Colorectal cancer (CRC) is one of the most common malignant tumors with the highest incidence and mortality rates worldwide. Immune checkpoint blockade (ICB) therapy has revolutionized the landscape of cancer treatment; however, most patients with CRC gain limited benefits from it. The immunosuppressive microenvironment of CRC is an important cause of tumor progression, metastasis, and immunotherapy resistance. This study aimed to reveal the key role of chemokine receptor 4 (CXCR4) in the immunosuppressive microenvironment and glutamine metabolism reprogramming using integrated single-cell transcriptomics and metabolomics analyses. The in vivo and in vitro experiments verified that CXCR4 mediated metabolic reprogramming in CRC cells by regulating the PI3K-Akt-SMAD4 pathway. Further co-culture experiments revealed that CXCR4 promoted the polarization of tumor-associated macrophages (TAMs) to M2 type through glutamine metabolic reprogramming and induced the exhaustion of CD8+ T cells, thereby intensifying immune escape. The knockdown of CXCR4 significantly increased the infiltration of CD8+ T cells and M1 TAMs, reduced the infiltration of M2 TAMs, effectively reshaped the immunosuppressive microenvironment of CRC-bearing mice, and significantly enhanced the immunotherapeutic effect against programmed cell death protein 1 (PD-1). This study discovered a novel mechanism by which CXCR4 drove CRC immune escape through the dual-axis regulation of the “glutamine metabolism-immune microenvironment.” Targeting CXCR4 not only inhibits tumor metabolic adaptability but also reverses TAMs polarization and T cell exhaustion, thereby effectively sensitizing PD-1 inhibitors. This study provides an important theoretical basis and a highly promising new combined treatment strategy for overcoming ICB resistance in patients with CRC.

Triple-negative breast cancer (TNBC) is a highly aggressive subtype with limited therapeutic options and poor prognosis, creating an urgent demand for novel strategies. Sonodynamic therapy (SDT) is a promising non-invasive approach, yet its clinical translation is restricted by low efficacy of traditional sonosensitizers and single-modal limitations. In this study, we constructed a zinc‑copper‑iron-based layered double hydroxide (ZnCuFe@LDHs) nanoplatform integrating SDT with synergistic ferroptosis and cuproptosis for targeted TNBC treatment. In vitro experiments with 4 T1 cells demonstrated efficient cellular internalization and lysosomal escape of ZnCuFe@LDHs. Under ultrasound stimulation, the nanoplatform generated abundant reactive oxygen species (ROS) and released Cu2+/Fe3+ in response to the acidic tumor microenvironment (TME) and elevated intracellular glutathione (GSH). These events synergistically triggered ferroptosis by inactivating glutathione peroxidase 4 (GPX4) and accumulating lipid peroxide, while inducing cuproptosis through Cu2+ overload, mitochondrial dysfunction, tricarboxylic acid cycle disruption and lipoylated dihydrolipoamide acetyltransferase (DLAT) oligomerization. Additionally, ZnCuFe@LDHs triggered immunogenic cell death (ICD) characterized by calreticulin (CRT) exposure and high-mobility group box 1 (HMGB1) release, promoting dendritic cell maturation and antitumor immunity. In vivo studies using 4 T1 subcutaneous xenograft models confirmed significant tumor growth suppression by ZnCuFe@LDH and ultrasound, with no obvious systemic toxicity. Serum biochemical analysis and histological examination of major organs validated favorable biocompatibility. Collectively, ZnCuFe@LDHs achieves potent targeted antitumor efficacy via the integration of SDT, ferroptosis, cuproptosis, andimmunogenic cell death(ICD). This quadruple-modal synergistic strategy offers a safe and translational therapeutic option for TNBC.

