Zhao Y, Wu J, Li Y
… +5 more, Cao Y, Zhu T, Guo Y, Yang C, Zhu D
EMBO Mol Med
· 2026 Mar · PMID 41644740
·
Full text
Acute rejection (AR) remains a critical challenge to graft survival in kidney transplantation. Although dextrorotatory-amino acids (D-AAs) have been recognized as biologically active compounds, their role in mediating im...Acute rejection (AR) remains a critical challenge to graft survival in kidney transplantation. Although dextrorotatory-amino acids (D-AAs) have been recognized as biologically active compounds, their role in mediating immunosuppression was poorly depicted. To address this, serum samples from renal transplant recipients were analyzed via [d0]/[d5]-estradiol-3-benzoate-17β-chloroformate (17β-EBC) based ion mobility-mass spectrometry (IM-MS) to assess D-AAs levels. scRNA-seq data from the GSE109564 dataset were analyzed. Additionally, murine skin and kidney transplantation models were utilized to assess the in vivo impact of d-kynurenine (D-Kyn) treatment on AR. Through analysis of patient serum and murine transplantation models, we identified D-Kyn as a key metabolite whose elevated levels correlate with stable graft function. We found that D-Kyn, more effectively than its chiral counterpart L-Kyn, inhibits the inflammatory activity of M1 macrophages. This suppression is mediated via the PHGDH/TLR4/Caspase-1 pathway, reducing the transcription and secretion of inflammatory cytokines. In murine models of skin and kidney transplantation, D-Kyn treatment demonstrated potent immunosuppressive effects, attenuating macrophage-mediated inflammation and CD8 + T cell activation, potentially through regulation of macrophage-derived IL-23a. Our findings reveal D-Kyn as a promising therapeutic candidate for preventing acute rejection and improving transplant outcomes and lay the foundation for future clinical applications from the perspective of dextrorotatory amino acids.
Baurès M, Vieira Aleixo AS, Pacreau E
… +14 more, Koshy A, Friedrich V, Diedisheim M, Raigel M, Hua Y, Dariane C, Boutillon F, Kenner L, Marine JC, Laverny G, Metzger D, Rambow F, Guidotti JE, Goffin V
EMBO Mol Med
· 2026 Mar · PMID 41629661
·
Full text
A critical knowledge gap in prostate cancer research is understanding whether castration-tolerant progenitor-like cells that reside in treatment-naïve tumors play a direct role in therapy resistance and tumor progression...A critical knowledge gap in prostate cancer research is understanding whether castration-tolerant progenitor-like cells that reside in treatment-naïve tumors play a direct role in therapy resistance and tumor progression. Herein, we reveal that the castration tolerance of LSC (Lin, Sca-1, CD49f) progenitor cells, the mouse equivalent of human prostatic Club cells, arises not from intrinsic properties, but from significant transcriptional reprogramming. Utilizing single-cell RNA sequencing of LSC cells isolated from prostate-specific Pten-deficient (Pten) mice, we identify the emergence of castration-resistant LSC cells enriched in stem-like features, driven by the transcription factor FOSL1/AP-1. We demonstrate that cells exhibiting Pten LSC characteristics are prevalent in aggressive double-negative prostate cancer (DNPC) subtypes recently identified in human castration-resistant prostate cancer (CRPC). Furthermore, our findings show that the dual-targeting agents JQ-1 and CX-6258-focused on FOSL1/AP-1 and PIM kinases, respectively-effectively suppress both the progenitor properties and the growth of mouse and human DNPC surrogates in vitro and in vivo. Thus, early eradication of castration-tolerant Club-like cells presents a promising therapeutic strategy to mitigate prostate cancer progression toward CRPC.
