Huang C, Huang Y, Huang B
… +12 more, Yao L, Zhang Z, Dong L, Guan C, Li J, Huang Z, Chen S, Jiang Y, Zhang Y, Wang J, Chen Y, Liu Z
EMBO Mol Med
· 2025 Nov · PMID 41068431
·
Full text
Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease without effective medical therapies. Emerging evidence have suggested a crosstalk between adipose tissue and vascular cells. Besides, brown adipose t...Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease without effective medical therapies. Emerging evidence have suggested a crosstalk between adipose tissue and vascular cells. Besides, brown adipose tissue is considered beneficial for cardiovascular health. Nevertheless, whether brown remodeling of white adipose tissue would protect against AAA remains unclear. Here, we showed that patients with AAA had a decreased browning level of adipose tissue, and induction of adipose tissue browning significantly reduced AAA incidence and attenuated AAA development in mice. Using LC-MS/MS and proteomic analysis, we further identified Follistatin-like 1 (FSTL1) as a novel vessel-protective adipokine secreted by browning adipocytes. Mechanistically, FSTL1 inhibited VSMC apoptosis through DIP2A/AKT signaling. Furthermore, we demonstrated that adipocyte-specific deficiency of FSTL1 abrogated the protective effect of browning induction. Moreover, supplementation of FSTL1 either systemically or patched into hydrogel placing around the abdominal aorta markedly limited aortic dilation and AAA progression. Our data suggest a protective role of adipose tissue browning and batokine FSTL1 in the development of AAA, which may represent a novel intervention strategy for AAA.
Hou Y, Wang Z, Wang W
… +10 more, Tang Q, Cai Y, Yu S, Wang J, Yan X, Wang G, Lobie PE, Zhang Y, Dai X, Ma S
EMBO Mol Med
· 2025 Nov · PMID 41039172
·
Full text
Advanced algorithms have significantly improved the efficiency of in vitro screening for protein-interactive compounds. However, target antigen (TAA/TSA)-based drug discovery remains challenging, as predictions of compou...Advanced algorithms have significantly improved the efficiency of in vitro screening for protein-interactive compounds. However, target antigen (TAA/TSA)-based drug discovery remains challenging, as predictions of compound-protein interaction (CPI) based solely on molecular structure fail to fully elucidate the underlying mechanisms. In this study, we utilized deep learning, specifically TransformerCPI to screen active molecules from a Chinese herb compound library based on protein sequences. Two natural products, Polyphyllin V and Polyphyllin H, were identified as targeting the pan-cancer marker CD133. Their anti-tumor efficacy and safety were confirmed across validation in cancer cell lines, tumor patient-derived organoids, and animal models. Despite their analogous structures and binding affinity to CD133, Polyphyllin V suppresses the PI3K-AKT pathway, inducing pyroptosis and blockage of mitophagy, whereas Polyphyllin H inhibits the Wnt/β-catenin pathway and triggers apoptosis. These distinct mechanisms underscore the potential of combining AI-driven screening with biological validation. This AI-to-patient pipeline identifies Polyphyllin V and Polyphyllin H as CD133-targeted drugs for pan-cancer therapy, and reveals the limitations of virtual screening alone and emphasizes the necessity of live model evaluation in AI-based therapeutic discovery.
