Müller F, McLachlan E, Costa AC
… +14 more, Qu J, Shrestha B, Wang Z, De Virgiliis F, Hutson TH, Zhou L, Kong G, Chadwick JS, La Montanara P, Yuan Z, Haberman N, Sousa MM, Palmisano I, Di Giovanni S
EMBO Mol Med
· 2026 Jun · PMID 42103934
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Olander S, Karaman S, Suomi F
… +11 more, Aguilar K, Zhaivoron A, Nedergaard M, Smeds L, Tiihonen J, Quintana A, Hidalgo J, Alitalo K, Ala-Laurila P, Ince-Dunn G, Suomalainen A
EMBO Mol Med
· 2026 May · PMID 42103933
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Retinopathy is a common symptom in mitochondrial diseases, and a leading cause of blindness in working-age individuals, often arising as a consequence of diabetes. Here, we demonstrate that postnatal loss of the replicat...Retinopathy is a common symptom in mitochondrial diseases, and a leading cause of blindness in working-age individuals, often arising as a consequence of diabetes. Here, we demonstrate that postnatal loss of the replicative helicase of mitochondrial DNA in the astrocytes and Müller glia induces neovascular retinopathy. In these retinas, the macroglia show pathological reactivation, leading to hallmark features of neovascularization with blood-retina-barrier leakage, secondary microgliosis, and complement cascade activation. Similar reactivation of astrocytes in the cerebral cortex does not compromise vascular integrity, indicating tissue-specific roles of mitochondrial metabolism in macroglia for vascular homeostasis. Three secreted angiogenic factors-Fgf2, Pgf, and Lcn2-known to contribute to diabetic retinopathy, were induced. Spike recordings of the most sensitive retinal ganglion cells revealed normal rod function and intact retinal coding. These findings highlight the critical role of glial mitochondrial metabolism in neovascular retinopathy, with important implications for therapy development for mitochondrial and common forms of vision loss.
Wang F, Zeng W, Zhang Z
… +8 more, Li N, Cui Z, Bai J, Yan J, Zhang Y, Miao Y, Gu L, Xiong B
EMBO Mol Med
· 2026 Jun · PMID 42103932
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The gut microbiota plays a vital role in maintaining the physiological function of host health and the pathogenesis of various diseases. However, its relationship with maternal age-associated decline in oocyte quality re...The gut microbiota plays a vital role in maintaining the physiological function of host health and the pathogenesis of various diseases. However, its relationship with maternal age-associated decline in oocyte quality remains elusive. Here, we report that establishment of gut microbiota from young donors in aged mice by fecal microbiota transplantation (FMT) is an effective method to rejuvenate the quality of maternally aged oocytes. Specifically, young gut microbiota promoted the ovulation and maturation of aged oocytes, and inhibited occurrence of cytoplasm fragmentation and spindle/chromosome abnormalities, hence enhancing the oocyte quality and female fertility. By integrating metagenome and untargeted metabolome of intestinal digesta, as well as targeted metabolome of ovaries and micro-transcriptome of oocytes, we identified that Bacteroides_caecimuris-modulated glutamic acid levels mediated the restorative effects of young gut microbiota on the aged oocytes through strengthening the mitochondria function. In addition, we demonstrated that in vivo supplementation of glutamic acid also enhanced the quality of aged oocytes, and the improvement of oocyte quality by glutamic acid was conserved across species. Altogether, our findings highlight the importance of gut microbiota in the oocyte aging and provide potential improvement strategies for age-related decline in oocyte quality and female fertility.
