Farini A, Tripodi L, Villa C
… +14 more, Strati F, Facoetti A, Baselli G, Troisi J, Landolfi A, Lonati C, Molinaro D, Wintzinger M, Gatti S, Cassani B, Caprioli F, Facciotti F, Quattrocelli M, Torrente Y
EMBO Mol Med
· 2026 Jun · PMID 42236982
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Farini A, Tripodi L, Villa C
… +14 more, Strati F, Facoetti A, Baselli G, Troisi J, Landolfi A, Lonati C, Molinaro D, Wintzinger M, Gatti S, Cassani B, Caprioli F, Facciotti F, Quattrocelli M, Torrente Y
EMBO Mol Med
· 2026 Jun · PMID 42236981
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Duchenne muscular dystrophy (DMD) is a progressive, severe muscle-wasting disease caused by mutations in DMD, encoding dystrophin, that leads to loss of muscle function with cardiac/respiratory failure and premature deat...Duchenne muscular dystrophy (DMD) is a progressive, severe muscle-wasting disease caused by mutations in DMD, encoding dystrophin, that leads to loss of muscle function with cardiac/respiratory failure and premature death. Since dystrophic muscles are sensed by infiltrating inflammatory cells, and gut microbial communities can cause immune dysregulation and metabolic syndrome, we sought to investigate whether intestinal bacteria support the muscle immune response in the mdx dystrophic murine model. We highlighted a strong correlation between DMD disease features and the relative abundance of Prevotella. Furthermore, the absence of gut microbes through the generation of mdx germ-free animal model, as well as modulation of the microbial community structure by antibiotic treatment, influenced muscle immunity and fibrosis. Intestinal colonization of mdx mice with eubiotic microbiota was sufficient to reduce inflammation and improve muscle pathology and function. This work identifies a potential role for the gut microbiota in the pathogenesis of DMD.
Fisher KL, Mpotje T, Nargan K
… +13 more, Moodley D, Rajkumar-Bhugeloo K, Baiyegunhi OO, Naidoo T, Madansein R, Sathekge M, Leslie A, Tomlinson G, Pollara G, Noursadeghi M, Steyn AJC, Ndung'u T, Marakalala MJ
EMBO Mol Med
· 2026 Jun · PMID 42230989
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Understanding drivers of tuberculosis (TB) associated lung pathological damage is vital in identifying targets for host directed therapies (HDT). NETosis is a neutrophil specific cell death characterized by release of ne...Understanding drivers of tuberculosis (TB) associated lung pathological damage is vital in identifying targets for host directed therapies (HDT). NETosis is a neutrophil specific cell death characterized by release of neutrophil extracellular traps (NETs). The role of NETosis in TB-associated lung damage and disease pathogenesis is still poorly understood. We analysed human lung TB granuloma samples using a proteomics approach, which revealed enrichment of neutrophil-associated proteins in necrotic regions of caseous and cavitary granulomas. Using immunohistochemistry (IHC), we validated the abundance of neutrophil-associated proteins, including myeloperoxidase (MPO), cytochrome b-245 beta chain (CYBB) and neutrophil cytosolic factor 1(NCF1), as well as NETosis markers, neutrophil elastase (NE) and citrullinated H3, in necrotizing caseum of human TB granulomas. MPO protein expression was also more abundant in the plasma of TB patients compared to healthy and latently infected (LTBI) participants. MPO directly correlated with an inflammatory disease marker, IP-10. In addition, MPO and IP-10 colocalized in caseous lesions. In-vitro drug inhibition assays were used to investigate potential drivers of NETosis, with pharmaceutical inhibition of MPO, NE and CYBB resulting in reduction of NETosis induced by Mycobacterium tuberculosis (Mtb). Using RT-qPCR we analysed the expression of 18 neutrophil associated genes in the blood of healthy (n = 20), latent TB infection (LTBI) (n = 20) and TB (n = 30) participants. We found that MPO, NCF1 and NCF2 were upregulated in the TB group. Furthermore, the NETosis-associated genes were induced in a human standardized antigen challenge model. Our data shows evidence of NETosis as an associate of lung pathological damage in TB and identifies key drivers of the neutrophil cell death that can be intercepted as potential HDT targets to reduce neutrophil driven lung pathological damage.
