thorough review of the prognostic and therapeutic implications of TGFBR3 is still lacking. In this review, we systematically examine the structural features of TGFBR3, and their functional relevance, providing an in-depth analysis of its dysregulation and molecular roles in diseases such as cancer, nervous system disorders, cardiovascular diseases (CVDs), diabetes and infectious diseases. Current experimental approaches are critically evaluated, and gaps in existing literature are highlighted to identify priorities for future research. By synthesizing emerging insights, this review aims to inform the development of TGFBR3-targeted therapies and support the design of innovative clinical and preclinical strategies.

YT521-B homology domain-containing family paralogs (YTHDFs), as RNA epigenetic modification effector proteins, fully or partially participate in N⁶-methyladenosine (m⁶A), N¹-methyladenosine (m¹A), and 5-methylcytosine (m⁵C) modifications, which play critical roles in tumor biology and contribute to obtaining and maintaining cancer hallmarks relying on their characteristic protein structures. Accumulating evidence has underscored the involvement of YTHDFs in manipulating RNA stability, translation, and RNA metabolism, thereby influencing tumor initiation, progression, and anti-tumor treatment efficacy through independent RNA epigenetic modification pathways. This review aims to illustrate the essential regulatory mechanisms and pathological consequences of YTHDFs in tumorigenesis and therapeutic resistance. Additionally, we highlight the potential of targeting YTHDFs for cancer therapy, offering promising avenues for the elimination of tumor cells and the amelioration of tumor treatment efficacy.

Depression, an emotional disorder characterized by persistent low mood and loss of pleasure, can be alleviated by mainstream clinical drugs (such as selective serotonin reuptake inhibitors). However, issues such as delayed efficacy, significant individual differences, and adverse reactions remain. Compared to traditional single-target drugs, natural products have shown unique potential in depression intervention due to their synergistic multi-component effects and multi-target, multi-pathway regulation. As the most abundant glial cells in the central nervous system, astrocytes are deeply involved in the pathology of depression and have become important targets for the antidepressant effects of natural products. Although existing studies have revealed the regulatory effects of natural products on the function of astrocytes, there is still a lack of systematic categorization and mechanism integration. This review comprehensively summarized the molecular mechanisms by which natural products regulated astrocyte function through a systematic literature review, objectively analyzes key bottlenecks in current translational research, and aims to provide a theoretical basis and technical pathway for optimizing depression treatment paradigms and promoting the clinical translation of natural product research.

Cytochromes P450 (CYP)3A4 as the richest P450 enzyme is responsible for the metabolism of about 50% drugs. However, severe drug-drug interactions (DDIs) frequently occur when CYP3A4 is strongly inhibited by xenobiotics, which is one of the major reasons for the withdrawal of already marketed drugs. Compared to reversible inhibition, time-dependent inactivation (TDI), including mechanism-based inactivation (MBI), quasi-irreversible inactivation, and affinity-labeling inactivation, results from chemical modification of the host enzyme by electrophilic inactivators or electrophilic intermediates and is more likely to result in adverse clinical consequences. Increasing phytomedicines have been identified as time-dependent inactivators of CYP3A4 with the rapid growth of global consumption of natural products. According to vast experimental and theoretical studies, functional groups with chemical reactivity existing in phytomedicines are mainly involved in TDI of CYP3A4. For better understanding of the structure-activity relationship between phytomedicine and CYP3A4, we systematically summarize chemical mechanisms of TDI, including furan, thiophene, acetylenes, and methylenedioxyphenyl (MDP)-containing phytomedicine-induced MBI, MDP, alkylamine, and hydrazine-containing phytomedicine-induced quasi-irreversible inactivation, and iminium-containing phytomedicine-induced affinity-labeling inactivation, and comprehensively classify known natural CYP3A4 time-dependent inactivators, including polyphenols, alkaloids, terpenoids, and coumarins, which will offer the guidance and evidence for rational drug combinations and avoid TDI-based DDIs in clinics.