Fluorine-containing compounds are ubiquitous in pharmacology, diagnostics, agrochemistry, and materials science. Fluoromethylation is a reliable method for introducing fluorine into the parent structure. Recently, fluorinated S-adenosyl-l-methionine (F-SAM) and its stabilized analogues have been utilized by methyltransferases to selectively fluoromethylate bioactive molecules. However, the inherent instability of F-SAM and the limited enzyme recognition of the stable analogues restrict their broader application. Therefore, next-generation fluoromethylation reagents for biocatalysis are highly desirable. Here, we engineered the carboxyl and base moieties of F-SAM with bioisosteric substitution and developed three F-SAM analogues. Among them, 7-deazaadenine-tetrazole-substituted F-SAM (F-7dz-tSAM) is highly stable and has kinetic properties comparable to those of SAM with several O-, S-, and C-methyltransferases and fluoromethylates natural products regio- and stereoselectively. Impressive turnover numbers and high conversions were achieved when halide methyltransferase was coupled for the regeneration of F-7dz-tSAM. With F-7dz-tSAM replacing SAM in biosynthesis pathways, we efficiently prepared fluorinated derivatives of two clinically used drugs, diosmin and physostigmine. More importantly, F-7dz-tSAM is utilized by the B12-dependent radical SAM methyltransferase CysS for radical fluoromethylation in better yield than the labile F-SAM.

Acute kidney injury (AKI) caused by ischemia-reperfusion (IR) is an independent risk factor for the progression of chronic kidney disease (CKD), yet there is a lack of effective clinical interventions. Although butylphthalide (NBP) has been proven to have multi-organ protective potential, its rapid in vivo metabolism and low bioavailability limit its clinical application. To overcome these limitations, we rationally designed and synthesized a layered double hydroxide (LDHs)-based nanocarrier system for NBP delivery (LDHs@NBP) via hydrothermal co-precipitation. Comprehensive characterization confirmed successful nanocomplex formation. Critically, LDHs@NBP exhibited accelerated NBP release under mildly acidic conditions, matching the pathological acidosis of injured and fibrotic renal tubules—thereby achieving pH-responsive drug release. Using both an in vivo rat model of unilateral renal ischemia-reperfusion injury (uIRI) and an in vitro TGF-β1-stimulated HK-2 cell model, we demonstrated that LDHs@NBP significantly attenuated renal dysfunction, suppressed interstitial fibrosis, and improved mitochondrial function. Importantly, all protective effects were abolished upon co-treatment with Mdivi-1, confirming mitophagy as the central mechanistic axis. Collectively, this study successfully constructed LDHs@NBP nanocomplexes with pH-responsive drug release properties. This system enhances mitophagy by activating the PINK1-Parkin pathway, thereby effectively blocking AKI-CKD transition. It provides a new strategy with good translational prospects for clinical intervention in kidney diseases.

Paclitaxel (PTX) remains a cornerstone chemotherapeutic agent in the clinical management of breast cancer. However, the therapeutic efficacy of PTX-based nanotherapeutics is remarkably compromised by tricky glycolytic reprogramming, suboptimal immunogenic cell death (ICD), and immunosuppressive tumor microenvironment (TME). To address these challenges in a coordinated mechanism-guided manner, we rationally engineered full-active self-assembled nanotriplets (diPCL NPs) comprising disulfide-bridged dimeric prodrugs of PTX, celecoxib (CXB; an ICD enhancer), and lonidamine (LND; a selective hexokinase II inhibitor). The diPCL NPs displayed excellent colloidal stability, rapid glutathione (GSH)-responsive cleavage and drug release under reduced conditions. Following intravenous administration, they achieved prolonged systemic circulation, preferential tumor accumulation via the enhanced permeability and retention (EPR) effect, and efficient intracellular activation—releasing PTX, CXB immediate, and LND simultaneously in response to elevated intratumoral GSH levels. In 4T1 and PTX-resistant 4T1/PTX murine models, diPCL NPs effectively reprogrammed glucose metabolism, robustly amplified ICD, and converted the immunosuppressive TME toward an immunostimulatory phenotype, thereby eliciting potent antitumor efficacy accompanied by no observable hematological or organ toxicity. Collectively, our work presents a mechanism-guided full-active self-assembling nanoplatform for highly effective and low-toxicity treatment against refractory breast cancer.

