Discovery of a novel hybrid coumarin-hydroxamate conjugate targeting the HDAC1-Sp1-FOSL2 signaling axis for breast cancer therapy.

BACKGROUND: Breast cancer is one of the most lethal cancers in women. Despite significant advances in the diagnosis and treatment of breast cancer, many patients still succumb to this disease, and thus, novel effective treatments are urgently needed. Natural product coumarin has been broadly investigated since it reveals various biological properties in the medicinal field. Accumulating evidence indicates that histone deacetylase inhibitors (HDACIs) are promising novel anti-breast cancer agents. However, most current HDACIs exhibit only moderate effects against solid tumors and are associated with severe side effects. Thus, to develop more effective HDACIs for breast cancer therapy, hydroxamate of HDACIs was linked to coumarin core, and coumarin-hydroxamate hybrids were designed and synthesized. METHODS: A substituted coumarin moiety was incorporated into the classic hydroxamate HDACIs by the pharmacophore fusion strategy. ZN444B was identified by using the HDACI screening kit and cell viability assay. Molecular docking was performed to explore the binding mode of ZN444B with HDAC1. Western blot, immunofluorescent staining, cell viability, colony formation and cell migration and flow cytometry assays were used to analyze the anti-breast cancer effects of ZN444B in vitro. Orthotopic studies in mouse models were applied for preclinical evaluation of efficacy and toxicity in vivo. Proteomic analysis, dual-luciferase reporter assay, chromatin immunoprecipitation, co-immunoprecipitation, immunofluorescent staining assays along with immunohistochemical (IHC) analysis were used to elucidate the molecular basis of the actions of ZN444B. RESULTS: We synthesized and identified a novel coumarin-hydroxamate conjugate, ZN444B which possesses promising anti-breast cancer activity both in vitro and in vivo. A molecular docking model showed that ZN444B binds to HDAC1 with high affinity. Further mechanistic studies revealed that ZN444B specifically decreases FOS-like antigen 2 (FOSL2) mRNA levels by inhibiting the deacetylase activity of HDAC1 on Sp1 at K703 and abrogates the binding ability of Sp1 to the FOSL2 promoter. Furthermore, FOSL2 expression positively correlates with breast cancer progression and metastasis. Silencing FOSL2 expression decreases the sensitivity of breast cancer cells to ZN444B treatment. In addition, ZN444B shows no systemic toxicity in mice. CONCLUSIONS: Our findings highlight the potential of FOSL2 as a new biomarker and therapeutic target for breast cancer and that targeting the HDAC1-Sp1-FOSL2 signaling axis with ZN444B may be a promising therapeutic strategy for breast cancer.

Grifolin Induces Cell Death of Human Lung Cancer A549 Cell Line via Inhibiting KRAS-Mediated Multiple Signaling Pathways.

In the current work, grifolin was obtained from the twigs and leaves of Daphne genkwa for the first time and displayed significant growth inhibition against human lung carcinoma A549 cells. Subsequent in vitro antitumor evaluation revealed that grifolin could induce remarkable cell apoptosis and G0/G1 phase arrest, as well as block cell migration and invasion. In addition, grifolin also disrupted cellular energy metabolism by inducing reactive oxygen species, reducing adenosine triphosphate and mitochondrial membrane potential, and damaging DNA synthesis. Further RNA-seq analysis demonstrated that treatment of grifolin on A549 cells led to gene enrichment in MAPK, PI3K/Akt and NF-κB signaling pathways, all of which were inhibited by grifolin according to immunoblotting experiments. Further mechanistical studies disclosed that the expression of a key upstream protein KRAS was also blocked, and the cell death triggered by grifolin could be rescued by a RAS activator ML-099. Moreover, pretreatment of ML-099 on A549 cells could reverse the grifolin-induced downregulation of key proteins in the three aforementioned pathways. These findings indicate that grifolin could induce cell death in A549 cell line by inhibiting KRAS-mediated multiple signaling pathways.

Comprehensive Analysis of the Function and Prognostic Value of TAS2Rs Family-Related Genes in Colon Cancer.