Zakrzewski P, Rice CM, Naveh C
… +25 more, Dowell I, Fleming K, Ramesh AV, Jones R, Moura PL, Cela D, Groves S, Fletcher-Jones S, Victory Y, Bhima M, Ebmeier S, Carey L, Butler M, Satchell SC, Berg A, Palolite N, Nyirenda J, Nyasulu W, Zgambo I, Attipa C, Wooldridge L, Davidson AD, Cunnington A, Moxon CA, Amulic B
EMBO Mol Med
· 2026 May · PMID 42204305
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Neutrophils are essential for defense against pathogens but excessive activation in systemic infections can drive immunopathology. We show that neutrophil degranulation can induce endothelial dysfunction via degradation...Neutrophils are essential for defense against pathogens but excessive activation in systemic infections can drive immunopathology. We show that neutrophil degranulation can induce endothelial dysfunction via degradation of the glycocalyx and increase of endothelial permeability. To identify targetable pathways regulating neutrophil degranulation in severe inflammation, we compared the proteomes of neutrophils isolated from patients with severe malaria and sepsis. We found significant upregulation of mitochondrial pathways, which was accompanied by increased rates of mitochondrial respiration and was linked to neutrophil immaturity. Malaria induced mitochondrial fusion and networking, while sepsis was associated with mitochondrial biogenesis. Immature neutrophils in both infections produced elevated levels of mitochondrial ROS, which enhanced release of primary and secondary granules via reorganization of cortical actin. Our study provides a mechanistic explanation for the hyperinflammatory nature of immature neutrophils and points to pharmacological scavenging of mitochondrial ROS as a potential therapeutic strategy to reduce endothelial damage in severe inflammation.
Li Q, Zhang Y, Luo H
… +9 more, Wu Y, Qin J, Wang L, Zhang Q, Yu T, Huang X, Guo S, Xie B, He H
EMBO Mol Med
· 2026 May · PMID 42192204
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Ascites, a hallmark of advanced ovarian cancer, severely impairs patient quality of life and contributes to therapeutic resistance. Current management strategies remain primarily palliative, highlighting the urgent need...Ascites, a hallmark of advanced ovarian cancer, severely impairs patient quality of life and contributes to therapeutic resistance. Current management strategies remain primarily palliative, highlighting the urgent need to elucidate the underlying mechanisms. Although TREM2 macrophages are enriched in malignant ascites, the role of soluble TREM2 (sTREM2) in regulating vascular function and ascites pathogenesis remains poorly understood. Here, we show that sTREM2 levels are elevated in malignant ascites and positively correlate with ascites volume. Using a combination of in vitro, in vivo, and ex vivo models, we demonstrate that sTREM2 promotes vascular permeability and drives ascites formation. Mechanistically, sTREM2 binds to nucleolin (NCL) on endothelial cells and activates the AKT/eNOS signaling pathway, which leads to VE-cadherin phosphorylation and ultimately vascular leakage. sTREM2-induced hyperpermeability was abolished by NCL knockdown or eNOS inhibition. Importantly, administration of a neutralizing antibody against sTREM2 significantly reduced ascites formation and tumor burden in mouse models. Our study identifies the sTREM2-NCL-AKT-eNOS axis as a critical driver of vascular leakage and malignant ascites in ovarian cancer, highlighting it as a promising therapeutic target.
