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PubMed2026

Chloramphenicol and tetracycline synergize with bacteriophage SeKF_13 to inactivate antimicrobial-resistant Salmonella Typhimurium.

UNLABELLED: Non-typhoidal Salmonella is estimated to cause up to 1 billion cases of global foodborne illness per year. Salmonella Typhimurium is a serovar of gravest worldwide concern as it is capable of infecting animal and human hosts and can also acquire antimicrobial resistance (AMR) determinants at a rapid rate. Recent advances in phage research have positioned them as especially useful for inactivation of Salmonella where antibiotics have proven no longer effective. Even more recently, phage-antibiotic synergy (PAS) has been proposed as a solution for AMR Salmonella, where synergistic combinations of phages and antibiotics are more effective than application of phage or antibiotic alone. Utilizing an in-house phage isolate, SeKF_13, we sought to determine the existence of PAS against a strain of Salmonella enterica serovar Typhimurium 14028 2a that is clinically resistant to bacteriostatic antibiotics chloramphenicol and tetracycline. Checkerboard assays revealed the presence of synergy when sub-lethal (sub-MIC) levels of either tetracycline or chloramphenicol were combined with phage SeKF_13 (P < 0.05; two-way ANOVA). Compared to tetracycline or chloramphenicol alone, the addition of phage also decreased the MICs of both antibiotics twofold. We also monitored the development of resistance and found that PAS significantly suppressed emergence of resistance compared to the antibacterial agents alone (P < 0.05; Tukey's HSD). Whole-genome sequencing revealed that SeKF_13 is devoid of genes encoding integrase, antimicrobial resistance, and virulence, ensuring safety in future applications. Together, our results suggest that combined treatment of phage and antibiotic can improve antimicrobial efficacy against antibiotic-resistant Salmonella enterica. IMPORTANCE: Salmonella enterica is a foodborne pathogen that causes one of the highest rates of foodborne illness worldwide. They are also capable of becoming resistant to antimicrobials very rapidly (i.e., antimicrobial resistance; AMR) due to their ability to acquire AMR determinants, undermining the effectiveness of current treatments. Bacteriophages (phages), viral predators of bacteria, have been proven to be effective in some cases, but recently, phage-antibiotic synergy has been proposed as a more effective solution than phages or antibiotics alone. We found this was, indeed, the case; using phage SeKF_13 and tetracycline or chloramphenicol (to which the Salmonella strain was resistant), we found that combination treatment was significantly more effective than either treatment alone. These results demonstrate that combined treatment of phage and antibiotic can bolster treatment efficacy against AMR Salmonella.

Salmonella typhimurium↗

PubMed2025

Synergistic targeting of cancer cells through simultaneous inhibition of key metabolic enzymes.

As cancer cell specific rewiring of metabolic networks creates potential therapeutic opportunities, we conducted a synthetic lethal screen utilizing inhibitors of metabolic pathways. Simultaneous administration of (R)-GNE-140 and BMS-986205 (Linrodostat) preferentially halted proliferation of ovarian cancer cells, but not of their non-oncogenically transformed progenitor cells. While (R)-GNE-140 inhibits lactate dehydrogenase (LDH)A/B and thus effective glycolysis, BMS-986205, in addition to its known inhibitory activity on Indoleamine 2,3-dioxygenase (IDO1), also restricts oxidative phosphorylation (OXPHOS), as revealed here. BMS-986205, which is being tested in multiple Phase III clinical trials, inhibits the ubiquinone reduction site of respiratory complex I and thus compromises mitochondrial ATP production. The energetic catastrophe caused by simultaneous interference with glycolysis and OXPHOS resulted in either cell death or the induction of senescence in tumor cells, with the latter being eliminated by senolytics. The frequent synergy observed with combined inhibitor treatment was comprehensively confirmed through testing on tumor cell lines from the DepMap panel and on human colorectal cancer organoids. These experiments revealed highly synergistic activity of the compounds in a third of the tested tumor cell lines, correlating with alterations in genes with known roles in metabolic regulation and demonstrating the therapeutic potential of metabolic intervention.

Humans↗

PubMed2026

Cranberry juice potentiates sensitivity of uropathogenic Escherichia coli (UPEC) strains to fosfomycin and decreases occurrence of spontaneous resistance.