Hamada N, AlAbdi L, Uehara T
… +16 more, Sasikarn L, Nishijo T, Suliman-Lavie R, Hashem MO, Alfadhel M, Alhefdhi S, Tabarki B, Alghamdi M, Iwamoto I, Takenouchi T, Kosaki K, Shifman S, Mizuno S, Ohno N, Alkuraya FS, Nagata KI
EMBO Mol Med
· 2026 Jun · PMID 42086905
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CEP152 is essential for centriole function and neurodevelopment, and pathogenic recessive variants in CEP152 cause primary microcephaly. We identified new compound heterozygous CEP152 variants, c.314 G > A,p.(W105*) and...CEP152 is essential for centriole function and neurodevelopment, and pathogenic recessive variants in CEP152 cause primary microcephaly. We identified new compound heterozygous CEP152 variants, c.314 G > A,p.(W105*) and c.2689 A > T,p.(K897*), in a microcephalic patient and analyzed them alongside a homozygous variant c.95 A > C,p.(Q32P) associated with severe microcephaly with marked gyral simplification. In vitro assays revealed distinct effects: p.K897* prevented centrosomal localization, p.W105* led to protein degradation, and p.Q32P retained centrosomal targeting but disrupted binding to Polo-like kinase 4, a key centriole biogenesis kinase and CEP152 partner. In vivo, both Cep152 and Cep152 knock-in mice displayed microcephaly; notably, Cep152 mice also exhibited severe cortical defects during brain development. Cellular analyses revealed centrosome dysfunction, mitotic errors, and increased apoptosis, which were exacerbated in Cep152 brains. Morphological examination, including electron microscopy, further demonstrated structural abnormalities of the centrosomes and centrioles in Cep152 brains. Electrophysiological and gene expression analyses confirmed variant-specific neuronal impairments, which correlate with clinical severity. Collectively, these findings demonstrate that distinct CEP152 variants disrupt neurodevelopment through different mechanisms, thereby explaining the spectrum of microcephaly severity and associated phenotypes.
Nam KH, Kim GR, Kim YR
… +3 more, Kwon YN, Kim SM, Choi JM
EMBO Mol Med
· 2026 Jun · PMID 42086904
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Costimulation blockade with CTLA-4 Ig (Abatacept) is a widely used strategy to suppress autoreactive T cells; however, its efficacy is often self-limiting due to concurrent depletion of regulatory T cells (Tregs), which...Costimulation blockade with CTLA-4 Ig (Abatacept) is a widely used strategy to suppress autoreactive T cells; however, its efficacy is often self-limiting due to concurrent depletion of regulatory T cells (Tregs), which depend on CD28 signaling for homeostasis. Here, we demonstrate that costimulation blockade paradoxically potentiates IL-2-driven Treg generation by selectively reprogramming intracellular cytokine signaling. We identified that IL-2 activates STAT3 only in the presence of TCR stimulation, as this pathway requires CD28-mediated PI3K-AKT signaling, which is abrogated by costimulation blockade. Consequently, CTLA-4 Ig uncouples STAT3 activation from IL-2 signaling while sparing STAT5, thereby enhancing TGF-β/Smad2/3 signaling to induce Foxp3 expression. This dual action-sustained STAT5 activation and increased Smad2/3 signaling-promoted robust Treg generation that ameliorated experimental autoimmune encephalomyelitis (EAE). Furthermore, we confirmed that this synergistic effect is conserved in human T cells from patients with multiple sclerosis (MS) upon CTLA-4 Ig and IL-2 cotreatment. Our findings suggest a strategy to expand the utility of CTLA-4 Ig therapy, providing a mechanistic rationale for combining costimulation blockade with IL-2 to restore immune tolerance in CNS autoimmunity.