George AM, Chen Y, Gladchuk S
… +24 more, Alcaide M, Dalal H, Meng P, Brueffer C, Saghir H, Kimbung S, Aaltonen K, Oton L, Rushton C, Birkeälv S, Jönsson M, Zackrisson S, Skarping I, Förnvik D, Zander L, Honeth G, Woodhouse S, Howarth K, Borg Å, Ehinger A, Malmberg M, Rydén L, Loman N, Saal LH
EMBO Mol Med
· 2026 May · PMID 42192203
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Persistent circulating tumor DNA (ctDNA) during neoadjuvant treatment (NAT) of early breast cancer (EBC) indicates high-risk disease. Similarly, detection of ctDNA post-resection indicates molecular residual disease (MRD...Persistent circulating tumor DNA (ctDNA) during neoadjuvant treatment (NAT) of early breast cancer (EBC) indicates high-risk disease. Similarly, detection of ctDNA post-resection indicates molecular residual disease (MRD) and impending relapse. For ctDNA to be integrated into EBC management, accessible and scalable diagnostics are required. Here we apply an ultrasensitive, personalized tumor-informed approach to ctDNA evaluation predicated on analyses of structural variants (SVs) using a novel digital PCR (dPCR) multiplex SV technology. 136 patients eligible for NAT (29.4% TNBC, 44.9% HR+ /HER2- and 24.3% HER2+), enrolled between December 2014 and March 2019, were analyzed from the prospective SCAN-B study (NCT02306096, substudy NeoCircle). ctDNA detection at baseline was 89.7%; end-NAT ctDNA-positivity (21.4%) and NAT ctDNA-non-response (13.1%) were significant predictors of disease recurrence and death, and both superior to pathologic complete response. Detection of ctDNA post-operatively or during adjuvant monitoring was significantly associated with distant recurrence (median lead-time 13.8 months, range 0-47.7 months). These findings validate SVs as an MRD analyte and provide evidence for clinical use of this approach in EBC.
Li N, Wang Y, Han L
… +13 more, Qiao O, Wang X, Hao H, Chen X, Wang P, Saeed S, Wang J, Bao F, Hou Y, Zhang L, Duan X, Rao S, Gong Y
EMBO Mol Med
· 2026 May · PMID 42185634
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Rhabdomyolysis-induced acute kidney injury (RM-AKI) is mediated primarily by myoglobin (Mb) toxicity, yet effective targeted therapies remain unavailable. Through computational structural modeling, we uncovered that the...Rhabdomyolysis-induced acute kidney injury (RM-AKI) is mediated primarily by myoglobin (Mb) toxicity, yet effective targeted therapies remain unavailable. Through computational structural modeling, we uncovered that the haptoglobin β-subunit (Hpβ) can bind Mb, forming a structurally stable complex. We then engineered a 55 kDa recombinant GST-Hpβ fusion protein and demonstrated that this engineered construct exhibits robust binding affinity for free Mb (17.8 kDa), thereby generating a stable 72.8 kDa GST-Hpβ-Mb complex. Significantly, this complex surpasses the molecular size threshold of the glomerular filtration barrier (~69 kDa), thereby preventing Mb from being filtered into the renal tubules and inflicting subsequent pathological damage. Further analysis revealed that the GST-Hpβ-Mb complex is expeditiously eliminated via CD163-mediated macrophage phagocytosis. Employing well-established RM-AKI murine models, we demonstrated that a single intraperitoneal administration of the GST-Hpβ fusion protein markedly improves survival, ameliorates renal function, and alleviates kidney damage, with protective effects lasting beyond a two-week period. In sum, the GST-Hpβ fusion protein offers a novel and promising biotherapeutic agent that addresses the fundamental pathophysiology of RM-AKI.
Kong M, Zhu C, Xue Y
… +5 more, Hong W, Zhang G, Jiang D, Xu Y, Guo J
EMBO Mol Med
· 2026 May · PMID 42168655
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In response to various stimuli, quiescent resident cardiac fibroblasts undergo metabolic, morphological, and functional alterations, transitioning into myofibroblasts that mediate cardiac fibrosis. In the present study,...In response to various stimuli, quiescent resident cardiac fibroblasts undergo metabolic, morphological, and functional alterations, transitioning into myofibroblasts that mediate cardiac fibrosis. In the present study, we investigated the role of interferon regulatory factor 7 (IRF7) in fibroblast activation and cardiac fibrosis. Knockdown of IRF7 in quiescent cardiac fibroblasts potentiated myofibroblast transition, whereas overexpression of IRF7 suppressed it. Furthermore, targeted deletion of IRF7 in fibroblasts or myofibroblasts exacerbated cardiac fibrosis and impaired heart function in animal models of heart failure. Integrated transcriptomic analysis revealed hexokinase 1 (HK1) as an IRF7 downstream target. Consistently, genetic deletion or pharmacological inhibition of HK1 protected mice from adverse cardiac remodeling. Mechanistically, HK1 contributed to the cellular lactate pool, promoting histone H3K9 lactylation and enabling the transcription of pro-fibrogenic molecules. Finally, the relevance of the IRF7-HK1 axis was verified in human heart specimens. In conclusion, our data unveil an IRF7-HK1 axis that contributes to the metaboloepigenetic reprogramming of fibroblast activation and cardiac fibrosis. Targeting this axis may yield new therapeutic solutions for heart failure intervention.
