Accurate prediction of drug-target interactions (DTI) is critical for drug discovery. Existing methods often rely on single-modal representations (e.g., sequences or graphs) or combine only two modalities, overlooking 3D structural features. To address this challenge, we propose TriMod-DTI, a triple-modal contrastive learning framework that incorporates 1D sequences, 2D graphs, and 3D structures of drugs and proteins, obtaining the universal and complementary feature represetations for DTI prediction. We design a Feature Extractor to capture drug and target features across the three modalities, thereby enriching their representations. We further propose a triple-modal contrastive learning strategy to align different modal representations of the same drug or protein in the latent space. By constructing cross-modal positive and negative sample pairs, this approach enhances the model’s discriminative ability. Experiments on three benchmark datasets demonstrate that TriMod-DTI outperforms state-of-the-art methods. The ablation studies validate the contributions of each modality. Moreover, case studies highlight its practical potential for DTI prediction and drug discovery. The source code of TriMod-DTI is available at https://github.com/klez1/TriMod-DTI .

Background: Taxane-based chemotherapy is the primary treatment for triple-negative breast cancer (TNBC), yet clinical outcomes remain unsatisfactory due to the persistence of chemoresistance. Identifying key factors that contribute to chemoresistance and understanding the associated molecular mechanisms is therefore essential. Method: The GEO databases were utilized to pinpoint factors related to chemoresistance, which were subsequently validated using clinical tissue samples. The role of UGCG in the malignant progression and chemoresistance of TNBC was assessed through various functional assays. Western blotting, qRT-PCR, and immunohistochemistry were employed to investigate the signaling pathways associated with UGCG in TNBC. Results: UGCG expression was notably elevated in chemoresistant breast cancer tissues and cells, as identified in GEO databases and confirmed through immunohistochemistry. Additionally, findings from our cohorts indicated that higher levels of UGCG expression correlated with a lower rate of pathological complete response (pCR), suggesting it could serve as an independent predictor of chemotherapy effectiveness. Gain- and loss-of-function experiments demonstrated that UGCG enhanced the proliferation, metastasis, and stemness of breast cancer cells. Furthermore, treatment with paclitaxel or docetaxel resulted in increased UGCG expression, which in turn reduced chemotherapy-induced cell apoptosis and improved drug resistance and metastatic capabilities. Mechanistically, UGCG was found to amplify the activation of NF-κB and Wnt/β-catenin pathways, and the use of inhibitors targeting these pathways diminished the UGCG-induced malignant effects. Conclusion: Our findings underscore the significant role of UGCG in the chemoresistance and progression of breast cancer, suggesting it as a predictive biomarker and potential therapeutic target to combat chemoresistance in this disease.

Triple-negative breast cancer (TNBC) is an exceptionally aggressive subtype of breast cancer. Despite the recognized interplay between tumors and tumor-associated macrophages in fostering drug resistance and disease progression, the precise mechanisms leading these interactions remain elusive. Our study revealed that the upregulation of collagen type V alpha 1 (COL5A1) in TNBC tissues, particularly in chemoresistant samples, was closely linked to an unfavorable prognosis. Functional assays unequivocally demonstrated that COL5A1 played a pivotal role in fueling cancer growth, metastasis, and resistance to doxorubicin, both in vitro and in vivo. Furthermore, we found that the cytokine IL-6, produced by COL5A1-overexpressing TNBC cells actively promoted M2 macrophage polarization. In turn, TGFβ from M2 macrophages drived TNBC doxorubicin resistance through the TGFβ/Smad3/COL5A1 signaling pathway, establishing a feedback loop between TNBC cells and macrophages. Mechanistically, COL5A1 interacted with TGM2, inhibiting its K48-linked ubiquitination-mediated degradation, thereby enhancing chemoresistance and increasing IL-6 secretion. In summary, our findings underscored the significant contribution of COL5A1 upregulation to TNBC progression and chemoresistance, highlighting its potential as a diagnostic and therapeutic biomarker for TNBC.

Due to the persistently high global incidence and mortality rates of cancer, developing novel therapeutic strategies is imperative. The replication factor C (RFC) family, a critical subset of DNA replication and repair, serves multifaceted roles in tumor progression. Despite its widely recognized importance, the pleiotropic mechanisms of the RFC family lack systematic illustration, particularly regarding each member specific contributions to cancer hallmarks. In the present review, mRNA expression of each RFC family member in pan‑cancer was profiled and the associations between their expression levels and tumor types evaluated. In addition, the effect of RFC expression on patients' survival across malignancies is assessed. Furthermore, the present review summarized current research on RFC family members in various malignancies with particular emphasis on the RFC‑like complexes, highlighting key findings and advancements in understanding their role in tumor biology. The signaling pathways associated with RFC family members are discussed and the molecular mechanisms elucidated. Finally, the clinical importance of RFC family members including prognosis, potential inhibitors and combination treatments are also discussed. The present review aimed to provide innovative perspectives for developing combinatorial molecular targeted therapies in the future.