EMBO Mol Med
· 2026 Jun · PMID 42082810
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Skin biology is commonly framed through signaling pathways that reprogram transcription in response to inflammatory and environmental cues. Here, a complementary perspective is proposed: epidermal homeostasis and disease...Skin biology is commonly framed through signaling pathways that reprogram transcription in response to inflammatory and environmental cues. Here, a complementary perspective is proposed: epidermal homeostasis and disease recurrence may also depend on the physical organization of the genome within the nucleus. HNRNPU/SAF-A has emerged as an RNA-dependent architectural factor that links RNA binding to chromatin topology, while architectural long non-coding RNAs provide precedents for how RNA can scaffold nuclear compartments and influence higher-order genome organization. Building on these concepts, the Epidermal Differentiation Complex is considered as a tractable epidermal locus in which RNA-dependent nuclear tethering may help stabilize barrier gene programs. This framework further suggests that chronic inflammation could remodel chromatin architecture in ways that persist after apparent resolution, generating a "structural scar" that biases future responses. Although this model remains hypothetical, it is now experimentally testable. By integrating architectural RNA biology with epidermal differentiation and inflammatory memory, this Perspective provides a roadmap for investigating how nuclear structure may contribute to epithelial state stability and how it may be altered in inflammatory skin disease.
Jurmeister P, Flach S, Bergmayr L
… +19 more, Schleich K, Chimal Calderon E, H Mochmann L, Zhdanovich Y, Klingler D, Pusztai A, Kübler A, Walz C, Westphalen CB, Beck A, Leitheiser M, Breimer GE, Rijken JA, Devriese L, Baumeister P, Skálová A, Schallenberg S, Klauschen F, Mock A
EMBO Mol Med
· 2026 Jun · PMID 42070010
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SMARCB1-deficient sinonasal carcinoma (SDSC) is a rare, highly aggressive malignancy with limited therapeutic options and no established preclinical models. Here, single-nucleus RNA sequencing (snRNAseq), spatial transcr...SMARCB1-deficient sinonasal carcinoma (SDSC) is a rare, highly aggressive malignancy with limited therapeutic options and no established preclinical models. Here, single-nucleus RNA sequencing (snRNAseq), spatial transcriptomics, and ex vivo patient-derived tissue slice culture (TSC) were combined to resolve intratumoral heterogeneity, niche organization, and treatment vulnerabilities in an index SDSC. snRNAseq identified three malignant subpopulations, including two specialized states marked by ALDH1A1 and NTN4. Spatial profiling mapped these states to distinct niches. The ALDH1A1+ compartment localized to a basal-associated niche with intermingled p63-positive basal cells adjacent to stroma, showed reduced proliferative activity, and displayed stem-like transcriptional features. Ex vivo drug testing revealed a striking response: the mTOR inhibitor Sapanisertib induced extensive tumor necrosis and was associated with near-complete depletion of ALDH1A1+ and NTN4+ states, accompanied by strong stress/apoptosis signatures and reduced endothelial cells. In an additional retrospective cohort of 12 SDSC, ALDH1A1 was present in all cases with heterogeneous spatial patterns and higher levels in recurrences. Mesothelin was expressed in the index case and a subset of tumors, supporting mesothelin-directed therapeutic strategies.
Vinette V, Castro A, Kim H
… +5 more, Trujillo C, Xie M, Gengenbacher M, Ioerger TR, Ehrt S
EMBO Mol Med
· 2026 Jun · PMID 42049954
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Alveolar macrophages are the first immune cells to encounter Mycobacterium tuberculosis (Mtb) in the lungs, but they frequently fail to eliminate this pathogen, allowing Mtb to persist and replicate. Interstitial macroph...Alveolar macrophages are the first immune cells to encounter Mycobacterium tuberculosis (Mtb) in the lungs, but they frequently fail to eliminate this pathogen, allowing Mtb to persist and replicate. Interstitial macrophages (IMs) are enlisted to restrict bacterial growth and limit immune evasion. While IMs have been implicated in controlling acute Mtb infection, their role during latent tuberculosis infection (LTBI) remains unexplored. To address this, we utilized a previously established mouse model of paucibacillary Mtb infection that recapitulates key aspects of human LTBI to deplete IMs during the latent phase. Depletion of IMs and recruited macrophages (RMs) led to TB relapse in 26% of mice compared to 2% in controls. Mice that relapsed exhibited an increased proportion of pro-inflammatory IMs and elevated concentrations of G-CSF, GM-CSF, IL-3, IL-12, IL-13, IL-17A, and KC in the lung. These findings demonstrate that IMs and RMs play a critical role in controlling latent Mtb and preventing TB relapse.