The pharmacodynamic material basis constitutes the central element of traditional Chinese medicine (TCM) in disease treatment. By summarizing the active compounds' characteristics, bioavailability, pharmacological effects, and molecular mechanisms, we can explain the complex interactions between TCMs and diseases. Previous studies have demonstrated that monoterpene glycosides and tannins are related to the pharmacological activity of Radix Paeoniae Alba (RPA). However, research on RPA has primarily focused on monoterpene glycosides, and the functional role of tannins in RPA has received little attention. Observations from animal studies indicate that monoterpene glycosides and tannins exhibit poor bioavailability. Carboxylesterase, produced by gut microbiota, is crucial for metabolizing these compounds in the intestine. Monoterpene glycosides and their gut metabolites can be absorbed into the bloodstream, exerting various pharmacological effects, including anti-inflammatory, immunomodulatory, and neuromodulator activities. In contrast, tannins consist of highly hydrophobic polyphenols that form insoluble protein-tannin complexes. Due to their inability to cross the intestinal barrier, tannins primarily exert localized pharmacological effects within the digestive system. This study systematically reviews the pharmacological activities and mechanisms of monoterpene glycosides and tannins in RPA, while establishing their therapeutic contributions to the herb's pharmacological effects.

Fatty acids (FAs) play a vital role in various physiological processes in the human body, and the analysis of FA isomers is of utmost importance in the research of various diseases and FA metabolic pathways. Over the last few years, the use of chemical derivatization methods to alter the composition of FAs has been found to be highly effective in overcoming the drawback of poor sensitivity in mass spectrometry (MS) analysis due to the poor ionizability of functional groups in FA molecules. Furthermore, certain chemical derivatization methods have enabled detection of C=C and differentiation of cis-trans isomers. As a result, the development and use of chemical derivatization-based MS to analyze FAs has gained significant interest. This review highlights technological innovations in the development of MS detection methods for unsaturated FAs (UFAs) based on chemical derivatization. Special emphasis is placed on two significant strategies: carboxyl group derivatization and C=C derivatization. In addition, it focuses on applications in various fields, discusses persistent challenges, and explores potential future directions. This review aims to provide a perspective on the advanced design and development of MS detection methods of FAs based on chemical derivatization.

This study presents the first development and validation of a static multiple light scattering (SMLS)-based method for real-time, non-invasive assessment of nanoparticle colloidal stability. Nanoparticles, leveraging their nanoscale advantages (e.g., targeted delivery, enhanced drug solubility, and controlled release), hold transformative potential in treating diseases. However, their clinical success hinges on colloidal stability, which dictates in vivo behavior, safety, and regulatory compliance. While dynamic light scattering (DLS) remains widely used, its inability to monitor dynamic transformations and reliance on sample dilution limit its accuracy. Here, we pioneer the application of SMLS to systematically evaluate colloidal stability across standardized particles and commercial nanoparticle formulations (liposomes, nanoparticles, micelles, and nanoemulsions). Results demonstrate that SMLS captures destabilization kinetics (aggregation, sedimentation, and creaming) in real-time without dilution, even at high concentrations, while DLS fails to distinguish polydisperse systems due to time-point sampling. The Turbiscan stability index (TSI) quantifies instability mechanisms, correlating with particle size distribution broadening. This first comprehensive validation of SMLS for nanoparticles reveals its superiority in reflecting native-state behavior, exemplified by minimal or the variations in the average transmission (ΔT) or backscattering intensity (ΔBS) fluctuations and low TSI values in four commercial formulations. By addressing a critical technological gap, this study establishes SMLS as an indispensable tool for optimizing nanoparticle design, ensuring compliance with U.S. Food and Drug Administration (FDA) in-use stability guidelines, and accelerating clinical translation.