Mann AP, Hussain S, Scodeller P
… +4 more, Moore HNB, Sherazee E, Russo RM, Ruoslahti E
EMBO Mol Med
· 2025 Nov · PMID 41034343
·
Full text
Traumatic brain injury (TBI) is a major clinical problem because of the high incidence and the severity of the subsequent sequelae. Despite extensive efforts, there are no therapeutic drugs clinically approved for treati...Traumatic brain injury (TBI) is a major clinical problem because of the high incidence and the severity of the subsequent sequelae. Despite extensive efforts, there are no therapeutic drugs clinically approved for treating acute TBI patients. To address this unmet need, we assessed the activity of the tetrapeptide, CAQK, in mice. When administered intravenously shortly after moderate or severe TBI, CAQK accumulates in the injured brain in mice and pigs. CAQK binds to an extracellular matrix glycoprotein complex that is upregulated in injured brain. Treatment of TBI mice with CAQK resulted in reduction in the size of the injury compared to control mice. There was reduced upregulation of the glycoprotein complex, less apoptosis, and lower expression of inflammatory markers in the injured area, indicating that CAQK alleviates neuroinflammation and the ensuing secondary injury. CAQK treatment also improved functional deficit in TBI mice, with no overt toxicity. Our findings suggest that CAQK may have therapeutic applications in TBI.
Angi B, Varanita T, Puthenparampil M
… +15 more, Scattolini V, Donadon M, Tavakoli M, Favero M, El Boustani M, Soddemann M, Biasutto L, Arcidiacono D, Ongaro A, Mattarei A, Trentin L, Wilson G, Gulbins E, Gallo P, Szabo I
EMBO Mol Med
· 2025 Nov · PMID 41023199
·
Full text
Multiple sclerosis (MS) is characterized by invasion of the brain by effector memory T (T) lymphocytes that have been activated by repeated auto-antigen stimulation. Existing therapies target these and other autoreactive...Multiple sclerosis (MS) is characterized by invasion of the brain by effector memory T (T) lymphocytes that have been activated by repeated auto-antigen stimulation. Existing therapies target these and other autoreactive lymphocytes but their side effects include general immunosuppression and toxicity. Because the Kv1.3 potassium channel is highly expressed by chronically activated autoreactive Ts, we investigated whether specific targeting of mitochondrial Kv1.3 using the pharmacological inhibitor PAPTP could selectively kill these Ts in patients and mice with MS. 1 µM PAPTP targeted and reduced the number of autoreactive Ts in blood samples from relapsing-remitting MS (RRMS) patients, leaving other T cell populations unaffected. Remarkably, pre-treatment of the entire T cell population with PAPTP during adoptive transfer of experimental autoimmune encephalomyelitis (EAE) killed Ts and completely prevented disease onset in this mouse model. Moreover, PAPTP selectively eliminated activated Ts and halted EAE progression when administered following disease onset. Our findings reveal the potential of PAPTP as an effective treatment for MS without adverse side effects.
EMBO Mol Med
· 2025 Nov · PMID 41023198
·
Full text
Multiple sclerosis (MS), a chronic autoimmune disorder, is characterized by the infiltration of autoreactive T cells into the central nervous system (CNS), leading to myelin destruction and neurological deficits. Current...Multiple sclerosis (MS), a chronic autoimmune disorder, is characterized by the infiltration of autoreactive T cells into the central nervous system (CNS), leading to myelin destruction and neurological deficits. Current therapies often lack specificity, resulting in broad immunosuppression and potential side effects. In this issue of , Angi, Varanita and colleagues (Angi et al, 2025) identify a novel therapeutic strategy in targeting the mitochondrial Kv1.3 channel in autoreactive T cells, offering a more selective approach to mitigate MS-like pathology.