The incidence of endometrial cancer (EC) continues to rise. Disulfidptosis, a novel form of cell death, may represent a potential therapeutic target in EC. Through bioinformatic analysis of The Cancer Genome Atlas (TCGA) database, E2F1 mRNA-stabilizing lncRNA (EMSLR) was identified as a lncRNA related to disulfidptosis in EC. Functional assays, including cell proliferation and xenograft assays, demonstrated that knockdown of EMSLR significantly impeded EC cell proliferation, whereas overexpression of EMSLR promoted cell viability. Additionally, EMSLR was found to be associated with glucose uptake and NADPH production in glucose-restricted culture conditions. Moreover, downregulation of EMSLR markedly increased cell death and induced cytoskeletal collapse under glucose deprivation, as evidenced by F-actin and cell death staining. Notably, we observed a strong correlation between EMSLR and the c-MYC-GLUT1 pathway. Mechanistically, EMSLR was found to mediate the expression and nuclear translocation of c-MYC, thereby regulating the progression of EC and its associated disulfidptosis. In conclusion, EMSLR is identified as a disulfidptosis-related gene in endometrial cancer. Elucidating the function and molecular mechanisms of EMSLR in EC presents a promising avenue for therapeutic intervention in patients.

The trifluoropropyl group is valuable in medicinal chemistry for enhancing drug stability and bioavailability. Selective trifluoropropylation is a challenge. Here, we have developed an enzymatic approach using a trifluoropropyl S-adenosylmethionine analogue (TP-SAM) and methyltransferases. Directed evolution of a halide methyltransferase (AclHMT) yielded a variant (W41L) that synthesizes TP-SAM from trifluoropropyl iodide and S-adenosylhomocysteine. Enzyme cascades comprising AclHMT (W41L) and engineered N-, C-, O-, and S-methyltransferases catalyze the selective trifluoropropylation of diverse substrates under mild conditions. This engineered biocatalytic system provides a versatile platform for synthesizing trifluoropropyl-containing bioactive molecules.

Autophagy is a cellular protective mechanism. As tumor cells are stimulated by drugs, autophagy is activated to increase their resistance to drugs. In gene regulation, microRNA (miRNA) plays a vital role. The diagnostic and prognostic potential of various miRNAs in cancer has been recognized, and for several years, miRNA-based therapeutic approaches have garnered significant interest in the oncology field. RAB10, a member of the RAB guanosine triphosphatase family, has been reported that it contributes to tumor resistance to chemotherapy. The bionanomaterial layered double hydroxide (LDH) is considered as an ideal gene delivery vehicle because of its nontoxicity, good biocompatibility, and slow drug release. According to our findings, we proved that miR-141-3p mediated breast cancer resistance to paclitaxel (PTX) by inhibiting autophagy through downregulation of RAB10, and LDH@miR-141-3p increased breast cancer cell sensitivity to PTX treatment, which provided a new idea for antitumor therapy.