Yang Q, Cui Y, Huang X
… +5 more, Liu J, Ma X, Gao GF, Pan H, Qin S
EMBO Mol Med
· 2026 Jun · PMID 42045679
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Hypertrophied adenoids in children can impair breathing and lead to obstructive sleep apnea (OSA), often accompanied by abnormal growth and weakened stamina and immunity. However, the cause of the pathological transforma...Hypertrophied adenoids in children can impair breathing and lead to obstructive sleep apnea (OSA), often accompanied by abnormal growth and weakened stamina and immunity. However, the cause of the pathological transformation in these originally immune-enhancing lymphoid tissues remains unclear. Our study provides the first single cell transcriptomic and immune repertoire atlas of adenoids from normal snoring to mild, moderate, and severe OSA, and identified markedly asynchronous functional modules, transcriptional regulatory networks and intercellular communications during the progression of OSA. Children with severe OSA exhibited exhibit active Hippo, Notch, and Wnt signaling, alongside significant downregulation of energy synthesis. Analysis revealed compromised T-cell and B-cell immunity, as well as reduced antigen processing by innate immune cells, coupled with diminished cell-cell communication in severe OSA group. T-cell receptor and B-cell receptor sequencing results also support more infection imprints and abnormal germinal centers and antibody class switching. Mechanistically, HIF1A-mediated hypoxic signaling likely drives the downregulation of key immune components (including HLA and interferon molecules), positioning it as a promising therapeutic target for OSA.
EMBO Mol Med
· 2026 Jun · PMID 42045678
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Despite the clinical success of CD19-directed CAR T-cell therapies, less than 50% of patients achieve long-term remission. Emerging evidence indicates that loss or reduced expression of CD19-due to mutations, deletions,...Despite the clinical success of CD19-directed CAR T-cell therapies, less than 50% of patients achieve long-term remission. Emerging evidence indicates that loss or reduced expression of CD19-due to mutations, deletions, alternative splicing-is a significant, underrecognized mechanism of treatment failure. Notably, CD19-negative subpopulations can be detected even prior to therapy, and patients with low CD19 expression consistently show poorer outcomes. Although current clinical guidelines do not mandate routine CD19 testing before treatment, this situation reflects both scientific and technical challenges. Importantly, patients with partial/ low CD19 expression may still benefit from therapy, complicating the definition of "target positivity." From a regulatory perspective, targeted therapies should ideally be used only when target expression is confirmed. This principle is difficult to implement, considering the scarcity of data and the difficulties of current diagnostic tools, risking both undertreatment and overtreatment. EU regulators have addressed the issue by introducing harmonized warnings in product information, but more is needed. We highlight this regulatory-clinical gap and advocate for improved diagnostic standards, better data integration, and dialogue among clinicians, developers, and regulators.
Molina-Berenguer M, Herrero-Martínez D, Vallbona-Garcia A
… +6 more, Vila-Julià F, Cámara Y, Vales Á, González-Aseguinolaza G, Torres-Torronteras J, Martí R
EMBO Mol Med
· 2026 Jun · PMID 41998139
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Hepatoencephalopathy due to mutations in the nuclear gene GFM1, known as combined oxidative phosphorylation (OXPHOS) deficiency type I (COXPD1), is an autosomal recessive mitochondrial disease caused by defects or defici...Hepatoencephalopathy due to mutations in the nuclear gene GFM1, known as combined oxidative phosphorylation (OXPHOS) deficiency type I (COXPD1), is an autosomal recessive mitochondrial disease caused by defects or deficiency of the mitochondrial translation elongation factor G1 (EFG1), with no currently available cure. Patients with COXPD1 develop a severe encephalopathy, sometimes combined with liver failure, with neonatal onset and rapid progression that normally causes premature death. The Gfm1 mouse recapitulates the COXPD1 molecular phenotype in liver and brain, with drastic reduction of EFG1 levels, impaired mitochondrial translation, and OXPHOS deficiency. We conducted a gene therapy study using two different recombinant adeno-associated virus (rAAV) vectors targeting the liver or the brain to introduce the human GFM1 gene into 6-week-old Gfm1 mice. Successful transduction of the liver and the brain was observed after four weeks, entailing substantial recovery from mitochondrial EFG1 depletion and OXPHOS correction in both tissues, which demonstrates that transgenic human EFG1 is functional in mouse mitochondrial translation. Our study constitutes the first evidence supporting AAV-mediated gene therapy as a potential treatment for COXPD1.