Borrmann S, Sulyok Z, Müller K
… +37 more, Fendel R, Sulyok M, Friesen J, Lalremruata A, Sandri TL, Nguyen TT, Calle CL, Knoblich A, Sefried S, Ibáñez J, Lorenz FR, Heimann HL, Weller DM, Steuder R, Adukpo S, Granados Bayon P, Molnár Z, Esen M, Metzger W, James ER, Ruben A, Abebe Y, Chakravarty S, Manoj A, Kc N, Murshedkar T, Hafalla JCR, Woldearegai TG, O'Rourke F, Held J, Billingsley P, Sim BKL, Richie TL, Hoffman SL, Kremsner PG, Matuschewski K, Mordmüller B
EMBO Mol Med
· 2025 Nov · PMID 41023197
·
Full text
To develop a Plasmodium falciparum (Pf) vaccine that precludes replication inside the host for improved vaccine safety, we tested chemo-attenuation (CVac) of sporozoites (SPZ) with atovaquone-proguanil (AP). In mice, P....To develop a Plasmodium falciparum (Pf) vaccine that precludes replication inside the host for improved vaccine safety, we tested chemo-attenuation (CVac) of sporozoites (SPZ) with atovaquone-proguanil (AP). In mice, P. berghei sporozoites administered with AP invaded hepatocytes, arrested early, and induced robust protection, which correlated with parasite-specific effector-memory CD8+ T cell responses. In a clinical trial of PfSPZ-CVac (AP), in which three doses of 5.12 × 10 or 1.5 × 10 PfSPZ were administered by direct venous inoculation combined with oral single-dose AP (1000/400 mg), blood stage infections were fully prevented during immunisation. 2/8 and 2/10 of vaccinees, respectively, were protected when challenged with 3.2 × 10 PfSPZ 10 weeks later, inferior to PfSPZ-CVac (chloroquine/CQ) that allows in-host replication. Comparative analysis of responses to 228 Pf proteins revealed that protection with PfSPZ-CVac (CQ) was associated with antibodies to two liver-stage antigens (LISP2, LSA1) and a multi-stage antigen (PfMSP5), but not to the major surface protein PfCSP. The complete arrest of high numbers of Pf sporozoites by single-dose AP should allow a significant dose-frequency reduction of the current daily AP malaria chemoprophylaxis regimen.
EMBO Mol Med
· 2025 Nov · PMID 41023196
·
Full text
Progress towards a much-needed malaria vaccine has accelerated in recent years. The most significant recent event was the independent licensure of the first two subunit vaccines against malaria, RTS,S/AS01 (Mosquirix) fr...Progress towards a much-needed malaria vaccine has accelerated in recent years. The most significant recent event was the independent licensure of the first two subunit vaccines against malaria, RTS,S/AS01 (Mosquirix) from GSK and R21/Matrix-M from the Serum Institute of India, which received full World Health Organisation (WHO) prequalification in 2022 and 2023, respectively. Both vaccines require a primary series of four doses to confer maximum protection to children against the most virulent species of malaria caused by . This immunisation series, given over a 12 to 18-month period, elicits an immune response that targets the free parasite form—called a sporozoite—during its journey from mosquito bite, through the dermis and on to the liver, where it infects hepatocytes. It elicits a predominantly B-cell response (with a modest CD4 T-cell response) specifically aimed at the circumsporozoite protein (CSP), the main sporozoite surface protein, aiming to block parasite colonisation of the liver. Whilst the licensure of these two vaccines heralds a landmark in global health, the level and durability of protection each confers is still uncertain, especially in infants and in areas of perennial, high-intensity transmission. Rather than quell enthusiasm for further vaccine development, however, this benchmark has bolstered efforts to find alternative strategies that complement or improve on overall vaccine efficacy and longevity. This enthusiasm is still urgent, with over half a million children under 5 still dying each year from malaria (Venkatesan P, 2025).
Catalano F, Stevic D, Zundo G
… +11 more, Huizer TF, Dammou Z, Vlaar EC, Katsavelis D, van den Bosch JC, van den Hout HJMP, Oussoren E, van der Ploeg AT, Ruijter GJG, Schaaf G, Pijnappel WWMP
EMBO Mol Med
· 2025 Nov · PMID 41023195
·
Full text
We present the SWAP design, a novel, structurally cohesive IGF2-based tag for modular receptor targeting during gene therapy for lysosomal storage disorders (LSDs). We found that IGF2's central loop is critical for high-...We present the SWAP design, a novel, structurally cohesive IGF2-based tag for modular receptor targeting during gene therapy for lysosomal storage disorders (LSDs). We found that IGF2's central loop is critical for high-affinity binding to the insulin receptor (IR) and IGF1 receptor (IGF1R)-both involved in glucose homeostasis-but is not required for interaction with the cation independent mannose 6-phosphate/IGF2 receptor (CI-M6P/IGF2R)-a key target for lysosomal delivery. This formed the basis for designing the Substitution of the central-loop With Augmenting Peptides (SWAP) tag. By replacing the central loop with alternative epitopes, SWAP ensures high-affinity multimodal receptor targeting while maintaining structural integrity. In vivo, lentiviral gene therapy employing IDS fused to SWAP variants containing ApoE and RAP12x2 inserts corrected Hunter disease pathology across multiple tissues, including liver, spleen, heart, bone, and brain, matching the efficacy of the traditional IGF2 tag. These findings position SWAP as a novel and effective tag design for IGF2-based therapeutics with a more favourable ligand-receptor interaction.