Doxorubicin (DOX)-based chemotherapy is the basic treatment for triple-negative breast cancer (TNBC). However, chemoresistance is still one of the major causes of metastasis, recurrence, and poor outcomes. Recently, a close relationship between chemoresistance and endoplasmic reticulum (ER) stress has been found. In this study, ER-associated degradation (ERAD)-related protein EDEM1 (ER degradation enhancing α-mannosidase-like 1) plays a vital role in DOX-induced ER stress, which is up-regulated in tumor cells and tissues. In vitro and in vivo experiments reveal the promoting role of EDEM1 in the progression and chemoresistance of TNBC. Besides, EDEM1 attenuates autophagy and reduces ER stress-related apoptosis, indicating its inhibitory effect on ER stress. Furthermore, EDEM1 promotes ERAD and enhances the antioxidant capacity of tumor cells. Mechanistically, EDEM1 competitively binds Kelch-like ECH-associated protein 1 to prevent the ubiquitination and degradation of nuclear factor erythroid 2-related factor 2 (Nrf2), leading to increased Nrf2 nuclear translocation and antioxidant response element activation to bolster antioxidant defense and cell survival. Moreover, both the expression and function of EDEM1 are down-regulated by miR-32-5p. Clinically, high EDEM1 expression is correlated with poor patient outcomes in breast cancer, especially in TNBC patients treated with DOX-based chemotherapy. These findings reveal EDEM1 as a regulator of ER homeostasis during cancer progression and chemoresistance, and a potential target for breast cancer therapy.

Breast cancer is one of the major malignant tumors among women worldwide. Long noncoding RNAs (lncRNAs) have been documented as significant modulators in the development and progression of various cancers; however, the contribution of lncRNAs to breast cancer remains largely unknown. In this study, we found a novel lncRNA (NONHSAT137675) whose expression was significantly increased in the breast cancer tissues. We named the novel lncRNA as lncRNA PRBC (PABPC1-related lncRNA in breast cancer) and identified it as a key lncRNA associated with breast cancer progression and prognosis. Functional analysis displayed that lncRNA PRBC could promote autophagy and progression of breast cancer. Mechanistically, we verified that lncRNA PRBC physically interacted with PABPC1 through RIP assay, and PABPC1 overexpression could reverse the inhibiting effect of lncRNA PRBC knockdown on the malignant behaviors in breast cancer cells. Knockdown of lncRNA PRBC interfered the translocation of PABPC1 from nucleus to cytoplasm as indicated by western blot and IF assays. Significantly, the cytoplasmic location of PABPC1 was required for the interaction between PABPC1 and AGO2, which could be enhanced by lncRNA PRBC overexpression, leading to strengthened recruitment of mRNA to RNA-induced silencing complex (RISC) and thus reinforcing the inhibition efficiency of miRNAs. In general, lncRNA PRBC played a critical role in malignant progression of breast cancer by inducing the cytoplasmic translocation of PABPC1 to further regulate the function of downstream miRNAs. This study provides novel insight on the molecular mechanism of breast cancer progression, and lncRNA PRBC might be a promising therapeutic target and prognostic predictor for breast cancer.

The sequences of the shRNA and siRNA oligonucleotides are listed.

ObjectiveTo examine the association between the weight-adjusted waist index (WWI) and the odds of type 2 diabetes mellitus(T2DM)among U.S. adults.MethodsData from the National Health and Nutrition Examination Survey (NHANES) spanning six years (2007–2018) were utilized, encompassing 31001 eligible participants. Weighted multivariate logistic regression models and smoothed fit curves were employed to assess the association between WWI and the odds of T2DM, as well as dose-response relationships in the overall population and the odds of T2DM in various subgroups.ResultsIn the fully adjusted continuous model, each one-unit increase in WWI was associated with a 1.14-fold increase in the odds of T2DM within the entire study population (2.14 [1.98,2.31], P < 0.0001). In the fully adjusted categorical model, when using the lowest tertile of WWI (T1) as the reference group, the second tertile (T2) and the third tertile (T3) were associated with a 0.88-fold (1.88 [1.64,2.17], P < 0.0001) and a 2.63-fold (3.63 [3.11,4.23], P < 0.0001) increase in the odds of T2DM. These findings indicated a positive correlation between WWI values and the odds of T2DM, aligning with the results of the smoothed-fitted curves. In the analysis of subgroups, in addition to maintaining consistency with the overall population results, we found interactions between age and hypertension subgroups.ConclusionIn conclusion, WWI was found to be positively associated with the odds of T2DM in U.S. adults.