Woo H, Jang Y, Kim S
… +12 more, Kim W, Zhang F, Mall R, Patel CN, Kurera M, Ngo C, Jiang SH, Nicotra A, Py BF, Zheng M, Man SM, Karki R
EMBO Mol Med
· 2026 Jun · PMID 41998138
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The NLRP3 inflammasome is a key driver in inflammatory, infectious, metabolic, and neurodegenerative diseases. Although the NLRP3 inhibitor CRID3 (also known as MCC950) exhibits potent activity, it cannot inhibit several...The NLRP3 inflammasome is a key driver in inflammatory, infectious, metabolic, and neurodegenerative diseases. Although the NLRP3 inhibitor CRID3 (also known as MCC950) exhibits potent activity, it cannot inhibit several hyperactive NLRP3 mutations associated with autoinflammatory syndromes and has not progressed clinically, underscoring the need for the development of new NLRP3 inhibitors. Through a high-throughput screening, we identified LOC14, an isothiazolinone-containing small molecule, as a selective NLRP3 inhibitor. Distinct from CRID3, which targets the NACHT domain, LOC14 binds to or near the LRR domain of NLRP3 and inhibits both CRID3-responsive and CRID3-non-responsive hyperactive or gain-of-function NLRP3 variants. Furthermore, we identified that the carbonyl oxygen of the isothiazol-3(2H)-one moiety is critical for inhibitory activity. In vivo, LOC14 exerted anti-inflammatory activity in mouse models of colitis, sepsis, and psoriasis, demonstrating broad physiological and therapeutic relevance. Our findings highlight isothiazolinone-containing compounds as selective NLRP3 inhibitors and provide a promising foundation for developing therapies targeting NLRP3-driven inflammatory diseases.
Tang R, Ye H, Chen G
… +11 more, Dong X, Li Z, Lin F, Huang T, Qiu L, Lin G, Wu M, Yu H, Zou J, Liu X, Cai Z
EMBO Mol Med
· 2026 Jun · PMID 41998137
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Immune suppression is one of the primary obstacles in neoantigen immunotherapy because tumors can rapidly adapt by reducing MHC-I expression or antigen presentation. Here, we developed a novel immunotherapy strategy that...Immune suppression is one of the primary obstacles in neoantigen immunotherapy because tumors can rapidly adapt by reducing MHC-I expression or antigen presentation. Here, we developed a novel immunotherapy strategy that combined vaccination of neoantigens with MICB α3 antigen, by using bacterial outer membrane vesicles (OMVs) as a versatile vector and adjuvant. This approach aims to simultaneously induce a neoantigen-specific cellular immune response and an anti-MICB α3 humoral immune response, to enhance the recognition and killing of tumor cells by immune cells. This strategy significantly improves the infiltration of neoantigen-specific T cells and NK cells, and reverses immunosuppression across various preclinical models. Mechanistically, ILC1s characterized by high GZMA/GZMB expression represent the primary subset accumulating within tumors and are responsible for enhancing antitumor immunity, which can induce Gasdermin D cleavage in tumor cells to initiate tumor pyroptosis for a cascade of cancer-immunity cycle. Overall, this study demonstrated that combined neoantigens and shared MICB α3 antigen for tumor vaccination enhances immune efficacy by eliciting ILC1s-mediated tumor pyroptosis and support the rationale and clinical translation for cancer immunotherapy.