Passadouro AS, Balfoort BM, Langeveld M
… +4 more, van Karnebeek CDM, van der Velden J, Houtkooper RH, Mosegaard S
EMBO Mol Med
· 2025 Nov · PMID 40983718
·
Full text
Inherited metabolic diseases are rare monogenic conditions that disrupt biochemical pathways, affecting energy production and homeostasis, often leading to damaging metabolite accumulation. These disorders are clinically...Inherited metabolic diseases are rare monogenic conditions that disrupt biochemical pathways, affecting energy production and homeostasis, often leading to damaging metabolite accumulation. These disorders are clinically heterogeneous and can impact all organs, including the heart. Metabolic cardiomyopathies present with varying severity and unpredictable prognosis, complicating patient care. Pre-clinical research aims to model these cardiomyopathies to understand their pathophysiological mechanisms and develop personalised treatments. Animal models have provided insights into cardiac pathology and treatment, but species differences limit data translation. Human induced pluripotent stem cells (hiPSC) offer a valuable tool for establishing disease models using reprogrammed somatic cells from patients and healthy donors, differentiated into disease-relevant cell types. Cardiomyocytes generated in significant numbers are crucial for investigating cardiac mechanisms and assessing patient-specific drug responses. This review summarises literature on metabolic cardiomyopathies, focusing on long-chain fatty acid oxidation disorders and Barth syndrome. We highlight cardiac readouts from various models and discuss the potential of hiPSC technologies as clinically relevant disease models.
Idris F, Ooi JSG, Ting DHR
… +15 more, Tan ETX, Wan C, Benke PI, Marzinek JK, Copping JM, Li QH, Ng LY, Lim SY, Walsh I, Allison JR, Bond PJ, Torta F, Nguyen-Khuong T, Chan KR, Alonso S
EMBO Mol Med
· 2025 Nov · PMID 40962941
·
Full text
Non-structural protein 1 (NS1) of dengue virus (DENV) harbours two conserved N-glycosylation sites at positions 130 and 207, whose biological roles have remained elusive. Using a clinically relevant mouse model of severe...Non-structural protein 1 (NS1) of dengue virus (DENV) harbours two conserved N-glycosylation sites at positions 130 and 207, whose biological roles have remained elusive. Using a clinically relevant mouse model of severe dengue, we showed that DENV that lacked N207 glycans on NS1 was significantly attenuated, and this phenotype was dominant over wild-type virulent DENV. Mice infected with this mutant exhibited accelerated viral clearance, milder lymphopenia and more functional DENV-specific CD8 T cells. Bulk and single-cell RNA sequencing, cytokine measurements and immune-phenotyping revealed blunted innate inflammatory responses early post-infection, which correlated with reduced PD-L1 expression on innate immune cells and reduced PD-1 T-cells in mice infected with de-glycosylated DENV. PD-1 blockade demonstrated the involvement of premature T-cell apoptosis through the PD-L1/PD-1 axis in DENV pathogenesis. Collectively, our findings support that N207-de-glycosylated NS1 inhibits early inflammatory responses, which restricts PD-L1 upregulation on innate immune cells, which in turn limits PD-L1/PD-1 mediated T-cell apoptosis. Our study uncovers a novel immune evasion strategy and identifies PD-L1/PD-1 as a novel mechanism of dengue immunopathogenesis.