Uropathogenic Escherichia coli (UPEC) is the leading cause of urinary tract infections (UTIs). The growing prevalence of antimicrobial resistance underscores the need for alternative or complementary strategies to enhance antibiotic activity. Fosfomycin (FOS) remains a recommended first-line treatment for uncomplicated UTIs due to its broad activity and low resistance rates; however, spontaneous resistance frequently arises through mutations in bacterial transport systems. Cranberry juice is known for its anti-adhesive and anti-infective properties; however, its potential to modulate antibiotic activity remains poorly understood. Here, we show that cranberry juice markedly potentiates the antibacterial activity of FOS and limits the emergence of resistance in UPEC clinical isolates. In 72% of the 32 tested isolates, cranberry juice significantly increased FOS inhibition activities and reduced spontaneous FOS-resistant mutant frequencies by up to five orders of magnitude. Whole-genome sequencing revealed distinct mutational patterns: FOS-resistant mutants selected without cranberry juice primarily carried glpT mutations, whereas those obtained with juice harbored mutations in uhpT or associated regulatory genes. Reporter assays indicated that cranberry juice represses glpT expression while maintaining UhpT-mediated FOS uptake, thereby sustaining antibiotic entry and activity. These results demonstrate that cranberry juice alters bacterial carbohydrate transport regulation to potentiate FOS activity and suppress resistance emergence. This study provides novel evidence that a natural product can enhance FOS activity, highlighting its potential as an antibiotic adjuvant for UTI management.IMPORTANCEAntimicrobial resistance is a growing threat to public health, and new strategies are needed to preserve the activity of existing antibiotics. This study reveals that cranberry juice, a widely consumed natural product, enhances the antibacterial activity of fosfomycin against uropathogenic Escherichia coli by modulating bacterial sugar transport systems. By shifting fosfomycin uptake from GlpT- to UhpT-mediated pathways, cranberry juice both potentiates antibiotic activity and suppresses the emergence of resistant mutants. These findings provide new insight into how dietary components can influence antibiotic response, offering a promising basis for developing natural adjuvants that extend the lifespan of current antimicrobial agents.

Fosfomycin↗

PubMed2021

Removal of peptidoglycan and inhibition of active cellular processes leads to daptomycin tolerance in Enterococcus faecalis.

Daptomycin is a cyclic lipopeptide antibiotic used in the clinic for treatment of severe enterococcal infections. Recent reports indicate that daptomycin targets active cellular processes, specifically, peptidoglycan biosynthesis. Within, we examined the efficacy of daptomycin against Enterococcus faecalis under a range of environmental growth conditions including inhibitors that target active cellular processes. Daptomycin was far less effective against cells in late stationary phase compared to cells in exponential phase, and this was independent of cellular ATP levels. Further, the addition of either the de novo protein synthesis inhibitor chloramphenicol or the fatty acid biosynthesis inhibitor cerulenin induced survival against daptomycin far better than controls. Alterations in metabolites associated with peptidoglycan synthesis correlated with protection against daptomycin. This was further supported as removal of peptidoglycan induced physiological daptomycin tolerance, a synergistic relation between daptomycin and fosfomycin, an inhibitor of the fist committed step peptidoglycan synthesis, was observed, as well as an additive effect when daptomycin was combined with ampicillin, which targets crosslinking of peptidoglycan strands. Removal of the peptidoglycan of Enterococcus faecium, Staphylococcus aureus, and Bacillus subtilis also resulted in significant protection against daptomycin in comparison to whole cells with intact cell walls. Based on these observations, we conclude that bacterial growth phase and metabolic activity, as well as the presence/absence of peptidoglycan are major contributors to the efficacy of daptomycin.

Anti-Bacterial Agents↗

PubMed2025

Integrating network pharmacology and experimental validation to uncover the synergistic effects of Huangqi ()-Ezhu () with 5-fluorouracil in colorectal cancer models.