In the realm of colon carcinoma, significant genetic and epigenetic diversity is observed, underscoring the necessity for tailored prognostic features that can guide personalized therapeutic strategies. In this study, we explored the association between the type 2 bitter taste receptor (TAS2Rs) family-related genes and colon cancer using RNA-sequencing and clinical datasets from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). Our preliminary analysis identified seven TAS2Rs genes associated with survival using univariate Cox regression analysis, all of which were observed to be overexpressed in colon cancer. Subsequently, based on these seven TAS2Rs prognostic genes, two colon cancer molecular subtypes (Cluster A and Cluster B) were defined. These subtypes exhibited distinct prognostic and immune characteristics, with Cluster A characterized by low immune cell infiltration and less favorable outcomes, while Cluster B was associated with high immune cell infiltration and better prognosis. Finally, we developed a robust scoring system using a gradient boosting machine (GBM) approach, integrated with the gene-pairing method, to predict the prognosis of colon cancer patients. This machine learning model could improve our predictive accuracy for colon cancer outcomes, underscoring its value in the precision oncology framework.

Inonotsutriol E from Inonotus obliquus exhibits promising anti breast cancer activity via regulating the JAK2/STAT3 signaling pathway.

The aim of the present study was to investigate the small molecule anticancer agents in the medicinal fungus Inonotus obliquus and further characterize their possible molecular mechanisms. Chemical fractionation of the ethanol extract of this fungus yielded a panel of lanostane triterpenoids (1-13) and their structures were characterized on the basis of spectroscopic methods. Subsequent preliminary biological screening on these triterpenoids revealed significant cytotoxicity against various tumor cell lines, and inonotsutriol E (ITE, 1) showed the best activity. Of note, ITE displayed stronger inhibitory effect on breast cancer (BC) than other tumor cell lines. Functional assays revealed that ITE significantly inhibited the growth and migration of BC cells and exerted promising antitumor activity in patient-derived organoids (PDO). Further mechanistic study demonstrated that the anti-BC activity of ITE was achieved via inhibiting JAK2/STAT3 signal axis. Taken together, the current work has demonstrated the therapeutic material basis of I. obliquus and provided further evidence for the traditional application of this medicinal species in cancer prevention and treatment.

Meroterpenoids from Daphne genkwa shows promising in vitro antitumor activity via inhibiting PI3K/Akt/mTOR signaling pathway in A549 cells.

Phytochemical investigation into the leaves and branches of Daphne genkwa afforded 25 meroterpenoids (1-16) including nine pairs of enantiomers (1a/1b-8a/8b and 12a/12b), among which 20 compounds have been reported in the present work for the first time. The structures with absolute configurations of the new molecules (excluding 10-13) were established via comprehensive spectroscopic analyses especially electronic circular dichroism (ECD) and Mosher's methods. A preliminary in vitro cell viability assay revealed remarkable cytotoxicities of selective compounds against A549 (lung), Hela (cervical), MDA-MB231 (breast) and MCF-7 (breast) cancer cells, and compound 8a showed the best inhibitory activity with IC50 values in the range of 3.12-4.67 µM toward the four cell lines. Subsequent in vitro antitumor evaluation of 8a disclosed that it could inhibit the proliferation and metastasis, as well as induce significant apoptosis and cycle arrest, of A549 cells. Further mechanistic investigations revealed that 8a could exert its antitumor activity via inhibiting the PI3K/Akt/mTOR signaling pathway.

Silencing Ribosomal Protein L22 Promotes Proliferation and Migration, and Inhibits Apoptosis of Gastric Cancer Cells by Regulating the Murine Double Minute 2-Protein 53 (MDM2-p53) Signaling Pathway.

BACKGROUND The aim of this study was to investigate the effect of ribosomal protein L22 (RPL22) on gastric cancer (GC) cell proliferation, migration, and apoptosis, and its correlation with the murine double minute 2-protein 53 (MDM2-p53) signaling pathway. MATERIAL AND METHODS The RPL22 expression in GC tissues and cells was detected by quantitative reverse transcription-polymerase chain reaction and western blotting. RPL22 was overexpressed in the MKN-45 cells by the transfection of a vector, pcDNA3.1 (pcDNA)-RPL22, whereas it was silenced in the MGC-803 cells by the transfection of short interfering (si) RNA (si-RPL22). Flow cytometric analysis, cell viability assays, wound healing assays, and transwell assays were utilized to explore the influences of RPL22 on the apoptosis, proliferation, migration, and invasion. Nutlin-3 (an MDM2-p53 inhibitor) was used to inhibit MDM2-p53 signaling. RESULTS The RPL22 expression was downregulated in GC tissues and cells. It was significantly lower in the advanced GC tissues than in the early GC tissues, and was significantly lower in the lymphatic metastatic tissues than in the non-lymphatic metastatic tissues. The transfection of si-RPL22 accelerated the ability of GC cells to proliferate and metastasize, whereas apoptosis was dampened. The transfection of pcDNA-RPL22 exerted the opposite effect on the GC cells; MDM2 expression was upregulated in RPL22-silenced GC cells, while the expression of p53 was downregulated. In vitro, treatment with nutlin-3 reversed the promoting effects of si-RPL22 on GC progression. CONCLUSIONS In vitro, the silencing of RPL22 aggravates GC by regulating the MDM2-p53 signaling pathway.