Background:Breast cancer is one of the most common cancers among women. Tumor cell proliferation is highly dependent on aerobic glycolysis, so regulating aerobic glycolysis in breast cancer cells is a promising therapeutic strategy. Resveratrol (Res), as a potential new anti-breast cancer drug, has been shown to regulate the glycolysis of cancer cells and inhibit the metastasis and recurrence of breast cancer. The nano drug delivery system can regulate the aerobic glycolysis metabolism by targeting the signaling factors and reaction products of the tumor aerobic glycolysis process to enhance the anti-tumor effect. Methods:A new albumin-modified layered double hydroxide resveratrol dosage form (BSA@LDHs-Res) was synthesized by hydrothermal co-precipitation. Characterization was carried out to determine the successful synthesis of the nanocarrier system. The bioactivity, glycolytic activity and biocompatibility were examined by in vitro cellular assays; in vivo experiments were performed to further evaluate the anti-tumor effects of the BSA@LDHs-Res dosage form for breast cancer. Results:In this study, we obtained for the first time a bovine serum albumin-modified BSA@LDHs-Res loaded dosage form, which was able to enter breast cancer cells SKBR3 and MDA-MB-231 via endocytosis and successfully escaped from lysosomal capture. BSA@LDHs-Res inhibited the proliferation, migration, and invasion of two types of breast cancer cells, induced apoptosis, and promoted the reduction of mitochondrial membrane potential and ROS. BSA@LDHs-Res inhibited the expression and viability of the key enzymes of glycolysis, hexokinase 2 (HK2), pyruvate kinase (PK), and lactate dehydrogenase, resulting in decreased glucose consumption, decreased lactate accumulation, and decreased intracellular ATP levels. BSA@LDHs-Res was examined in the mouse model with good anti-tumor effects. Conclusion:BSA@LDHs-Res is an efficient nanoreagent for the treatment of breast cancer. The albumin-modified resveratrol layered double hydroxide delivery system developed in this study will provide some theoretical references for further research and clinical application of tumor aerobic glycolysis.

Rab Proteins, A Subfamily Of The Ras Superfamily Of Small Gtpases, Are Critical Regulators Of Intracellular Vesicular Trafficking, Which Is Intricately Linked To Various Cellular Processes. These Proteins Play Essential Roles Not Only In Maintaining Cellular Homeostasis But Also In Mediating The Complex Interplay Between Cancer Cells and Their Microenvironment. Rab Proteins Can Act As Either Oncogenic Factors Or Tumor Suppressors, With Their Functions Highly Dependent On The Cellular Context. Mechanistic Studies Have Revealed That Rab Proteins Are Involved In A Variety Of Processes, Including Vesicular Transport, Tumor Microenvironment Regulation, Autophagy, Drug Resistance, and Metabolic Regulation, and Play Either A Promotional Or Inhibitory Role In Cancer Development. Consequently, Targeting Rab Gtpases To Restore Dysregulated Vesicular Transport Systems May Offer A Promising Therapeutic Strategy To Inhibit Cancer Progression. However, It Is Equally Important To Consider The Potential Risks Of Disrupting Rab Functions, As Their Roles Are Highly Context-Dependent and May Have Opposing Effects In Different Malignancies. This Review Focuses On The Multifaceted Involvement Of Rab Family Proteins In Cancer Progression Underscores Their Importance As Potential Therapeutic Targets and Underscores The Need For A Deeper Understanding Of Their Complex Roles In Tumorigenesis.

Breast cancer has the highest incidence of female cancers globally and is a significant cause of death among female cancers. The field of breast cancer immunotherapy is rapidly evolving, offering new treatment options and hope to patients. Immune checkpoint inhibitors (ICBs) fight cancer by reprogramming the host immune system, leading a new paradigm in the treatment and application of specific types of breast cancer. While, si-RNA-based RNA interference technology shows great therapeutic potential as an alternative to immune checkpoint antibodies. This study confirmed the potential of si-NEAT1 to inhibit immune escape and epithelial mesenchymal transition (EMT) in breast cancer, which was mainly achieved by targeting PD-L1 through miR-141-3p. We employed LDH@si-NEAT1 to treat breast cancer cells and analyzed the effects of LDH@si-NEAT1-treated breast cancer cells on CD3 + CD8+ T cells and tumor-associated macrophages (TAMs) using co-culture technique. The results showed that LDH@si-NEAT1 activated CD3 + CD8+ T cells, thereby inhibiting the immune escape of breast cancer cells, as well as converting M2-type TAMs to M1-type TAMs, remodeling the immunosuppressive microenvironment of breast cancer mice while inhibiting EMT of breast cancer, and synergistically enhancing the immunotherapeutic effect of anti-PD-1. In conclusion, the present study emphasizes that LDH@si-NEAT1 can effectively reverse the immunosuppressive microenvironment of breast cancer and inhibit EMT of breast cancer, which provides a promising strategy for finding beneficial enhanced immunotherapy for breast cancer patients.