JPX could directly bind with YTHDF2 and USP10, respectively. YTHDF2 knockdown increased BMP2 and activated the AKT pathway in cutaneous melanoma.

JPX knockout reduces the proliferation and migration of cutaneous melanoma cells.

Breast cancer remains a significant global health challenge, and its mechanisms of progression and metastasis are still not fully understood. In this study, analysis of TCGA and GEO datasets revealed a significant increase in CCT2 expression in breast cancer tissues, which was associated with poor prognosis in breast cancer patients. Functional analysis revealed that CCT2 promoted breast cancer growth and metastasis through activation of the JAK2/STAT3 signaling pathway. Additionally, the E3 ubiquitin ligase Trim21 facilitated CCT2 ubiquitination and degradation, significantly reversing the protumor effects of CCT2. Most interestingly, we discovered that exosomal CCT2 derived from breast cancer cells suppressed the activation and proinflammatory cytokine secretion of CD4+ T cell. Mechanistically, exosomal CCT2 constrained Ca2+-NFAT1 signaling, thereby reducing CD40L expression on CD4+ T cell. These findings highlight CCT2 upregulation as a potential driver of breast cancer progression and immune evasion. Our study provides new insights into the molecular mechanisms underlying breast cancer progression, suggesting that CCT2 is a promising therapeutic target and prognostic predictor for breast cancer.

The primer sequences used are listed.

AbstractTriple‐negative breast cancer (TNBC) is the most malignant subtype of breast cancer. TP53, which has a mutation rate of ≈70%–80% in TNBC patients, plays oncogenic roles when mutated. However, whether circRNAs can exert their effects on TNBC through regulating mutant TP53 has not been well evaluated. In this study, circCFL1, which is highly expressed in TNBC cells and tissues and has prognostic potential is identified. Functionally, circCFL1 promoted the proliferation, metastasis and stemness of TNBC cells. Mechanistically, circCFL1 acted as a scaffold to enhance the interaction between HDAC1 and c‐Myc, further promoting the stability of c‐Myc via deacetylation‐mediated inhibition of K48‐linked ubiquitylation. Stably expressed c‐Myc further enhanced the expression of mutp53 in TNBC cells with TP53 mutations by directly binding to the promoter of TP53, which promoted the stemness of TNBC cells via activation of the p‐AKT/WIP/YAP/TAZ pathway. Moreover, circCFL1 can facilitate the immune escape of TNBC cells by promoting the expression of PD‐L1 and suppressing the antitumor immunity of CD8+ T cells. In conclusion, the results revealed that circCFL1 plays an oncogenic role by promoting the HDAC1/c‐Myc/mutp53 axis, which can serve as a potential diagnostic biomarker and therapeutic target for TNBC patients with TP53 mutations.

BACKGROUND:Breast cancer is the most common malignant tumor, and metastasis remains the major cause of poor prognosis. Glucose metabolic reprogramming is one of the prominent hallmarks in cancer, providing nutrients and energy to support dramatically elevated tumor growth and metastasis. Nevertheless, the potential mechanistic links between glycolysis and breast cancer progression have not been thoroughly elucidated.METHODS:RNA-seq analysis was used to identify glucose metabolism-related circRNAs. The expression of circSIPA1L3 in breast cancer tissues and serum was examined by qRT-PCR, and further assessed its diagnostic value. We also evaluated the prognostic potential of circSIPA1L3 by analyzing a cohort of 238 breast cancer patients. Gain- and loss-of-function experiments, transcriptomic analysis, and molecular biology experiments were conducted to explore the biological function and regulatory mechanism of circSIPA1L3.RESULTS:Using RNA-seq analysis, circSIPA1L3 was identified as the critical mediator responsible for metabolic adaption upon energy stress. Gain- and loss-of-function experiments revealed that circSIPA1L3 exerted a stimulative effect on breast cancer progression and glycolysis, which could also be transported by exosomes and facilitated malignant behaviors among breast cancer cells. Significantly, the elevated lactate secretion caused by circSIPA1L3-mediated glycolysis enhancement promoted the recruitment of tumor associated macrophage and their tumor-promoting roles. Mechanistically, EIF4A3 induced the cyclization and cytoplasmic export of circSIPA1L3, which inhibited ubiquitin-mediated IGF2BP3 degradation through enhancing the UPS7-IGF2BP3 interaction. Furthermore, circSIPA1L3 increased mRNA stability of the lactate export carrier SLC16A1 and the glucose intake enhancer RAB11A through either strengthening their interaction with IGF2BP3 or sponging miR-665, leading to enhanced glycolytic metabolism. Clinically, elevated circSIPA1L3 expression indicated unfavorable prognosis base on the cohort of 238 breast cancer patients. Moreover, circSIPA1L3 was highly expressed in the serum of breast cancer patients and exhibited high diagnostic value for breast cancer patients.CONCLUSIONS:Our study highlights the oncogenic role of circSIPA1L3 through mediating glucose metabolism, which might serve as a promising diagnostic and prognostic biomarker and potential therapeutic target for breast cancer.