OBJECTIVE: To evaluate the effects of Huangqi (Radix Astragali Mongolici)-Ezhu (Rhizoma Curcumae Phaeocaulis) (HQEZ) on colorectal cancer therapies and to elucidate the potential mechanisms of HQEZ, especially in combination with 5-Fluorouracil (5-FU). METHODS: The anti-tumor effects of HQEZ were evaluated in colorectal cancer models both in vivo and in vitro. The network pharmacological assay was used to investigate potential mechanisms of HQEZ. Potential target genes were selected by Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, protein-protein interaction network (PPI) and molecular docking. Within key targets, potential targets related to drug sensitivity, especially the sensitivity to 5-FU, were evaluated in HCT116 in vitro by immunofluorescence, quantitative real-time polymerase chain reaction (qPCR) and Western-blot. Then, changes in potential targets were assessed in tumors from tumor-bearing mice and the expression of these targets was also evaluated in colorectal cancer (COAD) patients from the Cancer Genome Atlas Program (TCGA) database. RESULTS: HQEZ significantly enhanced the anti-tumor activity of 5-FU in vivo and inhibit the growth of HCT116 in vitro. By network pharmacological analysis, key targets, such as protein kinase B (AKT1), epidermal growth factor receptor (EGFR), adenosine triphosphate (ATP) binding cassette subfamily B member 1 (ABCB1, also named multidrug resistance protein 1, MDR1), ATP binding cassette subfamily G member 2 (ABCG2), thymidylate synthetase (TYMS, also named TS), prostaglandin-endoperoxide synthase 2 (PTGS2), matrix metallopeptidase 2 (MMP2), MMP9, toll like receptor 4 (TLR4), TLR9 and dihydropyrimidine dehydrogenase (DPYD), were identified. Additionally, 4 potential core active ingredients (Folate, Curcumin, quercetin and kaempferol) were identified to be important for the treatment of colorectal cancer with HQEZ. In key targets, chemoresistance related targets were validated to be affected by HQEZ. Furthermore, 5-FU sensitivity related targets, including MDR1, TS, EGFR, ribonucleotide reductase catalytic subunit M1, Breast and Ovarian Cancer Susceptibility Protein 1 (BRCA1) and mutl homolog 1 were also significantly reduced by HQEZ both in vitro and in vivo. Finally, these validated key targets and 5-FU sensitivity related targets were demonstrated to be up-regulated in COAD patients based on TCGA database. CONCLUSION: HQEZ has synergistic effects on the anti-tumor activity of 5-FU in the treatment of colorectal cancer both in vivo and in vitro. The beneficial effect of HQEZ results from the inhibition of the drug sensitivity targets associated with 5-FU. The combination therapy of HQEZ with 5-FU or other chemotherapeutic drugs will also improve the anti-tumor efficacy of chemotherapy.

Humans↗

PubMed2026

Magnolol Potentiates Sorafenib-induced Apoptosis and Inhibits Metastatic Signaling in Renal Carcinoma.

BACKGROUND/AIM: Sorafenib is a standard targeted therapy for renal cell carcinoma; however, resistance and limited efficacy remain clinical challenges. Magnolol, a bioactive compound derived from Magnolia officinalis, exhibits anti-cancer properties, and may enhance therapeutic responses. This study investigated whether magnolol potentiates the anti-tumor effects of sorafenib in murine renal carcinoma (Renca) cells and explored the underlying molecular mechanisms. MATERIALS AND METHODS: Cell viability was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and drug interactions were analyzed using the Chou-Talalay method. Apoptosis was evaluated by Annexin V/propidium iodide (PI) staining, cell-cycle analysis, and caspase activation. Western blotting and flow cytometry were performed to examine apoptotic pathways and epidermal growth factor receptor (EGFR)/SRC proto-oncogene, non-receptor tyrosine kinase (SRC)/nuclear factor kappa B (NF-κB) signaling. Transwell assays and protein expression profiling were used to analyze migration, invasion, and epithelial-mesenchymal transition (EMT) markers. RESULTS: Combination treatment synergistically reduced cell viability, with a combination index (CI) <1, and significantly enhanced apoptosis via activation of intrinsic and extrinsic pathways. Co-treatment suppressed EGFR/SRC proto-oncogene, SRC/ NF-κB signaling and reduced migration, invasion, and EMT-associated markers. CONCLUSION: Magnolol enhances sorafenib efficacy by promoting apoptosis and inhibiting survival and metastatic signaling pathways in renal carcinoma cells.

Lignans↗

PubMed2026

Mirvetuximab soravtansine plus pembrolizumab in recurrent folate receptor alpha-positive uterine serous carcinoma: a phase II trial.