Breast cancer (BC) is the most prevalent and highly heterogeneous malignancy affecting females worldwide, and its development is closely linked to metabolic reprogramming. In this study, label-free quantification (LFQ) was used to analyze the protein expression in exosomes secreted by BC drug-resistant cells, identifying RAS-associated binding protein (RAB) 10 as the most significantly upregulated protein. RAB10, a member of the small GTPase family with complex biological functions, is highly expressed in BC and is associated with poor prognosis. In this study, we mainly utilized mouse breast cancer 4T-1 cells (wild-type control cells) and tumor-induced 4T-1 cells (isolated from mouse in situ tumor tissues to simulate the phenotype of the in vivo tumor microenvironment), and on this basis, conducted in vitro functional verification and in vivo tumorigenesis experiments. A comprehensive multi-omics analysis, including metabolomics and proteomics, following RAB10 knockdown, demonstrated the crucial role of RAB10 in regulating central carbon metabolism, which is essential for autophagy and ferroptosis in BC cells. Our study further confirmed that RAB10 mediates metabolic reprogramming in BC cells by regulating the Slc37a2/mTOR pathway, leading to enhanced autophagy and inhibition of ferroptosis. This comprehensive multi-omics analysis elucidated the key molecular and regulatory mechanisms underlying RAB10-induced metabolic reprogramming in tumors, providing potential new therapeutic targets and biomarkers for prognostic assessment in BC treatment.

Breast cancer is the most common type of cancer among women. It is well-established that microRNAs (miRNAs) play a critical role in cancer development by either degrading messenger RNA (mRNA) or inhibiting its translation, thereby suppressing the expression of specific genes. In this study, we found that the expression level of miR-142-3p was significantly lower in breast cancer cells and tissues than in normal breast epithelial cells and adjacent tissues. We demonstrated that miR-142-3p could inhibit the proliferation, migration, epithelial-mesenchymal transition (EMT), and stemness of MCF 7 breast cancer cells, while also promoting apoptosis. Further investigation revealed that miR-142-3p directly targets CXCL12 and regulates its expression. Silencing CXCL12 (using CXCL12 siRNA) suppressed the migration, EMT, and stemness of MCF 7 cells, and these effects were reversed by inhibition of miR-142-3p. Additionally, we observed alterations in β-catenin protein levels, suggesting that miR-142-3p may modulate the WNT/β-catenin signaling pathway through targeting CXCL12 in MCF 7 cells. Subsequent experiments indicated that miR-142-3p also plays a crucial role in overcoming paclitaxel resistance in MCF 7/PTX cells. SOX2 protein levels, which are associated with paclitaxel resistance, proliferation, migration, and EMT, were higher in MCF 7/PTX cells compared to MCF 7 cells. Overall, our findings suggest that miR-142-3p influences breast cancer progression by targeting the CXCL12/WNT/β-catenin pathway, thereby affecting cell migration, EMT, stemness, and paclitaxel resistance.

Colorectal cancer (CRC), a major malignancy of the digestive system, poses a serious threat to human health. Metabolic reprogramming is a hallmark of cancer, promoting tumor growth and metastasis by altering the energy metabolism of tumor cells and reshaping the tumor microenvironment (TME). MicroRNAs with high expression levels play critical roles in the TME. In this study, miRNA-seq detected low expression of miR-654-3p in plasma exosomes from CRC patient samples. The molecular mechanism of miR-654-3p in CRC was analyzed and verified through in vivo and in vitro experiments. The results showed that miR-654-3p targeted POU2F1-mediated metabolic reprogramming to inhibit autophagy and epithelial-mesenchymal transition (EMT) in CRC. Furthermore, layered double hydroxide (LDH) nanoparticles were synthesized to construct LDH@miR-654-3p nanocomposites. This system was used to further elucidate the molecular mechanism of miR-654-3p in CRC, demonstrating the antitumor efficacy of LDH-loaded miR-654-3p and clarifying its underlying mechanisms. These findings provide a theoretical basis for the clinical translation of this nanotherapeutic strategy in CRC treatment.