Lopes-Rodrigues V, Nyantakyi SA, Lun X
… +12 more, Han X, Zhang J, Ramanujan A, Salim S, Saleeb M, Babes L, Chou AZ, Du L, Dong S, Chou JJ, Senger DL, Ibáñez CF
EMBO Mol Med
· 2025 Oct · PMID 40962940
·
Full text
Receptor transmembrane domains (TMDs) are crucially involved in relaying ligand information from extracellular to intracellular spaces and represent attractive targets for small molecule manipulation of receptor function...Receptor transmembrane domains (TMDs) are crucially involved in relaying ligand information from extracellular to intracellular spaces and represent attractive targets for small molecule manipulation of receptor function. Screening a library of over 8000 drug-like compounds with an assay based on the TMD of death receptor p75, we identified a novel small molecule capable of inhibiting p75-mediated migration of human melanoma cells. Employing medicinal chemistry, a more potent derivative termed Np75-4A22 was identified that blocked nerve growth factor (NGF)-mediated melanoma invasion at sub-micromolar concentrations. The specific interaction of Np75-4A22 with the p75 TMD was confirmed by 2D NMR. Mechanistically, Np75-4A22 was found to antagonize NGF-mediated recruitment of the actin-bundling protein fascin to p75, fascin association with the actin cytoskeleton and filopodia formation. Importantly, preclinical assessment of Np75-4A22 showed high oral bioavailability, low toxicity, and significant inhibition of melanoma lung invasion in mice. These results support further development of this approach as an alternative or complementary strategy for melanoma cancer patients that do not respond to conventional chemotherapy or immune checkpoint inhibitors.
Korff K, Müller-Reif JB, Fichtl D
… +8 more, Albrecht V, Schebesta AS, Itang ECM, Winter SV, Holdt LM, Teupser D, Mann M, Geyer PE
EMBO Mol Med
· 2025 Nov · PMID 40940569
·
Full text
Bead-based enrichment is a promising strategy to improve depth in plasma proteomics by overcoming the dynamic range barrier. However, its robustness against pre-analytical variation has not been sufficiently characterize...Bead-based enrichment is a promising strategy to improve depth in plasma proteomics by overcoming the dynamic range barrier. However, its robustness against pre-analytical variation has not been sufficiently characterized. Here, we systematically evaluate five plasma proteomics workflows, including three bead-based methods, a neat workflow, and a precipitation protocol using spike-ins of low-abundance proteins and defined cellular contaminants. We find that bead-based approaches enhance detection of low-abundance proteins but can be highly susceptible to systematic bias from platelet and PBMC contamination. This can inflate results by thousands of proteins, potentially explaining some of the high literature-reported numbers. A perchloric acid-based workflow shows resistance to erythrocyte and platelet-derived contamination. We investigate how centrifugation conditions, anticoagulant choice, and buffer-bead combinations modulate contamination profiles and demonstrate that bias can be mitigated by optimized sample handling. Altogether, we identify more than 13,000 different protein groups, including cellular components from the circulating proteome. Our results provide a quantitative framework for assessing workflow performance under variable sample quality and offer guidance for both biomarker discovery and quality control in clinical proteomics studies.