Immune checkpoint inhibitors (ICI) synergize preclinically with antibody drug conjugates (ADC), harboring anti-tubulin maytansinoid payloads. We conducted an investigator-initiated, single-arm, phase 2 trial of mirvetuximab soravtansine (MIRV), a folate receptor alpha (FOLR1/FRα)-targeting ADC with the maytansinoid payload, DM4, combined with pembrolizumab in female patients with recurrent FOLR1-expressing serous endometrial cancer (EC, NCT03835819). Co-primary objectives include objective response rate (ORR) and rate of progression-free survival at 6 months (PFS6); secondary objectives include PFS, overall survival, duration of response and safety. Exploratory objectives include correlation of tumor genomics and immunoprofiling with clinical activity. Eighteen patients initiated protocol therapy [MIRV 6 mg/kg adjusted ideal body weight IV and pembrolizumab 200 mg IV every 3 weeks]. Confirmed ORR is 28% (1 complete and 4 partial responses, 95% CI:10-53%), Kaplan Meier estimate of PFS6 is 24.4% (95% CI:7.7-46.1%) with 4 patients progression free at 6 months; trial was closed early for feasibility (planned sample size of 35 patients not reached) and hence these results are considered preliminary. G3 treatment-related adverse effects were rare with no grade ≥4 toxicities. We report a population of high FOLR1-expressing tumor-associated macrophages (CD163 + FOLR1 + ), suggesting potential on-target, off-tumor immune editing by MIRV. A composite biomarker score derived in this cohort correlates with objective response to MIRV and pembrolizumab.

Adult↗

PubMed2025

Reduction in ARGs and Mobile Genetic Elements Using 2-Bromoethane Sulfonate in an MFC-Powered Fenton System.

The integration of an MFC-powered Fenton (MFC-Fenton) system into the traditional anaerobic composting process can promote excess dewatered sludge (ES) decomposition. However, the antibiotic resistance gene (ARG) profiles in ES treated by MFC-Fenton systems remain poorly understood; in addition, the effect of adding 2-bromoethane sulfonate (BES, a methane inhibitor) during ES treatment using an MFC-Fenton system on ARG levels is largely unexplored. The present work focused on investigating the effects of BES and bioelectrochemical processes on ARG and MGE abundances and unraveling the ARG attenuation mechanism. According to our findings, adding BES promoted ARG reduction in ES in an MFC-Fenton system. The average ARG levels in the MFC-Fenton samples containing high BES contents (0.4 or 0.5 g BES/g VSS) markedly declined relative to those in samples containing lower BES levels. Moreover, macrolide transporter ATP-binding protein, macrolide-efflux protein, and macB levels markedly decreased as BES levels increased. BES supplementation and bioelectrochemical assistance were crucial for altering the ARG composition in the MFC-Fenton system. Changes in the microbial community composition had the greatest effect on the variation in ARG composition. Furthermore, the Actinobacteria and Firmicutes levels accounted for 52.8% of the overall ARG variation. Among MGEs, plasmids, insertion sequences, and integrons showed lower levels within the sludge metagenomes. Typically, sulI, sulII, tetG, and bla TEM levels were positively correlated with metal resistance genes (MRGs), and their levels markedly declined following the MFC-Fenton process. Thus, the collective evidence indicates that BES synergizes with bioelectrogenesis to reduce ARG abundance.

Sewage↗

PubMed2026

Therapeutic Potential of Terpenes in Lung Cancer: Modulation of 4-Oxo- Retinoic Acid, TNF-α, NF-κB, and HDAC2 Pathways.

Non-small cell lung cancer (NSCLC) includes various epithelial malignancies, such as squamous cell carcinoma, large cell carcinoma, and adenocarcinoma. Despite advancements in surgical resection, chemoradiotherapy, and multimodal therapies, NSCLC prognosis remains challenging due to its complex molecular landscape, drug resistance, and high treatment costs. Recent research highlights the potential of natural compounds, particularly terpenes and terpenoids, derived from essential oils (EOs), to enhance NSCLC treatment. These compounds exhibit anticancer properties and modulate key pathways like the 4-oxo-retinoic acid pathway, TNF-α signaling, NF-κB activation, and histone deacetylases (HDACs). Retinoids, a subclass of terpenes, show both chemopreventive and therapeutic benefits, especially when combined with other agents, though challenges in dosing and delivery methods limit their clinical application. Terpenes may also synergize with emerging therapies, such as antiangiogenic treatments and immunotherapy, to improve outcomes. Biomarkers, including genomic, epigenomic, and proteomic markers, play a critical role in predicting responses to terpene-based treatments, supporting personalized medicine. The integration of terpenes into existing regimens, in combination with conventional therapies, holds promise in overcoming clinical challenges, improving patient outcomes, and advancing natural compound use in modern oncology. Future research should focus on optimizing terpene therapies and addressing clinical hurdles.

Humans↗

PubMed2026

The Novel Hypomethylating Agent NTX-301 Reprograms Epigenetic and Hippo Signaling Pathways and Exhibits Preclinical Activity in Venetoclax-Resistant and TP53-Mutant AML.