EMBO Mol Med
· 2026 May · PMID 42168654
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The intestinal barrier is a dynamic interface integrating epithelial integrity, mucus architecture, and immune signaling to maintain host homeostasis. While microbial metabolites such as short-chain fatty acids, secondar...The intestinal barrier is a dynamic interface integrating epithelial integrity, mucus architecture, and immune signaling to maintain host homeostasis. While microbial metabolites such as short-chain fatty acids, secondary bile acids, and tryptophan derivatives regulate this system, translating these insights to human physiology is hindered by experimental models that fail to capture the intestine's full biological complexity. In this review, we conceptualize intestinal barrier failure as a sequential process comprising junctional remodeling, mucus depletion, and immune-driven permeability. We critically evaluate current in vitro and ex vivo models, highlighting how metabolic biases and reductionist designs in common platforms limit their predictive value. We argue that the primary bottleneck is not a lack of model diversity, but the absence of integrative, human-relevant strategies. Consequently, we propose a stepwise framework linking dynamic microbial fermentation to mechanistic epithelial systems and ex vivo human tissues. This approach moves beyond descriptive modeling toward functionally predictive platforms that align microbial metabolism with host responses across biological scales, ultimately informing clinical translation, precision nutrition, and therapeutic development.
Kong Y, Zhang Y, Xie E
… +5 more, Li X, Peng Z, Zhang J, Zhao Y, Yuan H
EMBO Mol Med
· 2026 Jun · PMID 42162447
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Hereditary hearing loss, the most prevalent genetic sensory disorder, lacks approved pharmacological therapies and represents a compelling target for gene correction. Pathogenic variants in KCNQ4 account for ~9.5% of aut...Hereditary hearing loss, the most prevalent genetic sensory disorder, lacks approved pharmacological therapies and represents a compelling target for gene correction. Pathogenic variants in KCNQ4 account for ~9.5% of autosomal dominant nonsyndromic cases. Prior gene-editing strategies disrupting mutant alleles have failed to achieve durable auditory rescue. Here we employed a knock-in mouse model harboring the human KCNQ4 c.961 G > A (p.G321S) mutation to evaluate precise base editing. Dual-AAV delivery of the adenine base editor ABE8e achieved 21.4-28.9% correction in the organ of Corti-the highest efficiency reported for genetic hearing loss. A dose-dependent therapeutic window emerged: higher doses promoted rapid recovery, whereas optimized lower doses minimized long-term toxicity and sustained functional benefit for at least 32 weeks. Treatment reduced auditory brainstem response thresholds by up to 49.09 dB SPL at optimal frequencies, mitigated degeneration of hair cells, spiral ganglion neurons, and auditory nerve fibers, and partially restored outer hair cell electrophysiology. These findings demonstrate the durability of precise mutation correction over allele-disruptive approaches and support clinical translation for KCNQ4-associated hearing loss.