BACKGROUND AND AIM:Diabetes retinopathy (DR) is a common microvascular complication of diabetes, and it is the main cause of global vision loss. The current observational research results show that the causal relationship between Vitamin D and DR is still controversial. Therefore, we conducted a Mendelian randomization study to determine the potential causal relationship between serum 25-hydroxyvitamin D 25(OH)D and DR. METHODS AND RESULTS:In this study, we selected aggregated data on serum 25(OH)D levels (GWAS ID: ebi-a-GCST90000615) and DR (GWAS ID: finn-b-DM_RETINOPATHY) from a large-scale GWAS database. Then use MR analysis to evaluate the possible causal relationship between them. We mainly use inverse variance weighted (IVW), supplemented by MR Egger and weighted median methods. Sensitivity analysis is also used to ensure the stability of the results, such as Cochran's Q-test, MR-PRESSO, MR-Egger interception test, and retention method. The MR analysis results showed that there was no significant causal relationship between 25(OH)D and DR (OR = 1.0128, 95%CI=(0.9593,1.0693), P = 0.6447); Similarly, there was no significant causal relationship between DR and serum 25 (OH) D levels (OR = 0.9900, 95% CI=(0.9758,1.0045), P = 0.1771). CONCLUSION:Our study found no significant causal relationship between serum 25(OH)D levels and DR, and vice versa. A larger sample size randomized controlled trial is needed to further reveal its potential causal relationship.

JPX overexpression induces the proliferation and migration of cutaneous melanoma cells.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with higher aggressiveness and poorer outcomes. Recently, long non-coding RNAs (lncRNAs) have become the crucial gene regulators in the progression of human cancers. However, the function and underlying mechanisms of lncRNAs in TNBC remains unclear. Based on public databases and bioinformatics analyses, the low expression of lncRNA MIDEAS-AS1 in breast cancer tissues was detected and further validated in a cohort of TNBC tissues. The effects of MIDEAS-AS1 on proliferation, migration, invasion were determined by in vitro and in vivo experiments. RNA pull-down assay and RNA immunoprecipitation (RIP) assay were carried out to reveal the interaction between MIDEAS-AS1 and MATR3. Luciferase reporter assay, Chromatin immunoprecipitation (ChIP) and qRT-PCR were used to evaluate the regulatory effect of MIDEAS-AS1/MATR3 complex on NCALD. LncRNA MIDEAS-AS1 was significantly downregulated in TNBC, which was correlated with poor overall survival (OS) and progression-free survival (PFS) in TNBC patients. MIDEAS-AS1 overexpression remarkably inhibited tumor growth and metastasis in vitro and in vivo. Mechanistically, MIDEAS-AS1 mainly located in the nucleus and interacted with the nuclear protein MATR3. Meanwhile, NCALD was selected as the downstream target, which was transcriptionally regulated by MIDEAS-AS1/MATR3 complex and further inactivated NF-κB signaling pathway. Furthermore, rescue experiment showed that the suppression of cell malignant phenotype caused by MIDEAS-AS1 overexpression could be reversed by inhibition of NCALD. Collectively, our results demonstrate that MIDEAS-AS1 serves as a tumor-suppressor in TNBC through modulating MATR3/NCALD axis, and MIDEAS-AS1 may function as a prognostic biomarker for TNBC.