Development of hydroxamate-based histone deacetylase inhibitors containing 1,2,4-oxadiazole moiety core with antitumor activities.

Histone deacetylases (HDACs) has proved to be promising target for the development of antitumor drugs. In this study, we reported the design and synthesis of a class of novel hydroxamate-based bis-substituted aromatic amide HDAC inhibitors with 1,2,4-oxadiazole core. Most newly synthesized compounds displayed excellent HDAC1 inhibitory effects and significant anti-proliferative activities. Among them, compounds 11a and 11c increased acetylation of histone H3 and H4 in dose-dependent manner. Furthermore, 11a and 11c remarkably induced apoptosis in HepG2 cancer cells. Finally, the high potency of compound 11a was rationalized by molecular docking studies.

Design, Synthesis and Biological Evaluation of Novel Coumarin-Based Hydroxamate Derivatives as Histone Deacetylase (Hdac) Inhibitors with Antitumor Activities.

A series of novel coumarin-based hydroxamate derivatives were designed and synthesized as histone deacetylase inhibitors (HDACis). Selective compounds showed a potent HDAC inhibition with nM IC50 values, with the best compound (10e) being nearly 90 times more active than vorinostat (SAHA) against HDAC1. Compounds 10e and 11d also increased the levels of acetylated histone H3 and H4, which is consistent with their strong HDAC inhibition. In addition, 10e and 11d displayed a higher potency toward human A549 and Hela cancer cell lines compared with SAHA. Moreover, 10e and 11d significantly arrested A549 cells at the G2/M phase and enhanced apoptosis. Molecular docking studies revealed the possible mode of interaction of compounds 10e and 12a with HDAC1. Our findings suggest that these novel coumarin-based HDAC inhibitors provide a promising scaffold for the development of new potential cancer chemotherapies.

MicroRNA regulation of Toll-like receptor signaling pathways in teleost fish.

The innate immune system is the first line defense mechanism that recognizes, responds to, controls or eliminates invading pathogens. Toll-like receptors (TLRs) are a critical family of pattern recognition receptors (PRRs) tightly regulated by complex mechanisms involving many molecules to ensure a beneficial outcome in response to foreign invaders. MicroRNAs (miRNAs), a transcriptional and posttranscriptional regulator family in a wide range of biological processes, have been identified as new molecules related to the regulation of TLR-signaling pathways in immune responses. To date, at least 22 TLR types have been identified in more than a dozen different fish species. However, the functions and underlying mechanisms of miRNAs in the regulation of inflammatory responses related to the TLR-signaling pathway in fish is lacking. In this review, we summarize the regulation of miRNA expression profiles in the presence of TLR ligands or pathogen infections in teleost fish. We focus on the effects of miRNAs in regulating TLR-signaling pathways by targeting multiple molecules, including TLRs themselves, TLR-associated signaling proteins, and TLR-induced cytokines. An understanding of the relationship between the TLR-signaling pathways and miRNAs may provide new insights for drug intervention to manipulate immune responses in fish.

Site-specific acetylation of the proteasome activator REGγ directs its heptameric structure and functions.

The proteasome activator REGγ has been reported to promote degradation of steroid receptor coactivator-3 and cyclin-dependent kinase inhibitors p21, p16, and p19 in a ubiquitin- and ATP-independent manner. A recent comparative analysis of REGγ expression in mouse and human tissues reveals a unique pattern of REGγ in specific cell types, suggesting undisclosed functions and biological importance of this molecule. Despite the emerging progress made in REGγ-related studies, how REGγ function is regulated remains to be explored. In this study, we report for the first time that REGγ can be acetylated mostly on its lysine 195 (Lys-195) residue by CREB binding protein (CBP), which can be reversed by sirtuin 1 (SIRT1) in mammalian cells. Site-directed mutagenesis abrogated acetylation at Lys-195 and significantly attenuated the capability of REGγ to degrade its target substrates, p21 and hepatitis C virus core protein. Mechanistically, acetylation at Lys-195 is important for the interactions between REGγ monomers and ultimately influences REGγ heptamerization. Biological analysis of cells containing REGγ-WT or REGγ-K195R mutant indicates an impact of acetylation on REGγ-mediated regulation of cell proliferation and cell cycle progression. These findings reveal a previously unknown mechanism in the regulation of REGγ assembly and activity, suggesting a potential venue for the intervention of the ubiquitin-independent REGγ proteasome activity.