Gan S, Li Y, Yin L
… +15 more, Yang X, Lou C, Li S, Lin M, Li X, Xu W, Zhou J, Hu P, Yao Z, Yuan Y, Sheng J, Zhang C, Yang W, Li Y, Huang H
EMBO Mol Med
· 2026 Mar · PMID 41618099
·
Full text
Oocyte activation is essential for successful fertilization and subsequent embryonic development. However, only a few disease-causing genes have been associated with sperm-derived oocyte activation failure, and the under...Oocyte activation is essential for successful fertilization and subsequent embryonic development. However, only a few disease-causing genes have been associated with sperm-derived oocyte activation failure, and the underlying molecular mechanisms and therapeutic approaches remain largely unknown. Here, we identified pathogenic mutations in HNRNPR from three infertile patients whose partners repeatedly failed to achieve transferable embryos despite undergoing both in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). Remarkably, artificial oocyte activation (AOA, Srcl₂) combined with ICSI successfully restored fertilization. Whole-exome sequencing revealed HNRNPR mutations shared among affected families. To establish causality, we generated a knock-in mouse model, in which males exhibited phenotypes consistent with those observed in patients. Mechanistically, ICSI with sperm from Hnrnpr-mutated mice was unable to induce normal calcium oscillations in oocytes, while spermatozoa from both humans and mice exhibited reduced expression and mislocalization of phospholipase C zeta (PLCζ). Further analyses demonstrated that hnRNPR regulates Plcz1 splicing in an m6A-dependent manner. Beyond Srcl₂ treatment, we also developed NusA-PLCζ to effectively restore oocyte activation. Collectively, these findings reveal a previously unrecognized molecular mechanism by which HNRNPR mutations cause sperm-borne oocyte activation failure and male infertility, while highlighting targeted therapeutic strategies to restore fertilization.
Cramer P, Neys SFH, Fiedler M
… +17 more, Lorenzetti R, Reinhard H, Janowska I, Staniek J, Kohl AK, Hadlova P, Huber M, Plachter B, Read C, Falcone V, von Einem J, Hoffmann K, Lenac Rovis T, Jonjic S, Kolb P, Rizzi M, Hengel H
EMBO Mol Med
· 2026 Feb · PMID 41559372
·
Full text
Virus infections elicit long-term IgG antibody and memory responses. Human cytomegalovirus (HCMV) is widespread in humans and disseminates despite the presence of virus-specific antibodies. Here, we report that the HCMV...Virus infections elicit long-term IgG antibody and memory responses. Human cytomegalovirus (HCMV) is widespread in humans and disseminates despite the presence of virus-specific antibodies. Here, we report that the HCMV Fcγ-binding glycoprotein 34 modulates humoral immunity by binding to IgG⁺ memory B cells. gp34-B cell receptor (BCR) interaction initiates activation of the PDK1/AKT/mTOR/S6 pathway and BCR internalization in a SYK-independent manner. Prolonged stimulation also induces B-cell activation via upregulation of CD69 and CD86. In a T-cell-dependent response, however, interaction with gp34 blocks B-cell proliferation, differentiation into plasmablasts, and soluble IgG production, while stimulating TNF-α secretion. Through gp34 stimulation on IgG⁺ B cells, neighboring IgM⁺ and IgA⁺ B cells are likewise impaired in proliferation, plasmablast formation, and immunoglobulin secretion. In summary, gp34 specifically interacts with IgG⁺ memory B cells, inducing a hyporesponsive state across the B-cell compartment through direct and indirect regulation. This reveals a novel mode of viral evasion from B-cell responses by suppressing secondary immunity.
Bernardo S, Brunet L, Thomas QD
… +26 more, Bracquemond D, Bouclier C, Colomb M, Mancini M, Fabbrizio E, Santos A, Rasamizafy SF, Maacha AM, Giry A, Bousquet-Mur E, Papon L, Goussard M, Fremin C, Pasquier A, Rodríguez M, Travert C, Pujol JL, Linares LK, Heron-Milhavet L, Djiane A, Ferrer I, Paz-Ares L, Quantin X, Montuenga LM, Tourriere H, Maraver A
EMBO Mol Med
· 2026 Feb · PMID 41545766
·
Full text
Despite major advances in the clinical management of non-small cell lung carcinoma (NSCLC), most patients treated with first-line platinum-based chemotherapy combined with immune checkpoint inhibitors will relapse, which...Despite major advances in the clinical management of non-small cell lung carcinoma (NSCLC), most patients treated with first-line platinum-based chemotherapy combined with immune checkpoint inhibitors will relapse, which constitutes an unmet medical need. Here, we found that various DNA damage inducers increase the levels of Notch Intracellular Domain (NICD), the active form of NOTCH1. Mechanistically, we revealed that, upon platinum treatment, the expression levels of both MDM2 and NICD were increased and that MDM2 stabilised NICD through ubiquitination. Using NSCLC patient-derived xenografts displaying intrinsic carboplatin resistance, we demonstrated that combining carboplatin with a γ-secretase inhibitor, which hinders NICD generation, significantly improves survival and reduces tumour growth compared with carboplatin monotherapy. Furthermore, in patients with NSCLC who received platinum-based chemotherapy, the level of MDM2 expression in the tumour correlated with poor progression-free survival, which further validates the key role of MDM2 in response to platinum compounds. Our findings present a new therapeutic opportunity for patients with NSCLC, the most common form of lung cancer.