Drug-induced liver injury (DILI) represents a major adverse drug reaction with significant clinical implications. The diversity of causative drug agents, incomplete understanding of pathogenic mechanisms, and absence of specific diagnostic biomarkers pose substantial challenges for DILI diagnosis and clinical management. This study aimed to characterize the metabolic heterogeneity across different types of DILI and identify high-specificity metabolic biomarkers for DILI classification. A multicenter targeted metabolomics study was conducted on 516 serum samples collected from 200 patients with DILI and 221 healthy controls. We characterized the metabolic dynamics throughout DILI progression, with significant disruptions presented in glutathione, fatty acid, and carnitine metabolism. By characterizing and comparing the metabolic profiles among antibiotics-, herbs-, non-steroidal anti-inflammatory drugs-, and statins-DILI patients, we constructed four drug-specific metabolic networks of DILI based on the metabolic coordination between metabolites. Notably, the elevated long-chain acylcarnitines (such as C18:1 Car and C16:2 Car) distinctively underlie herb-DILI's pathological progression. In monocrotaline-induced liver injury mouse models, hepatic carnitine acyltransferase II (Cpt2) mRNA expression was suppressed. Further, two-sample Mendelian randomization supported a causal relationship between C18:1 Car and total bilirubin levels. Finally, we developed a 10-metabolite classifier to distinguish between different DILI subtypes using machine learning algorithms, yielding accuracies of 0.915 and 0.904 on two independent test sets. These findings enhance the understanding of the metabolic heterogeneity in DILI and provide evidence supporting the use of responsive metabolic traits for the clinical diagnosis and treatment of DILI.

Ferroptosis, a regulated form of cell death characterized by lipid peroxidation (LPO), has emerged as a promising target in cancer therapy. In this study, we detected elevated levels of glutathione (GSH) peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) in human gastric adenocarcinoma tissues, indicating a suppression of ferroptosis in gastric cancer (GC). Apatinib (Apa), a vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitor, was found to induce ferroptosis through the classical SLC7A11/GSH/GPX4 pathway. However, long-term administration of high-dose Apa is associated with adverse side effects and the risk of drug resistance. To address these limitations, we developed a novel drug delivery system (DDS) using hyaluronic acid (HA)-modified poly (lactic-co-glycolic acid) (PLGA) nanoparticles for targeted co-delivery of Apa and chitosan-coated silver nanoparticles (Chi-Ag). Our results demonstrated that the combination of Apa and Chi-Ag exerted a synergistic cytotoxic effect against GC cells. This co-delivery system evidently increased oxidative stress at the tumor site and effectively promoted ferroptosis via modulation of the phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) signaling pathway. In summary, we present a targeted nanoplatform that enhances the antitumor efficacy of Apa at lower dosages by leveraging ferroptosis induction. This strategy holds promise for improving the clinical outcomes in patients with GC.

Scutellariae Radix (SR) is widely used in Chinese medicine for influenza treatment; however, the mechanisms underlying its effect remain unknown. Here, we report, for the first time, that the therapeutic effects of SR on influenza involve regulation of antiviral interferons (IFNs), type I and type III IFNs (IFN-Is and IFN-IIIs, respectively), particularly through the modulation of IFN-I production and its downstream effects in a cell type-specific manner. SR treatment resulted in symptomatic improvement in A/Puerto Rico/8/34 (H1N1) virus (PR8)-infected mice. It exhibited direct antiviral activity in the early stages of virus infection in A/WSN/33 (H1N1) (WSN)-infected Madin-Darby canine kidney (MDCK) cells. Next, we investigated the effects of SR on the upstream antiviral IFN pathways and downstream effects in human lung adenocarcinoma (A549) cells, human monocytic leukemia (THP-1) cells, and neutrophils (Neu). SR exhibited dual regulatory roles, enhancing the production and activity of antiviral IFNs via the nuclear factor-kappaB (NF-κB)/IFN regulatory factor 3 (IRF3) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathways. It also reduced IFN-I-induced neutrophil inflammation by inhibiting reactive oxygen species (ROS) and neutrophil extracellular trap (NET) production, and alleviated inflammation in A549 and THP-1 cells via NF-κB/cFOS or mitogen-activated protein kinase (MAPK)/c-Jun signaling. Subsequently, the importance of IFN-I/IFN-III was verified using IFN alpha receptor 1 (Ifnar1)^−/− and IFN lambda receptor 1 (Ifnlr1)^−/− mice. The absence of IFNAR or IFNLR significantly diminished the therapeutic effect of SR against influenza, highlighting its dependence on the IFN-I/IFN-III systems. Finally, a delayed drug administration experiment in PR8-infected mice revealed that the therapeutic effect of SR heavily relies on early induction of IFN. Overall, our findings offer valuable insights for the clinical utilization of SR, as well as for further exploration of antiviral treatments.