Rare flavanone-diarylheptanoid hybrids from Typha angustifolia shows anti breast cancer activity via activating TGF-ß1/Smad signaling pathway.

Four new flavanone-diarylheptanoid hetero dimers, typhatifolins A-D (1-4), were separated from the pollen of a widely distributed medicinal plant Typha angustifolia. Structures of these rare hybrids were elucidated by detailed interpretation of spectroscopic data, and their absolute configurations were determined on the basis of Mosher's method and ECD analyses. All the four compounds showed moderate to significant cytotoxicities against a panel of tumor cell lines with IC50 values ranging from 0.67 to 12.48 µM. Further in vitro antitumor evaluation for typhatifolin B (TTB, 2) on two breast cancer cells (4T1 and MDA-MB231) revealed that it could remarkably induce cell apoptosis and G0/G1 cycle arrest, as well as block cell migration and invasion. Mechanistically, TTB could exert its antitumor effect via activating the TGF-ß1 (transforming growth factor beta 1) signaling pathway as evidenced by RNA-seq analysis and immunoblotting experiments, which was further corroborated by treating cancer cells with a TGF-ß signaling inhibitor. Lastly, the in vivo anti breast cancer activity was demonstrated by applying the mixture of typhatifolins A-D to a preclinical animal model.

First total synthesis, antitumor evaluation and target identification of mornaphthoate E: A new tubulin inhibitor template acting on PI3K/Akt signaling pathway.

Mornaphthoate E (MPE) is a prenylated naphthoic acid methyl ester isolated from the roots of a famous Chinese medicinal plant Morinda officinalis and shows remarkable cytotoxicity against several human tumor cell lines. In the current project, the first total synthesis of (±)-MPE was achieved in seven steps and 5.6% overall yield. Then the in vitro anti-tumor activity of MPE was first assessed for both enantiomers in two breast cancer cells, with the levoisomer exerting slightly better potency. The in vivo anti-tumor effect was further verified by applying the racemate in an orthotopic autograft mouse model. Notably, MPE exerted promising anti-metastasis activity both in vitro and in vivo and showed no obvious toxicity on mice at the therapeutic dosage. Mechanistic investigations demonstrated that MPE acted as a tubulin polymerization stabilizer and disturbed the dynamic equilibrium of microtubules via regulating PI3K/Akt signaling. In conclusion, our work has provided a new chemical template for the future design and development of next-generation tubulin-targeting chemotherapies.

Functionalized Blood Small Extracellular Vesicles with Polydopamine Nanoparticles for Chemo-Thermal Therapy.

Small extracellular vesicles (sEVs) hold considerable promise for drug delivery due to their natural origin and inherent qualities. However, their clinical application is impeded by two main challenges: low yield and potential side effects. Therefore, it is crucial to obtain substantial quantities of sEVs that adhere to rigorous biosafety standards to ensure successful translation into clinical practice. To address this need, we propose exploring optimized methods for sourcing and separating sEVs, taking inspiration from clinical blood transfusion. In particular, we have identified blood sEVs as a viable alternative and developed a novel separation technique for their isolation. Our approach involves incubating dopamine solution with serum, resulting in the formation of polydopamine (PDA) nanoparticles on the surface of blood sEVs. These nanoparticles have minimal impact on blood sEVs, facilitating their easy separation under standard centrifugal conditions with high purity. This innovative technique enables the development of nanocarriers using blood sEVs with efficient drug-loading capabilities and enhanced pharmacokinetics. Additionally, the incorporation of PDA nanoparticles imparts a photothermal effect to the nanomedicines, enabling the integration of chemotherapy and photothermal therapy. Moreover, the photothermal effect holds the potential to facilitate the membrane fusion of sEVs and cells. In summary, our straightforward surface functionalization technique utilizing PDA effectively isolates blood sEVs and enables chemo-thermal tumor therapy. This approach significantly enhances the feasibility of translating sEV-based nanomedicines into clinical applications.