Haas J, Schudy S, Rauscher B
… +15 more, Muñoz Verdú A, Roßkopf S, Reich C, Donmez Yalcin G, Yalcin A, Seeger T, Dieterich C, Taft MH, Freichel M, Grimm D, Manstein D, Backs J, Frey N, Steinmetz L, Meder B
EMBO Mol Med
· 2026 Feb · PMID 41530494
·
Full text
Dysregulation of alternative splicing - mediated by factors such as RBM20 or SLM2 - can affect proper gene isoform control, disrupting gene isoform homeostasis and underpins severe cardiomyopathy in both animal models an...Dysregulation of alternative splicing - mediated by factors such as RBM20 or SLM2 - can affect proper gene isoform control, disrupting gene isoform homeostasis and underpins severe cardiomyopathy in both animal models and patients. Although innovative therapies target various sarcomeric components, the impact of isoform switching in cardiac disease remains poorly understood. Here, we applied nanopore long-read sequencing to map the full-length transcriptome of left ventricular tissue from thirteen nonfailing controls, ten patients with dilated cardiomyopathy (DCM), and ten with ischemic cardiomyopathy (ICM). Our analysis identified 78,520 transcripts, 31% of which represent novel isoforms of known genes. Notably, the transcriptomes of DCM and ICM were largely indistinguishable, indicating that end-stage heart failure is characterized by a convergent isoform landscape, irrespective of disease etiology. Among 11 prototypical sarcomere genes, 10 displayed highly significant isoform shifts (p = 5.23 × 10-2.89 × 10). Focusing on tropomyosin, we observed that while the predominant cardiac gene TPM1 showed moderate up-regulation of its transcript isoforms, transcripts derived from TPM3-typically expressed at lower levels in the healthy heart-were markedly increased in heart failure.
Tong B, Zhang X, Zhu D
… +15 more, Wang Y, Wei J, Ou Z, Liang H, Xu H, Zhang Z, Lei J, Zhou X, Wu D, Song Y, Wang K, Feng X, Tan L, Liao Z, Yang C
EMBO Mol Med
· 2026 Feb · PMID 41526766
·
Full text
Targeted protein degradation (TPD) is an emerging therapeutic approach that enables the degradation of undruggable targets via intracellular degradation systems. Extracellular vesicles (EVs) have shown potential to act a...Targeted protein degradation (TPD) is an emerging therapeutic approach that enables the degradation of undruggable targets via intracellular degradation systems. Extracellular vesicles (EVs) have shown potential to act as next-generation TPD platforms. However, the molecular mechanism underlying their degradation remains unknown, which restricts their application in TPD. In this study, we found that the autophagy-mediated lysosomal pathway was the major route by which EVs were degraded. MAP1LC3B recognized the LIR motifs of SQSTM1 and induced the degradation of EVs in the autophagy pathway. Based on the EV degradation mode, we developed an EV-based targeted protein degradation platform (EVTPD) using EVs loaded with the LIR motif of SQSTM1 as a degradation signal. Additionally, target protein-binding domains were integrated into the EVTPD to capture target proteins. EVTPD selectively degraded extracellular proteins without requiring receptors on target cells. Furthermore, dual-targeting EVTPD effectively degraded both TNF-α and IL-1β and exhibited potent anti-inflammatory effects in rat and goat models of intervertebral disc degeneration. This study has established a modular EV-based TPD strategy with multi-targeting potential.
EMBO Mol Med
· 2026 Feb · PMID 41514125
·
Full text
Metastatic malignant pleural effusion (MPE) represents advanced-stage cancer and is defined by the establishment of metastatic tumor foci within the pleural space. It is most commonly associated with high degrees of morb...Metastatic malignant pleural effusion (MPE) represents advanced-stage cancer and is defined by the establishment of metastatic tumor foci within the pleural space. It is most commonly associated with high degrees of morbidity and mortality. Annually, over 150,000 cancer patients in the United States develop MPE, which is associated with a dismal median survival of 3-12 months. As such, efforts must be made to understand the complex biological factors driving MPE pathophysiology. In this review, we discuss what is currently known and identify knowledge gaps regarding the intrinsic MPE biology of cancer cells and the heterotypic interactions between tumor cells and the immunologic pleural ecosystem. Furthermore, we discuss the clinical opportunities of studying MPE and identify promising directions for MPE research that may lead to a deeper understanding of the disease, ultimately aiming to enhance clinical outcomes for patients with advanced cancer.