MicroRNAs (miRNAs) are small RNA molecules with significant therapeutic potential for treating various diseases, underscoring the need for effective methods to screen drugs targeting disease-associated miRNAs. In this study, we introduce miRPVS, a rapid virtual screening approach designed to identify small molecule drugs targeting miRNA-protein complex. miRPVS identifies binding pockets on the surface of these complexes, expanding the scope of potential small molecule targets. It employs an equivariant graph neural network model to extract three-dimensional (3D) structure features of small molecules, enabling accurate prediction of docking scores. Using miRPVS, four complexes involved in pri-miRNA cleaving, pre-miRNA transport, and mRNA depress were identified as promising targets. For each target, hit compounds were screened from the ZINC20 database, which contains approximately 600 million drug-like small molecules. MiRPVS predicted the docking score for these compounds, with Pearson correlation coefficients between predicted and experimentally docked scores comparable to those obtained through twice docking. Notably, the average deviation was only 0.67% across the four complexes. Remarkably, the entire screening process for all four complexes was completed in 14 h using just four V100 GPUs. Additionally, we integrated AlphaFold3-predicted structures into the miRPVS workflow, enabling virtual screening of small molecules against miRNA-protein complexes without experimentally determined structures. miRPVS demonstrated performance comparable to traditional docking methods while significantly reducing computational time and resource requirements. This innovative approach holds great promise for accelerating the discovery of small molecule drugs targeting miRNA-regulated pathways, addressing a critical gap in miRNA therapeutics.

Immune checkpoint inhibitors (ICIs) have significantly advanced and revolutionized cancer treatment over the past decade; however, their clinical benefits have been limited to a subset of cancer patients. While ICI-based combinations have emerged as promising strategies, they risk broader toxicities and significant cost burdens. This highlights the critical need for the development of inhibitors that target multiple immune checkpoints. In this study, we developed a peptide that emulates the conserved sequence of the Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) C-terminal Src homology 2 (C-SH2) domain, which is capable of binding to immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in the cytoplasmic tails of multiple immune inhibitory receptors. By utilizing this peptide as the protein of interest (POI) ligand and coupling it with the von Hippel‒Lindau (VHL) ligand via a peptide linker, a proteolytic targeting chimera (PROTAC) named PROTAC of ITIM-targeting inhibitory peptide (PITIP) was constructed. PITIP effectively induced the degradation of multiple immune inhibitory receptors in a proteasome-dependent manner, thereby attenuating immunosuppressive signaling within T cells, natural killer (NK) cells, and macrophages. In vivo investigations demonstrated that PITIP elicited a robust antitumor immune response in xenograft and allograft tumor model mice, including those resistant to αPD-1 therapy. Moreover, the encapsulation of PITIP within liposomes conjugated with anti-CD45 antibodies enhanced the targeting of immune cells by PITIP, thereby improving the therapeutic efficacy of the antibodies. This study reports, for the first time, a universal strategy targeting the common structural motifs of immunosuppressive receptors, which facilitates broader and more extensive immune activation through the ubiquitination-mediated degradation of multiple immune checkpoints.