Progress in the discovery and development of small molecule methuosis inducers.

Current cancer chemotherapies rely mainly on the induction of apoptosis of tumor cells, while drug resistance arising from conventional chemicals has always been a big challenge. In recent years, more and more new types of cell deaths including methuosis have been extensively investigated and recognized as potential alternative targets for future cancer treatment. Methuosis is usually caused by excessive accumulation of macropinosomes owing to ectopic activation of macropinocytosis, which can be triggered by external stimuli such as chemical agents. Increasing reports demonstrate that many small molecule compounds could specifically induce methuosis in tumor cells while showing little or no effect on normal cells. This finding raises the possibility of targeting tumor cell methuosis as an effective strategy for the prevention of cancer. Based on fast-growing studies lately, we herein provide a comprehensive overview on the overall research progress of small molecule methuosis inducers. Promisingly, previous efforts and experiences will facilitate the development of next-generation anticancer therapies.

Heterogeneous Fenton treatment of shale gas fracturing flow-back wastewater by spherical Fe/Al2O3 catalyst.

In this work, efficient Fenton strategy have been proposed for degradation of shale gas fracturing flow-back wastewater using the spherical Fe/Al2O3 supported catalyst. Prior to actual fracturing fluid treatment, the typical model wastewaters such as p-nitrophenol and polyacrylamide were employed to evaluate the catalytic properties of prepared catalyst, and then Fenton treatment of the shale gas fracturing flow-back wastewater was performed on the self-assembled catalytic degradation reactor for continuous flow purification. Results showed that under the conditions of 0.25 mol L-1 impregnating concentration, pH 4, 50 g L-1 catalyst and 0.75 mL L-1 30% H2O2, the removal efficiency of p-nitrophenol and polyacrylamide reached 74% and 61%, respectively, while the COD removal of fracturing flow-back fluid was approximately 48% with the residual 88 mg L-1 COD, meeting the emission standards of the integrated wastewater discharge standard (GB 8978-1996, COD < 100 mg L-1). This work offers new alternatives for Fenton treatment of real wastewater by efficient and low-cost supported catalysts.

21,24-Cyclolanostanes revisited: Structural revision and biological evaluation.

Chemical fractionation of the EtOH extract of a medicinal macro fungus, Inonotus obliquus, afforded an array of lanostane-type triterpenoids (1-11) including two new ones (1 and 8). The structures of these compounds were determined on the basis of spectroscopic analyses, single crystal X-ray crystallography of 3-6 and biosynthetic considerations. With the confirmatory structural information provided by X-ray diffraction analysis in hand, several previously reported 21,24-cyclolanostanes, such as inonotsutriols A-C and (20R,21S,24S)-21,24-cyclopenta-3ß,21,25-trihydroxylanosta-8-ene, were structurally corrected. In addition, the NMR data of other types of 21,24-cyclo triterpenoids were also re-examined and structural revisions were thus suggested. Compounds 2, 6 and 8 showed significant cytostatic effects against a panel of tumor cell lines with IC50 values ranging from 7.80 to 18.5 µM. Further assays established that compound 2 exerted promising in vitro anti-breast cancer potential by inhibiting the proliferation and migration of 4T1 cells.

MLSP: A bioinformatics tool for predicting molecular subtypes and prognosis in patients with breast cancer.

The molecular landscape in breast cancer is characterized by large biological heterogeneity and variable clinical outcomes. Here, we performed an integrative multi-omics analysis of patients diagnosed with breast cancer. Using transcriptomic analysis, we identified three subtypes (cluster A, cluster B and cluster C) of breast cancer with distinct prognosis, clinical features, and genomic alterations: Cluster A was associated with higher genomic instability, immune suppression and worst prognosis outcome; cluster B was associated with high activation of immune-pathway, increased mutations and middle prognosis outcome; cluster C was linked to Luminal A subtype patients, moderate immune cell infiltration and best prognosis outcome. Combination of the three newly identified clusters with PAM50 subtypes, we proposed potential new precision strategies for 15 subtypes using L1000 database. Then, we developed a robust gene pair (RGP) score for prognosis outcome prediction of patients with breast cancer. The RGP score is based on a novel gene-pairing approach to eliminate batch effects caused by differences in heterogeneous patient cohorts and transcriptomic data distributions, and it was validated in ten cohorts of patients with breast cancer. Finally, we developed a user-friendly web-tool (https://sujiezhulab.shinyapps.io/BRCA/) to predict subtype, treatment strategies and prognosis states for patients with breast cancer.