EMBO Mol Med
· 2026 Feb · PMID 41514124
·
Full text
Diamond-Blackfan anemia syndrome (DBAS) is marked by defective erythropoiesis caused by impaired ribosome biogenesis and aberrant signaling. Here, we investigate how ribosomal stress-induced activation of the NLRP1 infla...Diamond-Blackfan anemia syndrome (DBAS) is marked by defective erythropoiesis caused by impaired ribosome biogenesis and aberrant signaling. Here, we investigate how ribosomal stress-induced activation of the NLRP1 inflammasome affects erythroid differentiation in DBAS. We demonstrate that FDA/EMA-approved tyrosine kinase inhibitors (TKIs) effectively mitigate defective erythropoiesis by inhibiting NLRP1 inflammasome activation. In K562 cells, nilotinib suppresses the ZAKα/P38/NLRP1/CASP1 axis, leading to increased GATA1 levels and upregulation of key erythroid genes. These effects were validated in human CD34⁺ hematopoietic stem and progenitor cells (HSPCs) and zebrafish models, where nilotinib, imatinib, and dasatinib promoted erythropoiesis while reducing caspase-1 activity. In Rps19-deficient zebrafish, RPS19-deficient human HSPCs, and HSPCs from DBAS patients, TKIs rescued erythroid differentiation and restored hemoglobin levels. Our findings highlight that targeting the NLRP1 inflammasome with TKIs may provide a novel therapeutic strategy for DBAS and other ribosomopathies.
Das D, Wyatt A, Sivaprasad S
… +8 more, Wahl V, Qiao S, Ectors F, Moosa ZM, Newton CL, Fritz M, Millar RP, Boehm U
EMBO Mol Med
· 2026 Feb · PMID 41507463
·
Full text
G protein-coupled receptors (GPCRs) carry out the majority of cellular transmembrane signaling. Many pathologies have underlying GPCR mutations, most of which cause misfolding and GPCR cell surface trafficking failure. L...G protein-coupled receptors (GPCRs) carry out the majority of cellular transmembrane signaling. Many pathologies have underlying GPCR mutations, most of which cause misfolding and GPCR cell surface trafficking failure. Large libraries of existing small molecule GPCR ligands could be repurposed as pharmacological chaperones (PCs) which restore mutant GPCR folding and function, presenting an exciting alternative to complex gene repair, yet such in vivo studies are limited. Therefore, as proof-of-concept, we use one such known ligand/PC, Org42599/Org43553, to show functional rescue in mice bearing an inactivating human luteinizing hormone receptor (LHR) mutation. Mutant males had delayed puberty and Leydig cell LHR signaling impairment, however, fertility was unaffected. Mutant females had irregular estrous cycles, anovulation, abrogated ovarian LHR signaling, and complete infertility. PC treatment of mutant females restored LH signaling and estrous cyclicity. To characterize treatment efficacy, we developed an AI algorithm that reliably identified inherent differences among experimental groups, enabling functional analysis of the treatment effect in vivo. Our data set the stage to integrate AI analysis with GPCR-targeting PC molecules to treat diverse GPCR-based diseases.
EMBO Mol Med
· 2026 Feb · PMID 41484207
·
Full text
Targeting oncogenic fusion proteins remains a major challenge in pediatric oncology. In this issue of , Suresh et al (2025) demonstrate that incomplete inhibition of EWS::FLI1 in Ewing sarcoma paradoxically promotes meta...Targeting oncogenic fusion proteins remains a major challenge in pediatric oncology. In this issue of , Suresh et al (2025) demonstrate that incomplete inhibition of EWS::FLI1 in Ewing sarcoma paradoxically promotes metastatic behavior, revealing critical implications for therapeutic strategies.