Uridine diphosphate (UDP)-glucuronosyltransferases (UGTs) are a family of enzymes with highly similar amino acid sequences, making it challenging to distinguish between their roles. Developing selective probes and inhibitors is essential for understanding the unique functions of each isoform. In this study, we synthesized four novel naphthalimide-based fluorescent probes bearing nitrogen-containing substituents at the 4-position and identified N-butyl-4-methylpiperazine-1,8-naphthalimide (BAD3) as a highly selective and sensitive substrate for UGT1A4. Using BAD3, we established an inhibitor screening platform and identified ursolic acid (T7) as a promising lead compound from a natural product library. Structure-activity relationship (SAR) studies revealed that esterification at the 3-hydroxyl group significantly enhanced inhibitory activity, yielding two potent inhibitors, T25 and T26, while modifications at the 28-carboxyl group reduced activity. Further characterization confirmed T25 (inhibition constant (K_i) = 0.64 μM) and T26 (K_i = 0.61 μM) as selective and competitive UGT1A4 inhibitors. Molecular docking revealed that the 28-carboxyl group plays a crucial role by forming a salt bridge with Arg258 in the UGT1A4 active site. In vivo studies demonstrated that T25 significantly altered the pharmacokinetic profile of BAD3, confirming its inhibitory effect on UGT1A4 in animals. Together, BAD3 and the selective inhibitors T25/T26 serve as valuable molecular tools for studying the physiological and pharmacological roles of UGT1A4.

Osteoporosis, characterized by excessive bone resorption driven by heightened osteoclast activity, remains a major health concern with molecular mechanisms that are not fully understood. This study explores the role of mammalian Sterile 20-like kinase 4 (MST4), a member of the Sterile 20 (Ste20) kinase family, in osteoclast differentiation and function. Analysis of blood samples from osteoporosis patients revealed a significant increase in MST4 expression compared to healthy controls, with a negative correlation to bone mineral density (BMD). In vitro experiments using stem cell-derived osteoclast models showed that MST4 knockdown reduced osteoclast differentiation and bone resorption activity, whereas MST4 overexpression enhanced these processes. In vivo studies with ovariectomized (OVX) mouse models further corroborated these findings. Mechanistically, MST4 was found to promote tumor necrosis factor receptor-associated factor 6 (TRAF6) autoubiquitination through phosphorylation, a critical event for osteoclast activation. Collectively, these results identify MST4 as a key regulator of osteoclast-mediated bone resorption in osteoporosis, suggesting that targeting the MST4–TRAF6 signaling axis may offer a novel therapeutic strategy to prevent bone loss.

Nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of oxidative stress and inflammasome, plays a critical role in modulating pyroptosis. In this study, we identified NU6300 as a novel small-molecule activator of Nrf2 that restores mitochondrial function, alleviates oxidative stress, and suppresses inflammasome activation and pyroptosis. Mechanistically, NU6300 covalently modified Kelch-like ECH-associated protein 1 (Keap1) at cysteine-489, disrupting the Keap1-Nrf2 interaction, thereby promoting Nrf2 nuclear translocation and transcription of antioxidant genes. Notably, NU6300 inhibits NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation and gasdermin D (GSDMD)-mediated pyroptosis through redox-dependent mechanisms, representing the first evidence that covalent modification of Keap1 at cysteine-489 by NU6300 bridges Nrf2 activation and inflammasome suppression. In vivo, NU6300 exhibits potent antioxidant and anti-inflammatory protection against acetaminophen (APAP)-induced acute liver injury in mice. Collectively, these findings demonstrate that NU6300 is a novel Nrf2 activator and offers a promising therapeutic strategy for pyroptosis-driven inflammatory diseases.