Objective: Postmenopausal osteoporosis (PMOP) is a common systemic metabolic bone disorder that is owing to the reduced estrogen secretion and imbalance of bone absorption and bone formation in postmenopausal women. Ferroptosis has been identified as a novel modulatory mechanism of osteoporosis. Nevertheless, the particular modulatory mechanism between ferroptosis and PMOP is still unclear. The objective of the current investigation was to detect potential biomarkers connected to ferroptosis in PMOP and discover its probable mechanism through bioinformatics. Methods: We downloaded PMOP-related microarray datasets from the database of Gene Expression Omnibus (GEO) and obtained the differentially expressed genes (DEGs). Utilizing bioinformatics analysis, the DEGs were intersected with the ferroptosis dataset to obtain ferroptosis-connected mRNAs. Enrichment analysis employing KOBAS 3.0 was conducted to comprehend the biological functions and enrichment pathways of the DEGs. The generation of the protein-protein interaction (PPI) network was conducted with the aim of identifying central genes. Lastly, the coexpression and competitive endogenous RNA (ceRNA) networks were built using Cytoscape. With the help of external datasets GSE56815 to verify the reliability of the hub genes by plotting ROC curves. Results: We identified 178 DE microRNAs (miRNAs), 138 DE circular RNAs (circRNAs), and 86 ferroptosis-related mRNAs. Enrichment analysis exhibited that mRNAs were primarily connected with the signaling pathways of PI3K/Akt, metabolism, mTOR, FoxO, HIF-1, AMPK, MAPK, ferroptosis, VEGF, and NOD-like receptors. Generation of the PPI network detected eight hub genes. The circRNA/miR-23b-3p/PTEN axis may relieve PMOP by inhibiting ferroptosis through targeting the pathway of PI3K/Akt signaling, which is a vital modulatory pathway for PMOP progression. Moreover, the ROC curves ultimately indicates that the four hub genes have greater diagnostic importance in PMOP samples in contrast to the normal group samples, which may be possible markers for PMOP diagnosis. Conclusions: Bioinformatics analysis identified four hub genes, namely, PTEN, SIRT1, VEGFA, and KRAS, as potential biomarkers for PMOP diagnosis and management. Moreover, the circRNA/miR-23b-3p/PTEN axis may relieve PMOP by suppressing ferroptosis through targeting the pathway of PI3K/Akt signaling, providing a new avenue to explore the pathogenesis of PMOP.

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that is suggested to be associated with hypoxia. This study is the first to identify a novel circular RNA (circRNA), circTBC1D14, whose expression is significantly upregulated in TNBC. The authors confirm that high circTBC1D14 expression is associated with a poor prognosis in patients with breast cancer. circTBC1D14-associated mass spectrometry and RNA-binding protein-related bioinformatics strategies indicate that FUS can interact with circTBC1D14, which can bind to the downstream flanking sequence of circTBC1D14 to induce cyclization. FUS is an essential biomarker associated with stress granules (SGs), and the authors find that hypoxic conditions can induce FUS-circTBC1D14-associated SG formation in the cytoplasm after modification by protein PRMT1. Subsequently, circTBC1D14 increases the stability of PRMT1 by inhibiting its K48-regulated polyubiquitination, leading to the upregulation of PRMT1 expression. In addition, FUS-circTBC1D14 SGs can initiate a cascade of SG-linked proteins to recognize and control the elimination of SGs by recruiting LAMP1 and enhancing lysosome-associated autophagy flux, thus contributing to the maintenance of cellular homeostasis and promoting tumor progression in TNBC. Overall, these findings reveal that circTBC1D14 is a potential prognostic indicator that can serve as a therapeutic target for TNBC treatment.

Mitophagy, which selectively eliminates the dysfunctional and excess mitochondria by autophagy, is crucial for cellular homeostasis under stresses such as hypoxia. Dysregulation of mitophagy has been increasingly linked to many disorders including neurodegenerative disease and cancer. Triple-negative breast cancer (TNBC), a highly aggressive breast cancer subtype, is reported to be characterized by hypoxia. However, the role of mitophagy in hypoxic TNBC as well as the underlying molecular mechanism is largely unexplored. Here, we identified GPCPD1 (glycerophosphocholine phosphodiesterase 1), a key enzyme in choline metabolism, as an essential mediator in hypoxia-induced mitophagy. Under the hypoxic condition, we found that GPCPD1 was depalmitoylated by LYPLA1, which facilitated the relocating of GPCPD1 to the outer mitochondrial membrane (OMM). Mitochondria-localized GPCPD1 could bind to VDAC1, the substrate for PRKN/PARKIN-dependent ubiquitination, thus interfering with the oligomerization of VDAC1. The increased monomer of VDAC1 provided more anchor sites to recruit PRKN-mediated polyubiquitination, which consequently triggered mitophagy. In addition, we found that GPCPD1-mediated mitophagy exerted a promotive effect on tumor growth and metastasis in TNBC both in vitro and in vivo. We further determined that GPCPD1 could serve as an independent prognostic indicator in TNBC. In conclusion, our study provides important insights into a mechanistic understanding of hypoxia-induced mitophagy and elucidates that GPCPD1 could act as a potential target for the future development of novel therapy for TNBC patients.