Tong Y, Becker M, Schierloh U
… +24 more, Natividade da Silva F, Haataja L, Cai Y, Patel KA, Kobaisi F, Mirshahi UL, Colclough K, Javed MS, Wakeling MN, Fantuzzi F, Lytrivi M, Sawatani T, Arroyo MN, Yi X, Vinci C, Montaser H, Pachera N, Otonkoski T, Igoillo-Esteve M, Scharfmann R, Hattersley AT, Arvan P, De Beaufort C, Cnop M
EMBO Mol Med
· 2026 Feb · PMID 41484206
·
Full text
The INS c.16 C > T (insulin p.Arg6Cys, R6C) variant was reported to cause autosomal dominant monogenic diabetes, yet its pathogenicity has been questioned. R6C preproinsulin exhibits impaired translocation into the endop...The INS c.16 C > T (insulin p.Arg6Cys, R6C) variant was reported to cause autosomal dominant monogenic diabetes, yet its pathogenicity has been questioned. R6C preproinsulin exhibits impaired translocation into the endoplasmic reticulum (ER). We explored R6C pathogenicity using integrative clinical, genetic, and functional approaches.Homozygous INS R6C individuals presented early-onset insulin-treated diabetes, whereas heterozygous carriers showed variable or absent glycemic phenotypes. Population-level analysis revealed no significant enrichment of diabetes among heterozygotes. Heterozygous R6C patient's induced pluripotent stem cell (iPSC)-derived pancreatic β cells exhibited minimal defects, while homozygous R6C β cells displayed preproinsulin accumulation and reduced insulin content and secretion. In vivo, homozygous R6C β cell transplants recapitulated insulin deficiency and responded poorly to GLP-1 receptor agonist. Homozygous R6C β cells had a gene signature of attenuated translation, translocation and ER related pathways.Our findings establish R6C as a recessive loss-of-function mutation, prompting a clinical reassessment of heterozygous R6C carriers. This study highlights the power of population genetic databases, patients' iPSC-based modeling and multi-modal variant classification frameworks for dissecting the consequences of genetic variants in monogenic diabetes.
Suresh V, Hafemeister C, Konstantinou A
… +13 more, Grissenberger S, Sturtzel C, Zylka MM, Cidre-Aranaz F, Wenninger-Weinzierl A, Queiroz K, Kurek D, Distel M, Obenauf A, Grünewald TGP, Halbritter F, Kovar H, Fock V
EMBO Mol Med
· 2026 Feb · PMID 41484205
·
Full text
Tumor cell plasticity drives metastasis and therapy resistance, yet its regulation by oncoprotein dosage dynamics remains poorly understood. In Ewing sarcoma (EwS), variations in EWS::FLI1 (EF) fusion oncoprotein activit...Tumor cell plasticity drives metastasis and therapy resistance, yet its regulation by oncoprotein dosage dynamics remains poorly understood. In Ewing sarcoma (EwS), variations in EWS::FLI1 (EF) fusion oncoprotein activity have been associated with epithelial-mesenchymal plasticity (EMP). Using degron technology, we precisely modulated endogenous EF in EwS cells and linked phenotypic states to distinct oncoprotein dosages. Strikingly, modest EF depletion promoted a pro-metastatic phenotype that diminished upon near-complete EF loss, revealing a paradoxical effect of submaximal EF inhibition. Nascent RNA-sequencing uncovered distinct gene clusters with heterogenous transcriptional responses to graded EF loss. Genes most sensitive to subtle EF depletion harbored GGAA microsatellites within EF-bound enhancers, while chromatin profiling uncovered candidate cofactors regulating EF-repressed EMP programs. Transient EF depletion followed by rapid restoration, modelling oncoprotein fluctuations, caused persistent dysregulation of genes functionally linked to enhanced extravasation and metastatic burden in preclinical models. This study highlights the therapeutic challenge of incomplete EF elimination, serving a paradigm in which oncoprotein dosage dynamics act as non-genetic drivers of disease progression and reveal novel vulnerabilities of advanced disease.