PURPOSE: Hypomethylating agent (HMA) and the BCL-2 inhibitor venetoclax (VEN) combinations have evolved into first-line therapies for patients with acute myeloid leukemia (AML), yielding high response rates. However, most patients ultimately relapse, particularly those with TP53 mutations. We investigated mechanisms of action and therapeutic efficacy of NTX-301, a next-generation HMA. EXPERIMENTAL DESIGN: Methods used include flow cytometry-based cell viability assays, Western blotting, reverse-phase protein arrays, RNA sequencing, Cytometry by Time-Of-Flight single-cell mass cytometry, and methylation profiling in various therapy-resistant AML models. RESULTS: We demonstrate that NTX-301 exhibits superior efficacy compared with 5-azacytidine (5-AZA) in 5-AZA- or VEN-resistant AML. It synergizes with VEN in VEN- or VEN/HMA-resistant and TP53-mutant AML blasts and stem/progenitor cells (combination index <1). NTX-301 inhibits DNA methyltransferase 1 (DNMT1) and increases p73 and caspase 8 (CASP8)/activated CASP8 levels in TP53 wild-type and TP53-mutant AML and activates p53 signaling. It extends survival (≥45%) in both xenograft and patient-derived xenograft models. Methylation profiling revealed that NTX-301 is a more targeted HMA compared with 5-AZA, enabling suppression of functionally enriched genes/pathways. Pathway analysis of 954 commonly hypomethylated genes showed profoundly greater enrichment of Hippo signaling in NTX-301-treated compared with 5-AZA-treated cells and enrichment of insulin signaling, VEGF pathway, and cell cycle selectively in NTX-301- but not in 5-AZA-treated cells. NTX-301-mediated Hippo signaling was validated at protein levels. CONCLUSIONS: Data suggest that NTX-301 exerts potent antileukemic activities superior to 5-AZA and synergizes with VEN in VEN-resistant and TP53-mutant AML, in part by suppressing DNMT1, inducing DNA damage responses and apoptosis through p53 signaling, and demethylating LATS1/2, thereby activating Hippo signaling.

Humans↗

PubMed2026

Glutathione reductase deficiency potentiates the immunogenicity of ferroptosis and cuproptosis via amplified reactive oxygen species accumulation and cGAS-STING pathway activation.

BACKGROUND: Cancer remains a major therapeutic challenge due to drug resistance and metastasis, processes driven by oxidative stress and redox imbalance. Targeting this vulnerability through ferroptosis (iron-dependent lipid peroxidation) and cuproptosis (copper-driven mitochondrial dysfunction), two ROS-mediated cell death pathways, offers a promising therapeutic strategy. However, clinical translation is hindered by incomplete understanding of their redox regulation and limited immunogenicity. METHODS: A genome-wide CRISPR knockout screen was performed to identify key regulators of ferroptosis. Genetic depletion or pharmacological inhibition of candidate genes was evaluated across multiple cancer cell lines for sensitivity to ferroptosis inducer RSL3 and the cuproptosis inducer elesclomol (Es). Antitumor efficacy was assessed in xenograft, orthotopic, metastatic, and syngeneic mouse models, alone or combined with immune checkpoint inhibitors. Mechanistic studies also examined ROS production, mitochondrial stress, mitochondrial DNA release, cGAS-STING activation, and immune responses within the tumor microenvironment. RESULTS: Glutathione reductase (GSR), a central enzyme maintaining reduced glutathione (GSH) homeostasis, was identified as the top suppressor of ferroptosis. GSR knockout or pharmacological inhibition markedly sensitized diverse cancer cell lines to RSL3-induced ferroptosis, while GSR overexpression conferred resistance. Strikingly, GSR depletion also enhanced sensitivity to cuproptosis triggered by the copper ionophore Es. In multiple in vivo tumor models, GSR inhibition synergizes with RSL3 or Es to suppress tumor growth, inhibit lung metastasis, and prolong survival. Mechanistically, GSR deficiency amplified ROS production, induced mitochondrial stress, and triggered the cytosolic mitochondrial DNA release under ferroptotic or cuproptotic stress, activating the cGAS-STING pathway in vitro and in vivo. This increased inflammatory cytokine production, promoted immunogenic cell death, and enhanced the release of damage-associated molecular patterns (DAMPs), including HMGB1. Together, GSR inhibition combined with a ferroptosis or cuproptosis inducer transformed the tumor microenvironment into a highly immune stimulatory state, thereby enhancing the efficacy of immune checkpoint blockade through increased dendritic cell activation and T-cell infiltration and activation. CONCLUSIONS: GSR represents a key molecular node connecting and modulating ferroptosis and cuproptosis through redox regulation. Targeting GSR amplifies ROS-mediated immunogenic cell death, triggers cGAS-STING activation in cancer cells, and enhances the efficacy of cancer immunotherapy, providing a promising redox-based therapeutic strategy.