Fluorine and fluorine-containing functional groups play important roles in drugs and agrochemicals. Recently, SAM-dependent methyltransferases and several SAM analogues have been reported for fluoromethyl transfer through a nucleophilic mechanism. However, fluoromethylation of unactivated carbon centers is very challenging, and their substitution usually involves a radical mechanism. To date, no biocatalysts have been developed for fluoromethylation of unactivated carbon centers. In this study, we found that the B12-dependent radical SAM methyltransferase (B12-RSMT) QCMT can fluoromethylate the glutamine Cα position of peptides with fluorinated SAM (F-SAM) generated in situ by the enzyme AclHMT. QCMT can cleave F-SAM to produce the 5'-dA radical. The significant reaction intermediate CH2FCbI was characterized by HR-MS, 19F NMR spectroscopy and X-ray crystallography. In addition, B12-RSMTs CysS and GenD1 can also transfer fluoromethyl groups onto natural products. We also found that F-SAM is not compulsory. The reduced B12-RSMTs can directly generate CH2FCbI with CH2FI and transfer the CH2F group when SAM is used as the radical initiator. Our results demonstrate a radical-mediated enzymatic strategy for fluoromethylation with abiological cofactors and expand radical SAM enzymes to the field of fluorine chemistry.

OBJECTIVES:To study the molecular mechanisms of LDH-loaded si-NEAT1 for regulating paclitaxel resistance and tumor-associated macrophage (TAM) polarization in breast cancer. METHODS:qRT-PCR and Western blotting were used to detect the expression of lncRNA NEAT1, miR-133b, and PD-L1 in breast cancer SKBR3 cells and paclitaxel-resistant SKBR3 cells (SKBR3-PR). The effects of transfection with si-NEAT1 and miR-133b mimics on MRP, MCRP and PD-L1 expressions and cell proliferation, migration and apoptosis were investigated using qRT-PCR, Western blotting, scratch and Transwell assays, and flow cytometry. Rescue experiments were conducted using si-NEAT1 and miR-133b inhibitor. Human THP-1 macrophages were cultured in the presence of conditioned media (CM) derived from SKBR3 and SKBR3-PR cells with or with si-NEAT1 transfection for comparison of IL-4-induced macrophage polarization by detecting the surface markers. LDH@si-NEAT1 nanocarriers were constructed, and their effects on MRP, MCRP and PD-L1 expressions and cell behaviors of the tumor cells were examined. THP-1 cells were treated with the CM from LDH@si-NEAT1-treated tumor cells, and the changes in their polarization were assessed. RESULTS:SKBR3-PR cells showered significantly upregulated NEAT1 and PD-L1 expressions and lowered miR-133b expression as compared with their parental cells. Transfection with si-NEAT1 and miR-133b mimics inhibited viability, promoted apoptosis and enhanced MRP and BCRP expressions in SKBR3-PR cells. NEAT1 knockdown obvious upregulated miR-133b and downregulated PD-L1, MRP and BCRP expressions. The CM from SKBR3-PR cells obviously promoted M2 polarization of THP-1 macrophages, which was significantly inhibited by CM from si-NEAT1-transfected cells. Treatment with LDH@si-NEAT1 effectively inhibited migration and invasion, promoted apoptosis, and reduced MRP, BCRP and PD-L1 expressions in the tumor cells. The CM from LDH@si-NEAT1-treated SKBR3-PR cells significantly downregulated Arg-1, CD163, IL-10, and PD-L1 and upregulated miR-133b expression in THP-1 macrophages. CONCLUSIONS:LDH@si-NEAT1 reduces paclitaxel resistance of breast cancer cells and inhibits TAM polarization by targeting the miR-133b/PD-L1 axis.