Radke K, Aaltonen K, Muciño-Olmos EA
… +23 more, Esfandyari J, Adamska A, Siaw JT, Adamic D, Lago C, Mañas A, Seger A, Hansson K, Rogova O, Lehn S, Mason DJ, O'Donovan DJ, Roberts I, Lock A, Brennan J, Pietras K, Davies EJ, Spégel P, Bedoya-Reina OC, Brown D, Thompson NT, Spadoni C, Bexell D
EMBO Mol Med
· 2026 Feb · PMID 41437160
·
Full text
Relapse and treatment resistance are common in children with high-risk neuroblastoma, and novel therapies are needed. Conventional drug discovery is slow, expensive, often fails in practice, and consequently falls short...Relapse and treatment resistance are common in children with high-risk neuroblastoma, and novel therapies are needed. Conventional drug discovery is slow, expensive, often fails in practice, and consequently falls short in addressing pediatric and rare conditions. In such instances, drug repurposing is a promising strategy. Here, we used two independent in silico prediction tools including machine learning to identify approved drugs for repurposing against neuroblastoma. The combination of statins and phenothiazines showed strong synergistic effects in human neuroblastoma organoids, decreased tumor growth, and prolonged survival in MYCN-amplified neuroblastoma patient-derived xenografts. The drug combination altered cholesterol metabolism through two different mechanisms and induced a phenotypic change toward an adrenergic state in vitro, which was associated with enhanced chemosensitivity. Integration of the drug combination into standard-of-care chemotherapy regressed tumors and prolonged survival in chemoresistant patient-derived xenografts. Thus, a combination of safe and approved medications added to standard-of-care chemotherapy outperforms chemotherapy alone in chemoresistant neuroblastoma.
Biswas SR, Tomsick PL, Kelly C
… +8 more, Lester BA, Milner JP, Henry SN, Soto Y, Brindley S, DeFoor N, Morton PD, Pickrell AM
EMBO Mol Med
· 2026 Feb · PMID 41429945
·
Full text
Leigh syndrome (LS) is a complex, genetic mitochondrial disorder defined by neurodegenerative phenotypes with pediatric manifestation. However, recent clinical studies report behavioral phenotypes in human LS patients th...Leigh syndrome (LS) is a complex, genetic mitochondrial disorder defined by neurodegenerative phenotypes with pediatric manifestation. However, recent clinical studies report behavioral phenotypes in human LS patients that are more reminiscent of neurodevelopmental delays. To determine if disruptions in epochs of rapid brain growth during infancy precede the hallmark brain lesions that arise during childhood, we evaluated neural and glial precursor cellular dynamics in a mouse model of LS. Loss of Complex I significantly impacted neural stem cell proliferation, neuronal and oligodendroglial progeny, lineage progression, and displayed overt differences in specific brain regions across postnatal development. Our findings show that these disruptions in all categories occur specifically within the subventricular zone and corpus callosum prior to the age when these mice experience neurodegeneration. Given that LS is considered a neurodegenerative disease, we propose that there are neurodevelopmental signatures predating classic diagnosis in LS.
Zahedi K, Barone S, Brooks M
… +4 more, Zhang W, Yu JJ, Zaidman NA, Soleimani M
EMBO Mol Med
· 2026 Feb · PMID 41429944
·
Full text
The epithelium of kidney cysts in mouse Tuberous Sclerosis complex (TSC) models and TSC patients is composed of proliferating A-intercalated cells. The ablation of the Foxi1 gene abolished renal cystogenesis in principal...The epithelium of kidney cysts in mouse Tuberous Sclerosis complex (TSC) models and TSC patients is composed of proliferating A-intercalated cells. The ablation of the Foxi1 gene abolished renal cystogenesis in principal cell-specific Tsc1 knockout (Tsc1-KO) mice. RNAseq studies comparing kidneys of Tsc1-KO vs. wild-type (WT) and Tsc1/Foxi1-double-knockout identified c-Kit, a tyrosine kinase receptor (RTK), as a transcript whose expression significantly increased in Tsc1-KO mice. Overexpression of FOXI1 in kidney M-1 cells significantly increased c-Kit expression levels. Kidney cystogenesis was abolished in Tsc1-KO mice by inactivating the c-Kit gene via the generation of Tsc1/c-Kit-double-knockout mice. The treatment of Tsc1-KO mice with Imatinib, a specific inhibitor of c-KIT, significantly diminished kidney cystogenesis. Renal cystogenesis was associated with ERK1/2, AKT, and RSK1-mediated phospho-inactivation of TSC2. In contrast, activation of ERK1/2, AKT, and RSK1, as well as phosphorylation of TSC2, was notably reduced in the kidneys of Tsc1/c-Kit-dKO mice. We propose that c-KIT is a crucial mediator of TSC renal cystogenesis and that its inhibition may constitute a novel approach for the treatment of kidney cysts in TSC.