Feng S, Ma E, Na X
… +18 more, Wang Z, Tai W, Bao X, Wang M, Chang H, Wu B, Liu M, Li J, Shi H, Yang C, Xi M, Yang H, Li Y, Zhu Y, Wang P, Zhao L, Zhao A, Cheng G
EMBO Mol Med
· 2025 Nov · PMID 40940568
·
Full text
Vaccination offers the most effective protection against contagious infectious diseases primarily by inducing humoral immunity. Vaccination efficacy is influenced by various factors. We report that dietary administration...Vaccination offers the most effective protection against contagious infectious diseases primarily by inducing humoral immunity. Vaccination efficacy is influenced by various factors. We report that dietary administration of arachidonic acid (ARA) significantly boosts rabies vaccine-induced production of neutralizing antibodies and protection against lethal rabies virus (RABV) infection in mice. In human volunteers, oral supplementation of ARA accelerates the expression of neutralizing antibodies to the levels sufficient for protection against RABV as early as one week after primary immunization. Mechanistically, ARA is enriched in lymph nodes and metabolized into immune modulators there. One of the ARA metabolites, prostaglandin I (PGI), via the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) axis, upregulates the expression of costimulatory molecule CD86, and activates activation-induced cytidine deaminase (AID) in B cells. These results suggest that ARA can be a potent dietary adjuvant to foster germinal center (GC) B cell response and humoral immunity.
Xu J, Mao X, Liu Z
… +17 more, Jiang N, Wong XE, Liu D, Wang Y, Zhan H, Liu S, Yu J, Yuan R, Bai Q, Bai X, Huang W, Xie R, Krenn V, Kirchhoff F, Wang H, Guo Z, Bian S
EMBO Mol Med
· 2025 Oct · PMID 40926052
·
Full text
Primary microcephaly, a rare congenital condition characterized by reduced brain size, occurs due to impaired neurogenesis during brain development. Through whole-exome sequencing, we identified compound heterozygous los...Primary microcephaly, a rare congenital condition characterized by reduced brain size, occurs due to impaired neurogenesis during brain development. Through whole-exome sequencing, we identified compound heterozygous loss-of-function mutations in CENTRIN 3 (CETN3) in a 5-year-old patient with primary microcephaly. As CETN3 has not been previously linked to microcephaly, we investigated its potential function in neurodevelopment in human pluripotent stem cell-derived cerebral organoids. We showed that CETN3-knockout (KO) organoids successfully recapitulated the microcephaly phenotype of reduced size compared to the control organoids. Through transcriptomic, histological, and protein analyses, we found that CETN3 deficiency directly interferes with neuronal differentiation and reduces proliferative capacity in neural stem/progenitor cells by impairing centrosome assembly required in cell cycle progression, consequently activating apoptosis. Furthermore, our data uncovered previously undocumented indirect effects of CETN3 through interaction with RNA splicing machinery involved in brain development. These findings expand the scope of known regulatory mechanisms of CETN3 in brain development and its etiological roles in human brain malformation.
Carlini MJ, Espinoza-Derout J, Van Alstyne M
… +8 more, Tisdale S, Workman E, Triplett MK, Tattoli I, Yadav S, Henderson CE, Watterson DM, Pellizzoni L
EMBO Mol Med
· 2025 Oct · PMID 40926051
·
Full text
Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by ubiquitous deficiency in the SMN protein. The identification of disease modifiers is key to understanding pathogenic mechanisms and broadening the ra...Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by ubiquitous deficiency in the SMN protein. The identification of disease modifiers is key to understanding pathogenic mechanisms and broadening the range of targets for developing SMA therapies that complement SMN upregulation. Here, we report a cell-based screen that identified inhibitors of p38 mitogen-activated protein kinase (p38 MAPK) as suppressors of proliferation defects induced by SMN deficiency in mouse fibroblasts. We further show that SMN deficiency induces p38 MAPK activation and that pharmacological inhibition of this pathway improves motor function in SMA mice through SMN-independent neuroprotective effects. Using a highly optimized p38 MAPK inhibitor (MW150) and combinatorial treatment in SMA mice, we observed synergistic enhancement of the phenotypic benefit induced by either MW150 or an SMN-inducing drug alone. By promoting motor neuron survival, pharmacological inhibition of p38 MAPK synergizes with SMN induction and enables enhanced synaptic rewiring of motor neurons within sensory-motor spinal circuits. These studies identify the p38 MAPK pathway as a therapeutic target and MW150 as a neuroprotective drug for combination therapy in SMA.