Diaz-Marin R, Hata M, Guber V
… +4 more, De Guire V, Wilson AM, Crespo-Garcia S, Sapieha P
EMBO Mol Med
· 2026 Jun · PMID 42156503
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Neovascular age-related macular degeneration (nAMD) is a prominent cause of blindness in the elderly, characterized by pathological subretinal choroidal neovascularization (CNV). While age and genetics predispose to AMD,...Neovascular age-related macular degeneration (nAMD) is a prominent cause of blindness in the elderly, characterized by pathological subretinal choroidal neovascularization (CNV). While age and genetics predispose to AMD, modifiable factors such as body adiposity are also thought to contribute. In a mouse model of nAMD, we identified a role for adipose tissue (AT) in exacerbating CNV, specifically pathways in adipocytes expressing Prdm16. Laser-induced CNV in the retina led to heightened expression of genes associated with browning and inflammation in distal inguinal white AT (iWAT). Selective deletion of the browning-associated transcription factor Prdm16 in adipocytes inhibited AT browning and reduced CNV. Reintroduction of Prdm16-expressing adipose tissue was sufficient to aggravate CNV in Prdm16-deficient mice. Ex vivo experimentation suggested that Prdm16-expressing adipocytes secrete angiogenic factors such as IGFBP5 and contribute to pathological angiogenesis. Thus, Prdm16-expressing adipocytes contribute to CNV, highlighting communication between the retina and distal tissues in the pathogenesis of AMD.
Buzo K, Bizzozero L, Lentini M
… +16 more, Opattova A, Hernández-Suárez B, Torres M, Chiabotto G, Nisticò C, De Lazzari G, R Zanella E, Grasso G, Mariella E, Durinikova E, Linnebacher M, Sartore-Bianchi A, Siena S, Trusolino L, Bardelli A, Arena S
EMBO Mol Med
· 2026 Jun · PMID 42156502
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Molecular therapies targeting the EGFR/MAPK pathway have improved outcomes in colorectal cancer (CRC), yet acquired resistance remains a major clinical challenge. Oncogenic signaling can activate stress response pathways...Molecular therapies targeting the EGFR/MAPK pathway have improved outcomes in colorectal cancer (CRC), yet acquired resistance remains a major clinical challenge. Oncogenic signaling can activate stress response pathways that sustain tumor survival under therapeutic pressure. Among these, the DNA damage response (DDR) maintains genomic integrity and may represent a targetable vulnerability in resistant tumors. To investigate this, we developed a preclinical platform of CRC models with acquired resistance to anti-EGFR agents ("ARes platform"). A targeted pharmacological screen of DDR inhibitors identified WEE1 kinase as a leading therapeutic candidate. Validation in xenograft models and patient-derived organoids confirmed that anti-EGFR-resistant CRCs retained, and in some cases increased, sensitivity to WEE1 inhibition. Mechanistically, resistant cells exhibited elevated DNA damage, heightened replication stress, and accelerated mitotic entry, culminating in cell death upon WEE1 blockade. These findings establish WEE1 as a promising therapeutic target in CRC with acquired resistance to EGFR inhibition and support the clinical evaluation of WEE1 inhibitors, alone or combined with DNA-damaging agents, for patients progressing on anti-EGFR-based therapies.
Deng S, Fang Y, Xue J
… +9 more, Wang R, Zhou X, Li C, Li N, Wang S, Zhang Y, Wang H, Yu J, Xu J
EMBO Mol Med
· 2026 May · PMID 42141271
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CD3 ligand 1 (CD3L1, ITPRIPL1), an emerging immune checkpoint, sustains immune privilege in the testis and facilitates tumor immune evasion. Targeting CD3L1 with a monoclonal antibody demonstrates potent antitumor activi...CD3 ligand 1 (CD3L1, ITPRIPL1), an emerging immune checkpoint, sustains immune privilege in the testis and facilitates tumor immune evasion. Targeting CD3L1 with a monoclonal antibody demonstrates potent antitumor activity in preclinical models and spontaneous tumors in companion animals. In an ongoing clinical trial, anti-CD3L1 therapy unexpectedly activated tumor-associated macrophages (TAMs) within the tumor microenvironment (TME), surpassing its anticipated role in T-cell reactivation. Mechanistic studies identified neuropilin-2 (NRP2) as the primary receptor on macrophages and uncovered the CD3L1-NRP2 axis as a critical driver of immunosuppressive M2 TAM polarization. Strikingly, in T-cell-deficient osteosarcoma models, anti-CD3L1 treatment reprogrammed TAMs toward an anti-tumor M1 phenotype, suppressing tumor progression. Clinical data corroborated these findings, revealing profound TME remodeling in advanced solid tumors. Our results elucidate a dual role for CD3L1 in immune evasion, mediated through both T-cell suppression and macrophage polarization, and highlight anti-CD3L1 as a multifaceted therapeutic strategy that enhances antigen presentation via TAM modulation.