Organofluorine compounds have attracted substantial attention owing to their wide application in agrochemistry. Fluorinase (FlA) is a unique enzyme in nature that can incorporate fluorine into an organic molecule. Chlorinase (SalL) has a similar mechanism as fluorinase and can use chloride but not fluoride as a substrate to generate 5 '-chloro-deoxyadenosine (5 '-ClDA) from S-adenosyl-l-methionine (SAM). Therefore, identifying the features that lead to this selectivity for halide ions is highly important. Here, we engineered SalL to gain the function of FlA. We found that residue Tyr70 plays a key role in this conversion through alanine scanning. Site-saturation mutagenesis experiments demonstrated that Y70A/C/S/T/G all exhibited obvious fluorinase activity. The G131S mutant of SalL, in which the previously thought crucial residue Ser158 for fluoride binding in FlA was introduced, did not exhibit fluorination activity. Compared with the Y70T single mutant, the double mutant Y70T/W129F increased 5 '-fluoro-5-deoxyadenosine (5 '-FDA) production by 76%. The quantum mechanics (QM)/molecular mechanics (MM) calculations suggested that the lower energy barriers and shorter nucleophilic distance from F- to SAM in the mutants than in the SalL wild-type may contribute to the activity. Therefore, our study not only renders SalL the activity of FlA but also sheds light on the enzyme selectivity between fluoride versus chloride.

Fluorine is a unique element with important roles in medicinal chemistry, agrochemistry, and materials chemistry. The fluoroethyl group is an important fluoroalkyl functional unit that is widely used in clinical drugs, F-19 probes and F-18 PET diagnostic drugs. Chemo- and regioselective fluoroethylation is difficult in chemical synthesis. To date, no enzymatic reaction for selective fluoroethylation has been reported. Based on the widespread natural methyl donor S-adenosine-l-methionine (SAM), we designed and synthesized a fluoroethyl SAM analogue (FEt-SAM). A stability study revealed that FEt-SAM was very labile under physiological conditions and gave the fluorine-elimination product vinyl-SAM. We circumvented this problem by replacing the S in FEt-SAM with Se to give fluoroethyl Se-adenosyl-l-selenomethionine (FEt-SeAM). By using halide methyltransferase (HMT) and its mutant for the in situ production of FEt-SeAM, we created cascade reactions of the HMT mutant with methyltransferases and fluoroethylated several O-, N-, S-, and C-nucleophiles. For methyltransferases that did not recognize FEt-SeAM well, such as DnrK and NovO, simple mutagenesis of the conserved hydrophobic residues (Leu and Ile) in the SAM binding pocket to smaller amino acids significantly increased the activities. Therefore, we have provided a useful tool for the late-stage fluoroethylation of natural products and drugs. This method could also be used to enzymatically prepare probes for F-19 NMR and F-18 PET tests.

Breast cancer (BC) is one of the frequent tumors that seriously endanger the physical and mental well-being in women with strong heterogeneity, and its pathogenesis involves multiple risk factors. Depending on the type of BC, hormonal therapy, targeted therapy, and immunotherapy are the current systemic treatment options along with conventional chemotherapy. Despite significant progress in understanding BC pathogenesis and therapeutic options, there is still a need to identify new therapeutic targets and develop more effective treatments. According to recent sequencing and profiling studies, non-coding (nc) RNAs genes are deregulated in human cancers via deletion, amplification, abnormal epigenetic, or transcriptional regulation, and similarly, the expression of many ncRNAs is altered in breast cancer cell lines and tissues. The ability of single ncRNAs to regulate the expression of multiple downstream gene targets and related pathways provides a theoretical basis for studying them for cancer therapeutic drug development and targeted delivery. Therefore, it is far-reaching to explore the role of ncRNAs in tumor development and their potential as therapeutic targets. Here, our review outlines the potential of two major ncRNAs, long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) as diagnostic and prognostic biomarkers as well as targets for new therapeutic strategies in breast cancer.