Chen X, Cheng ML, Huang XY
… +8 more, Sun MX, Li RT, Wu M, Li YY, Xu Q, Guan MY, Zhao H, Qin CF
EMBO Mol Med
· 2025 Oct · PMID 40926050
·
Full text
Traditional live attenuated vaccines (LAVs) are typically developed through serial passaging or genetic engineering to introduce specific mutations or deletions. While viral RNA secondary or tertiary structures have been...Traditional live attenuated vaccines (LAVs) are typically developed through serial passaging or genetic engineering to introduce specific mutations or deletions. While viral RNA secondary or tertiary structures have been well-documented for their multiple functions, including binding with specific host proteins, their potential for LAV design remains largely unexplored. Herein, using Zika virus (ZIKV) as a model, we demonstrate that targeted disruption of the primary sequence or tertiary structure of a specific viral RNA element responsible for Musashi-1 (MSI1) binding leads to a tissue-specific attenuation phenotype in multiple animal models. The engineered MSI1-binding-deficient ZIKV mutants (MBD) maintained full competence in MSI1-deficient tissues but were significantly restricted in ZIKV-vulnerable tissues (brain, testis, eye and placenta) and exhibited substantially reduced vertical transmission in mice. Importantly, a single immunization with MBD ZIKV induced robust immune responses and conferred protection against ZIKV challenge in both mice and non-human primates. Thus, our study demonstrates that manipulating viral RNA structures that interact with host proteins represents a powerful platform for developing the next generation of LAVs against emerging viruses.
Zhu C, Hong W, Zhu Y
… +5 more, Xue Y, Fang Z, Jiang D, Xu Y, Kong M
EMBO Mol Med
· 2025 Oct · PMID 40921878
·
Full text
Cardiac fibrosis contributes to adverse cardiac remodeling and loss of heart function eventually leading to heart failure (HF). Resident cardiac fibroblasts are the principal source of myofibroblasts that produce extrace...Cardiac fibrosis contributes to adverse cardiac remodeling and loss of heart function eventually leading to heart failure (HF). Resident cardiac fibroblasts are the principal source of myofibroblasts that produce extracellular matrix proteins to mediate cardiac fibrosis. We report that TET3 depletion in cultured cardiac fibroblasts blocked transition to myofibroblasts in response to different pro-fibrogenic stimuli. Consistently, deletion of TET3 from quiescent or activated fibroblast (myofibroblast) attenuated cardiac fibrosis and rescued heart function in mice. Importantly, a small-molecule TET3-specific degrader Bobcat339 displayed therapeutic potential by mitigating cardiac fibrosis and normalizing heart function when administered post-surgery. Integrated transcriptomic analysis identified the mechanosensor Piezo2 as a downstream target for TET3. Piezo2 inhibition dampened fibroblast activation in vitro and ameliorated cardiac fibrosis in vivo. Mechanistically, Piezo2 promoted fibroblast activation by modulating the activities of mechanosensitive transcription factors. Finally, relevance of TET3 and Piezo2 was verified in heart specimens collected from HF patients. In conclusion, our data demonstrate that TET3 is a pivotal regulator of cardiac fibrosis and can be potentially targeted for the intervention of heart failure.