Zhao Y, Chen X, Tang L
… +6 more, Liu H, Kang B, Zheng S, Ouyang S, Xie Y, You F
EMBO Mol Med
· 2026 Jun · PMID 42135568
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Effective cancer immunotherapy requires enhancing tumor-targeted immune responses while limiting pathological inflammation, highlighting an urgent need for single agents that can achieve this balance. Here, we reported t...Effective cancer immunotherapy requires enhancing tumor-targeted immune responses while limiting pathological inflammation, highlighting an urgent need for single agents that can achieve this balance. Here, we reported that Betrixaban (BT), an FDA-approved Factor Xa inhibitor, functioned as a dual immunomodulator that enhanced antitumor immune responses and suppressed hyperinflammation. BT enhanced innate tumor sensing and adaptive immune responses, partly via epigenetic modulation. In mouse tumor models, BT treatment inhibited tumor growth, accompanied by increased infiltration of activated CD8 T cells. Combining BT with immune checkpoint blockade synergistically enhanced antitumor efficacy. Additionally, BT attenuated pathological inflammation by reducing LPS-induced proinflammatory cytokine production and improving survival in a sepsis model. Mechanistically, BT induced a noncanonical, DNA-independent activation of the cGAS-STING pathway, triggering type I interferon signaling without provoking a full inflammatory cascade. These findings highlighted BT as a strategy to promote antitumor immunity while restraining inflammation, potentially improving cancer immunotherapy with reduced inflammatory toxicity.
Girbal-González M, Rodríguez-Banqueri A, Swaid H
… +13 more, Mendes SR, Garzón-Flores L, Ramírez-Larrota JS, Cueva C, Moreno-Arribas MV, Regl C, Huber CG, Scherf KA, Rodríguez-Lagunas MJ, Franch-Masferrer À, Eckhard U, Pérez-Cano FJ, Gomis-Rüth FX
EMBO Mol Med
· 2026 Jun · PMID 42135567
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Coeliac disease (CD) is an autoimmune enteropathy triggered by proline-rich gluten immunogenic peptides (GIPs), for which no curative therapy exists. We developed celiacase (Clc), a recombinant prolyl endopeptidase engin...Coeliac disease (CD) is an autoimmune enteropathy triggered by proline-rich gluten immunogenic peptides (GIPs), for which no curative therapy exists. We developed celiacase (Clc), a recombinant prolyl endopeptidase engineered from pitcher plant neprosin to enhance expression, stability, and activity. Clc showed maximal activity at gastric pH, synergized with and resisted pepsin, and efficiently cleaved GIPs, including the highly immunogenic 33-mer, outperforming Aspergillus niger prolyl endopeptidase in degrading GIPs from wheat flour and gliadin. At an enzyme-to-gliadin ratio of 1:250, Clc reduced GIP levels by up to 99% in a dynamic human gastrointestinal simulator. Ex vivo, Clc-digested 33-mer fragments failed to elicit cytokine responses in mouse and rat macrophages and duodenal biopsies from CD patients. In vivo, low-dose Clc (1:75-1:380) degraded gliadin and attenuated pathology in gliadin-fed mice, reducing villus atrophy, inflammation, antibody responses, and gluten-induced dysbiosis, while restoring immune-regulatory markers and microbial metabolic pathways. In summary, Clc is a potent, acid-stable glutenase with promise as a therapeutic adjunct or alternative to a gluten-free diet for CD patients.