Noncoding RNA-mediated macrophage and cancer cell crosstalk in hepatocellular carcinoma.

The tumor microenvironment (TME) is a well-recognized system that plays an essential role in tumor initiation, development, and progression. Intense intercellular communication between tumor cells and other cells (especially macrophages) occurs in the TME and is mediated by cell-to-cell contact and/or soluble messengers. Emerging evidence indicates that noncoding RNAs (ncRNAs) are critical regulators of the relationship between cells within the TME. In this review, we provide an update on the regulation of ncRNAs (primarily micro RNAs [miRNAs], long ncRNAs [lncRNAs], and circular RNAs [circRNAs]) in the crosstalk between macrophages and tumor cells in hepatocellular carcinoma (HCC). These ncRNAs are derived from macrophages or tumor cells and act as oncogenes or tumor suppressors, contributing to tumor progression not only by regulating the physiological and pathological processes of tumor cells but also by controlling macrophage infiltration, activation, polarization, and function. Herein, we also explore the options available for clinical therapeutic strategies targeting crosstalk-related ncRNAs to treat HCC. A better understanding of the relationship between macrophages and tumor cells mediated by ncRNAs will uncover new diagnostic biomarkers and pharmacological targets in cancer.

Nanomedicines for the Efficient Treatment of Intracellular Bacteria: The "ART" Principle.

Infections induced by bacteria at present are a severe threat to public health. Compared with extracellular bacteria, intracellular bacteria are harder to get rid of and readily induce chronic inflammation as well as autoimmune disorders. As the development of new antibiotics becomes more and more difficult, the construction of new antibiotic dosage forms is one of the optimal choices for the elimination of intracellular bacteria, and, to date, various nanomedicines have been exploited. However, current nanomedicines have limited treatment efficiency for intracellular bacteria due to the multiple biological barriers. Here in this short review, we focus on systemically administered nanomedicines and divide the treatment of intracellular bacteria with nanomedicines into three steps: 1) Accumulation at the infection site; 2) Recognition of infected cells; 3) Targeting of intracellular bacteria. Furthermore, we summarize how nanomedicines are elaborately designed to achieve the "ART" principle and discuss the problems of experimental models construction. Through this review, we want to remind that the golden approach for the building of cell and animal experimental models should be established, and nanomedicines should be also endowed with the versatility to follow the "ART" principle, efficiently improving the treatment efficiency of nanomedicines for intracellular bacteria.

Alteration of MDM2 by the Small Molecule YF438 Exerts Antitumor Effects in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) exhibits a high mortality rate and is the most aggressive subtype of breast cancer. As previous studies have shown that histone deacetylases (HDAC) may represent molecular targets for TNBC treatment, we screened a small library of synthetic molecules and identified a potent HDAC inhibitor (HDACi), YF438, which exerts effective anti-TNBC activity both in vitro and in vivo. Proteomic and biochemical studies revealed that YF438 significantly downregulated mouse double minute 2 homolog (MDM2) expression. In parallel, loss of MDM2 expression or blocking MDM2 E3 ligase activity rendered TNBC cells less sensitive to YF438 treatment, revealing an essential role of MDM2 E3 ligase activity in YF438-induced inhibition of TNBC. Mechanistically, YF438 disturbed the interaction between HDAC1 and MDM2, induced the dissociation of MDM2-MDMX, and subsequently increased MDM2 self-ubiquitination to accelerate its degradation, which ultimately inhibited growth and metastasis of TNBC cells. In addition, analysis of clinical tissue samples demonstrated high expression levels of MDM2 in TNBC, and MDM2 protein levels closely correlated with TNBC progression and metastasis. Collectively, these findings show that MDM2 plays an essential role in TNBC progression and targeting the HDAC1-MDM2-MDMX signaling axis with YF438 may provide a promising therapeutic option for TNBC. Furthermore, this novel underlying mechanism of a hydroxamate-based HDACi in altering MDM2 highlights the need for further development of HDACi for TNBC treatment. SIGNIFICANCE: This study uncovers the essential role of MDM2 in TNBC progression and suggests that targeting the HDAC1-MDM2-MDMX axis with a hydroxamate-based HDACi could be a promising therapeutic strategy for TNBC.