Zhao R, Wu L, Zhang Y
… +18 more, Ma J, Liu D, Zheng Y, Kong T, Ma R, Gao Z, Chai Y, Liu Y, Tian Y, Xia Y, Hou Y, Lu J, Cong Z, Huang B, Tan W, Xue J, Gao GF, Wang Q
EMBO Mol Med
· 2025 Oct · PMID 40921877
·
Full text
The global outbreak of the mpox in humans, caused by the mpox virus (MPXV), underscores the urgent need for safe and effective therapeutics. In this study, we characterized the dominant MPXV immunogens, M1R and B6R, by s...The global outbreak of the mpox in humans, caused by the mpox virus (MPXV), underscores the urgent need for safe and effective therapeutics. In this study, we characterized the dominant MPXV immunogens, M1R and B6R, by sequencing monoclonal antibodies (MAbs) from the immunized mice and analyzing their epitopes and functions through in vitro and in vivo assessments of binding and antiviral activities. Several broadly effective anti-M1R and anti-B6R neutralizing MAbs were identified and they exhibited enhanced antiviral effects against MPXV or vaccinia virus (VACV) when used in antibody cocktail and bispecific antibody designs. Notably, the VH-CH1 switch region-inserting format of bispecific antibodies exhibited robust protective efficacy against VACV in a mouse model. Collectively, our study characterized the epitope and functional maps of anti-M1R and anti-B6R MAbs and developed promising broad-spectrum antibody candidates for the treatment of MPXV and other orthopoxvirus infections.
Feng Y, He Y, Zuo R
… +10 more, Gong W, Gao Y, Wang Y, Wang Y, Chen W, Chen L, Luo Y, Yuan D, Chen P, Guo H
EMBO Mol Med
· 2025 Oct · PMID 40897859
·
Full text
Resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) remains a critical clinical challenge in EGFR mutant lung adenocarcinoma (LUAD). Therefore, it is urgent to explore personalized treat...Resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) remains a critical clinical challenge in EGFR mutant lung adenocarcinoma (LUAD). Therefore, it is urgent to explore personalized treatment strategies based on distinct resistance mechanisms to reverse EGFR-TKI resistance. Herein, we found that HER2 S310F mutation contributes to third-generation EGFR-TKI resistance, driven by the accumulation of neurotransmitter 5-hydroxytryptamine (5-HT). Mechanistically, 5-HT interacted with 5-HT3 receptor, triggering calcium ion (Ca) influx and subsequent activation of the Ca/CAMKK2/AMPK pathway. This pathway activation conferred ferroptosis resistance, thereby driving aumolertinib resistance. 5-HT3 receptor (HTR3) antagonists were pinpointed as potential agents for reversing aumolertinib resistance through drug library screening and transcriptomics analysis. We demonstrated that pharmacologically targeting 5-HT/HTR3 signaling with the clinically approved HTR3 antagonist palonosetron effectively restores aumolertinib sensitivity. Importantly, we showed that elevated 5-HT levels in patient plasma play a potential role in predicting EGFR-TKI resistance. Our data highlight the critical role of 5-HT and ferroptosis in the development of aumolertinib resistance, and propose HTR3 antagonists as a novel combination therapy strategy for LUAD treatment with aumolertinib.
EMBO Mol Med
· 2025 Sep · PMID 40859056
·
Full text
Adeno-associated virus-based gene therapy offers a promising treatment paradigm for inner ear diseases; however, the genetic heterogeneity of hereditary deafness requires gene-specific strategies and optimization of curr...Adeno-associated virus-based gene therapy offers a promising treatment paradigm for inner ear diseases; however, the genetic heterogeneity of hereditary deafness requires gene-specific strategies and optimization of current approaches to identify the range of treatable conditions and improve therapeutic outcomes. To consider the therapeutic potential for a hearing loss gene not previously explored, we investigated the gene encoding the chloride intracellular channel protein CLIC5, mutations in which lead to DFNB103 in humans and deafness and circling behavior in a Clic5-deficient mouse model. In this study, we utilized two constructs to deliver the wild-type Clic5 coding sequence into Clic5-deficient mice: single-stranded and self-complementary adeno-associated virus, the latter known for rapid onset of transgene expression. We report a robust restoration of CLIC5 expression using either construct, including prevention of morphological degeneration and preserving auditory and vestibular function. Interestingly, the self-complementary construct achieved comparable functional recovery to single-stranded construct but at a lower titer. These findings highlight the potential of self-complementary adeno-associated virus to reduce dose requirements, minimize toxicity and broaden clinical utility for inner ear therapies.