EMBO Mol Med
· 2026 Feb · PMID 41429943
·
Full text
Tuberous Sclerosis Complex (TSC) is a multisystem disorder marked by benign tumors in brain, lung, and kidney. While the loss-of-function mutations in or have been known for decades, the molecular basis that converts t...Tuberous Sclerosis Complex (TSC) is a multisystem disorder marked by benign tumors in brain, lung, and kidney. While the loss-of-function mutations in or have been known for decades, the molecular basis that converts these mutations into cystic kidney lesions has remained elusive. In this issue of , Zahedi and colleagues now uncover an unexpected culprit: the proto-oncogene receptor tyrosine kinase c-KIT. Their work identifies c-KIT as a pivotal driver of renal cystogenesis in TSC and suggests that its pharmacologic inhibition could complement existing mTOR-targeted therapy.
Hough SH, Jhujh SS, Awwad SW
… +25 more, Lewis OE, Lam S, Thomas JC, Mosler T, Bader A, Bartik L, McKee S, Amudhavalli S, Colin E, Damseh N, Clement E, Cacheiro P, Majumdar A, Smedley D, Fluss J, Giannini R, Thiffault I, Zagnoli Vieira G, Belotserkovskaya R, Smerdon SJ, Beli P, Galanty Y, Carnie CJ, Stewart GS, Jackson SP
EMBO Mol Med
· 2026 Feb · PMID 41420108
·
Full text
Ubiquitin E3 ligases play crucial roles in the DNA damage response (DDR) by modulating the turnover, localization, activation, and interactions of DDR and DNA replication proteins. We performed a CRISPR-Cas9 knockout scr...Ubiquitin E3 ligases play crucial roles in the DNA damage response (DDR) by modulating the turnover, localization, activation, and interactions of DDR and DNA replication proteins. We performed a CRISPR-Cas9 knockout screen focused on ubiquitin E3 ligases and related proteins with the DNA topoisomerase I inhibitor camptothecin. This led us to establish that MAEA, a core subunit of the CTLH E3 ligase complex, is a critical regulator of homologous recombination and the replication stress response. In tandem, we identified eight patients with variants in MAEA who present with a neurodevelopmental disorder that we term DIADEM (Developmental delay and Intellectual disability Associated with DEfects in MAEA). Analysis of patient-derived cell lines and mutation modeling reveal an underlying defect in HR-dependent DNA repair and replication fork restart and protection as a likely cause of disease. Mechanistically, we find that MAEA dysfunction hinders DNA repair by reducing the efficiency of RAD51 loading at sites of DNA damage, which we propose may contribute to the presentation of DIADEM by compromising genome integrity and cell division during development.
Campos-Ribeiro MA, Donnarumma E, Nolte H
… +11 more, Cobine P, Vimont E, Milenkovic D, Hernandez-Camacho JD, Langa-Vives F, Kornobis E, Pénard E, Yde S, Langer T, Paquis-Flucklinger V, Wai T
EMBO Mol Med
· 2026 Feb · PMID 41420107
·
Full text
Mutations in CHCHD10, a mitochondrial intermembrane space (IMS) protein implicated in proteostasis and cristae maintenance, cause mitochondrial disease. Knock-in mice modeling the human CHCHD10 variant associated with AL...Mutations in CHCHD10, a mitochondrial intermembrane space (IMS) protein implicated in proteostasis and cristae maintenance, cause mitochondrial disease. Knock-in mice modeling the human CHCHD10 variant associated with ALS-FTD develop a mitochondrial cardiomyopathy driven by CHCHD10 aggregation and activation of the mitochondrial integrated stress response (mtISR). We show that cardiac dysfunction is associated with dual defects originating at the onset of disease: (1) bioenergetic failure linked to impaired mitochondrial copper homeostasis and cytochrome c oxidation, and (2) maladaptive mtISR signaling via the OMA1-DELE1-HRI axis. Using protease-inactive Oma1 knock-in mice, we show that blunting mtISR in Chchd10 mice delays cardiomyopathy onset without rescuing CHCHD10 insolubility, cristae defects or OXPHOS impairment. Proteomic profiling of insoluble mitochondrial proteins in Chchd10 mice reveals widespread disruptions of mitochondrial proteostasis, including IMS proteins involved in cytochrome c biogenesis. Defective respiration in mutant mitochondria is rescued by the addition of cytochrome c, pinpointing IMS proteostasis disruption as a key pathogenic mechanism. Thus, mutant CHCHD10 insolubility compromises metabolic resilience by impairing bioenergetics and stress adaptation, offering new perspectives for the development of therapeutic targets.