EMBO Mol Med
· 2026 May · PMID 41992042
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The past decade has defined molecular hallmarks of aging, yet interventions that extend lifespan in short-lived organisms show limited and context-dependent translation to humans. Comparative studies of exceptional longe...The past decade has defined molecular hallmarks of aging, yet interventions that extend lifespan in short-lived organisms show limited and context-dependent translation to humans. Comparative studies of exceptional longevity remain largely genome-centric, although genomic instability alone cannot comprehensively explain aging-related pathologies. Many age-associated failures emerge at the level of cellular organelles whose stability underpins tissue function. The pathways that sustain these structures operate through proteomic, metabolic, and lipid networks that are insufficiently captured by genomic or transcriptomic analyses. Notably, longer organismal lifespan increases the requirement for sustained organelle functionality and fidelity. This Perspective proposes that the next conceptual advance in geroscience will come from comparative organelle biology. Examining mammals with divergent lifespans, including species evolutionarily closer to humans, can reveal how long-lived lineages evolved organelle-level architecture and resilience mechanisms that support cellular function over decades. I introduce the Comparative Metabolic Longevity Cell Atlas (CMLCA), a cross-mammalian platform integrating standardized cellular systems, organelle-resolved multi-omics, and computational analysis to identify conserved features of resilience and inform next-generation strategies to improve human healthspan.
EMBO Mol Med
· 2026 May · PMID 41986508
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Sepsis is a life-threatening syndrome resulting from a dysregulated host response to an infection and is considered as a major global health priority. Despite increased metabolic energy needs to fight the infection and t...Sepsis is a life-threatening syndrome resulting from a dysregulated host response to an infection and is considered as a major global health priority. Despite increased metabolic energy needs to fight the infection and to sustain the inflammatory response, anorexia is one of the main characteristics of sickness behaviour during sepsis. In this review, we address the question of how feeding behaviour is regulated under basal conditions at the level of the hypothalamus, with specific focus on the orexigenic agouti-related peptide (AgRP)/neuropeptide Y (NPY)-expressing neurons and the anorexigenic pro-opiomelanocortin (POMC)/cocaine and amphetamine-regulated transcript (CART)-expressing neurons present in the arcuate nucleus. This is mediated by neural and humoral pathways involving the vagal nerve, and the blood-brain barrier and circumventricular organs, respectively. Furthermore, we discuss recent advances in how sepsis affects these appetite-controlling mechanisms by impairing the central integration of these peripheral signals and suggest potential therapeutic targets that might prevent or revert sepsis-associated anorexia.
Malviya M, Baniya S, Wong E
… +8 more, Jain T, Manoranjan B, Vogt KC, Kehs Z, Silberman PC, Dao T, Li Y, Scheinberg DA
EMBO Mol Med
· 2026 Jun · PMID 41981294
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The systemic administration of therapeutic agents, particularly large, charged molecules such as antibodies, has limited efficacy in treating central nervous system (CNS) disorders. In addition, the slow progression of n...The systemic administration of therapeutic agents, particularly large, charged molecules such as antibodies, has limited efficacy in treating central nervous system (CNS) disorders. In addition, the slow progression of neurodegenerative diseases makes repeated intrathecal injections unfeasible. Alzheimer's disease is characterized by the accumulation of Aβ amyloid plaques. Microglia contribute to the clearance of Aβ, but are inhibited by the expression of CD33. Therefore, antibody blocking of CD33 may enhance the phagocytosis of Aβ by microglial cells, slowing AD progression. Here, we use cells as "targeted cellular micropharmacies" that are retained in the CNS to deliver therapeutic proteins directly into the brain. To achieve this, we genetically engineered CD4 T-cells to express: (1) a chimeric antigen receptor against GD2 to retain the cells in the brain, (2) ectopic FoxP3 to reduce inflammation, (3) secreted IL-2 to promote cell longevity, and (4) secreted anti-CD33 scFv antibody. Our proof-of-concept demonstrates that therapeutic antibodies can be delivered to the brain for at least 8 weeks to treat neurological disorders. Other agents could be similarly delivered into the brain by this platform.