Wang W, Pan Z, Jing H
… +13 more, Shi R, Wu L, Wang J, Chen B, Mu J, Zhang Z, Wu T, Li Q, Shi J, Kuang Y, He L, Wang L, Sang Q
EMBO Mol Med
· 2026 Jun · PMID 42120494
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Precise regulation of alternative splicing (AS) of maternal mRNAs is crucial for maintaining mRNA homeostasis and for acquiring oocyte competence. However, the regulatory factors and mechanisms of AS regulating oocyte co...Precise regulation of alternative splicing (AS) of maternal mRNAs is crucial for maintaining mRNA homeostasis and for acquiring oocyte competence. However, the regulatory factors and mechanisms of AS regulating oocyte competence and human fertility remain largely unknown. Here, we identified biallelic variants in CCDC174 that cause human oocyte competence defects and female infertility. Oocyte-specific knockout of Ccdc174 resulted in oocyte maturation arrest and female infertility in mice, and transcriptomic and proteomic analyses indicated that deletion of Ccdc174 disrupted mRNA and protein homeostasis as well as AS in oocytes. Importantly, we found that CCDC174 interacted with the splicing machinery-related PRP19/CDC5L complex, and loss of CCDC174 led to aberrant activation of the expression of these complex members in oocytes. In addition, in vitro studies indicated that patient-derived variants impaired the expression of CCDC174 and its binding to RNAs or CDC5L. Taken together, our study not only show that CCDC174 is a novel AS regulator that maintains mRNA homeostasis and oocyte competence, but also decipher the critical role of CCDC174 deficiency in the pathogenesis of female infertility.
Sekar A, Selvadurai BR, Chatterjee R
… +34 more, Pal L, Verma A, Belugali Nataraj N, Drago Garcia D, Giri S, Genna A, Karatekin F, Gupta N, Ramesh-Kumar D, Zerbib M, Vinik Y, Avioz T, Weizman E, David E, Schäffer AA, Pan Y, Huang H, van Weerden WM, Corey E, Hunt H, Greenstein AE, Blecher-Gonen R, Oren R, Afek A, Amit I, Lev S, Ku A, Kartal S, R Bright J, T Lis R, L Dahut W, Sowalsky AG, Ruppin E, Yarden Y
EMBO Mol Med
· 2026 Jun · PMID 42120493
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Approximately 50% of prostate cancer (PCa) patients harbor fusions involving the TMPRSS2 and ERG genes. Despite this, tailored therapies targeting the fused gene, tERG, remain undeveloped. Our study analyzed biopsy sampl...Approximately 50% of prostate cancer (PCa) patients harbor fusions involving the TMPRSS2 and ERG genes. Despite this, tailored therapies targeting the fused gene, tERG, remain undeveloped. Our study analyzed biopsy samples from two clinical trials assessing the efficacy of androgen receptor (AR) signaling inhibitors (ARSIs). The results revealed that tERG promotes resistance to ARSIs and is associated with elevated levels of the glucocorticoid receptor (GR). Subsequent assays showed that GR directly interacts with tERG, alleviates allosteric autoinhibition, and prevents chemotherapy-induced tERG degradation. In PCa models, either inhibiting GR or lowering cortisol levels suppressed tumor growth in tERG-positive models, but not in tERG-negative models. In addition, patient-derived fusion-positive xenografts displayed enhanced sensitivity to combined GR and AR inhibitors. Collectively, these findings highlight TMPRSS2-ERG as a new biomarker and propose that simultaneous inhibition of GR and AR may specifically benefit tERG-positive patients. However, GR stimulatory corticosteroid therapies may not be advisable for this patient subgroup.
EMBO Mol Med
· 2026 May · PMID 42106571
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With a steady increase in the number of at-risk patients, invasive fungal infections now represent a significant public health problem. These infections, caused by major pathogens such as Aspergillus, Candida, Cryptococc...With a steady increase in the number of at-risk patients, invasive fungal infections now represent a significant public health problem. These infections, caused by major pathogens such as Aspergillus, Candida, Cryptococcus, and Pneumocystis, affect increasingly diverse patient profiles, primarily immunocompromised individuals, with mortality rates often exceeding 50%. Managing these patients remains challenging, as very few systemic antifungals are currently available, compounded by major resistance issues related to the overuse and misuse of these drugs in clinical practice and agriculture. Fortunately, the field of medical mycology has benefited in recent years from major advances in pathogen-directed therapies, including new compounds, repurposing, new formulations, and the identification of new specific fungal targets. Although most immunomodulatory strategies are far from being implemented in clinical practice, recent breakthroughs in translational research have provided unprecedented hope in developing host-directed approaches leveraging cellular aspects and humoral mediators of immunopathogenesis.