Ferroptosis↗

PubMed2025

Pharmacologic activation of Δ133p53α reduces cellular senescence in progeria patients-derived cells.

BACKGROUND: Patients with Hutchinson-Gilford progeria syndrome (HGPS) show accelerated aging phenotypes and have shortened lifespan, with implications in physiological aging processes as well. While therapeutic approaches targeting the disease-causing abnormal protein, progerin, have been developed, further efforts to explore mechanistically distinct and complementary strategies are still critical to better treatment regimens. We previously showed that lentiviral vector-driven expression of Δ133p53α, a natural inhibitory isoform of p53, rescued HGPS patients-derived fibroblasts from early entry into cellular senescence, which is a downstream event of progerin-induced DNA damage. We also performed a quantitative high-throughput screen (qHTS) of approved drug and investigational agent libraries, leading to the identification of celastrol and AZD1981 as compounds that upregulate Δ133p53α protein levels. METHODS: To investigate whether celastrol and ADZ1981 upregulate endogenous Δ133p53α in HGPS-derived fibroblasts and reduce their senescence-associated phenotypes, we performed western blot assays (Δ133p53α, progerin, and p21WAF1, which mediates p53-induced senescence and is inhibited by Δ133p53α), senescence-associated β-galactosidase (SA-β-gal) staining, enzyme-linked immunosorbent assay (IL-6, which is a proinflammatory cytokine secreted from senescent cells), and qRT-PCR assays (p21WAF1 and IL-6). RESULTS: Treatment with celastrol (0.1 μM for 24 h) or AZD1981 (10 μM for 24 h) reproducibly increased Δ133p53α expression and decreased p21WAF1 expression in two strains of fibroblasts derived from HGPS patients. These compounds reduced the percentage of SA-β-gal-positive senescent cells and the secretion of IL-6 into culture medium in both of these fibroblast strains, irrespective of their different basal levels of senescence and IL-6 secretion. These compounds had no effect on the level of progerin. CONCLUSION: Celastrol and ADZ1981 upregulate endogenous Δ133p53α and, reproducing the effects of its vector-driven expression, inhibit cellular senescence and IL-6 secretion in HGPS-derived fibroblasts. Their progerin-independent action suggests that they may synergize with currently available progerin-targeting therapies. This study also warrants further investigation of these compounds for potential applications in other diseases and conditions in which Δ133p53α-regulated senescence plays a role.

Hutchinson-Gilford progeria syndrome↗

PubMed2026

Targeting PRMT9 overcomes venetoclax resistance in AML by modulating splicing and inhibiting translation.

Arginine methylation catalyzed by protein arginine methyltransferases (PRMTs) is required for cancer cell proliferation, but whether PRMTs mediate resistance to therapy remains unclear. Here, we performed loss-of-function screens in venetoclax-resistant (VEN-R) acute myeloid leukemia (AML) patient-derived xenograft cells and found that PRMT9 plays a critical role in promoting VEN resistance. Specifically, VEN-R AML samples exhibited high levels of PRMT9, and PRMT9 inhibition resensitized AML cells to VEN treatment. In preclinical resistant models, genetic ablation of PRMT9 synergized with VEN to eradicate AML cells. Consistently, pharmacologic inhibition of PRMT9 combined with VEN produced similar effects in VEN-R AML mouse models. Mechanistically, PRMT9 ablation disrupted RNA splicing by inducing exon skipping in mRNA encoding ALG13, an uridine diphosphate (UDP)-N-acetylglucosaminyltransferase subunit, thereby downregulating expression of the VEN efflux transporter encoded by the adenosine triphosphate-binding cassette subfamily C member 1 gene. PRMT9 inhibition also suppressed protein synthesis, leading to downregulation of short-lived oncoproteins such as MCL1. These findings establish a connection between PRMT9-mediated arginine methylation and poor VEN responsiveness and demonstrate that targeting PRMT9 may represent a viable strategy to overcome VEN resistance.

Protein-Arginine N-Methyltransferases↗