An abnormal inflammatory response is one of the main pathogenic mechanisms of abdominal aortic aneurysms (AAAs), and tranilast, an antiallergic drug, has anti-inflammatory properties. The effect and mechanism of action of tranilast on AAAs remain incompletely defined. To evaluate the preventive and therapeutic effects on experimental AAAs induced by intra-aortic elastase infusion in mice, tranilast was administered either before or after elastase infusion and continued until the experimental endpoint. Bioinformatics analysis and corresponding validation experiments were used to explore the possible mechanisms by which tranilast affects AAA progression. Compared with vehicle treatment, both tranilast pre-treatment and post-treatment therapies markedly inhibited aneurysmal aortic expansion. Treatment with tranilast attenuated the degradation of aneurysmal medial elastin and the depletion of smooth muscle cells. Aortic leukocyte accumulation was significantly lower in aneurysmal aortas from tranilast-treated mice than in those from vehicle-treated mice. Mural abnormal angiogenesis and aortic matrix metalloproteinase (MMP) 2 and 9 expression levels were also reduced after tranilast treatment. Bioinformatics analysis revealed that nucleotide-binding oligomerization domain-like receptor family protein 3 (NLRP3) may be a hub target through which tranilast affects AAAs. NLRP3 expression levels were lower in the aneurysmal aortas of tranilast-treated mice than in those of vehicle-treated elastase-infused mice. Both Nlrp3 deficiency and treatment with the NLRP3 inhibitor MCC950 attenuated experimental AAAs. However, cotreatment with tranilast had no additive or synergistic influence on AAA suppression. Additionally, tranilast treatment reduced caspase 1 cleavage by the NLRP3 inflammasome and consequently interleukin-1β secretion in peritoneal macrophages in vitro. These findings indicate that the protective effect of tranilast on AAA may be partially mediated by the inhibition of the NLRP3 inflammasome pathway and may represent a potential drug for the treatment of AAA in the clinic.

Osteoporosis, the most prevalent skeletal disorder, is primarily driven by aberrantly increased osteoclast formation and/or activity. Targeting hyperactive osteoclasts remains the cornerstone of current therapeutic strategies. Crebanine (Cre), a natural isoquinoline-derived alkaloid with diverse pharmacological activities, has not yet been explored for osteoporosis treatment. This study aimed to evaluate the therapeutic potential of Cre against ovariectomy (OVX)-induced osteoporosis and elucidate its underlying mechanisms. Cre dose-dependently inhibited in vitro osteoclast differentiation, actin ring formation, and bone resorption by downregulating nuclear factor of activated T cells 1 (NFATc1) and key osteoclast-related genes. Simultaneously, Cre enhanced osteoblast differentiation and mineralization, upregulated osteoblast marker genes, and restored hydrogen peroxide-impaired alkaline phosphatase (ALP) activity impaired by hydrogen peroxide, indicating dual regulation of bone remodeling. Mechanistically, Cre activated sirtuin 1 (Sirt1), promoting p65 deacetylation, inactivated IκB kinase (IKK), and stabilized IκBα, thus inhibiting nuclear factor-kappaB (NF-κB) signaling. Additionally, Cre reduced reactive oxygen species (ROS) by upregulating antioxidant enzymes (heme oxygenase-1 (HO-1), catalase) and suppressing nicotinamide adenine dinucleotide (NAD) phosphate (NADPH) oxidases (NOX1/4). Furthermore, Cre specifically bound to the predicted site of receptor activator of NF-κB (RANK), blocking RANK ligand (RANKL)-RANK interaction and disrupting downstream protein kinase B (Akt) and mitogen-activated protein kinase (MAPK) signaling pathways. In the OVX mouse model, Cre significantly attenuated bone loss and osteoclastogenesis. Crucially, Cre showed no toxicity in liver or kidney function tests. Collectively, these findings demonstrate that Cre exerts dual therapeutic effects, inhibiting osteoclastogenesis via Sirt1-mediated NF-κB/ROS suppression and promoting osteoblast activity, providing a promising therapeutic strategy for osteoporosis.