Wu Y, Yang X, Bai Y
… +23 more, Li C, Wang P, Xu Q, Li H, Rao X, Xu Y, Chen J, Cao H, Zhang Q, Zhao M, Zhan R, Fan X, Hou Y, Liu J, Lu HS, Wang T, Gao WD, Huang L, Xiao H, Zu L, Daugherty A, Xu M, Zheng L
EMBO Mol Med
· 2026 May · PMID 41975084
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Cardiac microvascular endothelial cells (CMECs) dysfunction is a well-recognized mediator of heart failure with preserved ejection fraction (HFpEF), but the underlying mechanism remains unclear. Here we find that scaveng...Cardiac microvascular endothelial cells (CMECs) dysfunction is a well-recognized mediator of heart failure with preserved ejection fraction (HFpEF), but the underlying mechanism remains unclear. Here we find that scavenger receptor class B type I (SR-B1) is predominantly expressed in CMECs and decreased significantly in HFpEF. Endothelial-specific SR-B1 deficiency exacerbates cardiac pathological remodeling and diastolic dysfunction in HFpEF, which can be prevented by endothelial SR-B1 reconstitution through adeno-associated virus serotype 1 (AAV1)-mediated delivery in endothelial-specific SR-B1-deficient mice. Single-cardiac-endothelial-cell transcriptomics and lineage-tracing system reveal that inflammatory CMECs subcluster activation is responsible for the deteriorating HFpEF progression induced by endothelial SR-B1 loss, rather than endothelial-to-mesenchymal transition. Mechanistically, SR-B1 loss drives increased CXCL10 secretion, which orchestrates CMECs activation and CXCR3-positive T-cell cardiotropism to promote diastolic dysfunction-a process associated with endothelial IRF1 activation. Most importantly, the SR-B1-CXCL10-CXCR3 axis is activated in human HFpEF cardiac tissue, and the elevated CXCL10 level in plasma is independently associated with a higher HFpEF prevalence. This study uncovers that activation of the SR-B1-CXCL10-CXCR3 axis in CMECs aggravates HFpEF pathogenesis through the accumulation of CXCR3-positive T-cells in hearts.
Ma F, Li Y, Xiang C
… +21 more, Wang B, Lv J, Shang Z, Zhang W, Qin Z, Pu Y, Li K, Wei J, Tan SB, Feng J, Teng H, Zhang P, Deng J, Wang Y, Zhang C, Tian S, Li G, Kang M, Du C, Han Y, Ding C
EMBO Mol Med
· 2026 May · PMID 41965870
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Immunotherapy has revolutionized cancer treatment, yet many patients show non-sensitivity. Here, we collected treatment-naïve samples from 190 esophageal squamous cell carcinoma (ESCC) patients undergoing anti-programmed...Immunotherapy has revolutionized cancer treatment, yet many patients show non-sensitivity. Here, we collected treatment-naïve samples from 190 esophageal squamous cell carcinoma (ESCC) patients undergoing anti-programmed death 1 (PD1) immunotherapy for proteome, phosphoproteome, and immunohistochemistry (IHC) analysis. Proteome-based stratification of ESCC identifies three proteomic subtypes (G-I-G-III) related to immunotherapy response and different molecular features, revealing that patients with high mitochondrial complex I protein expression show sensitivity to anti-PD1 immunotherapy. High mitochondrial complex I protein expression of ESCC cells or patient-derived organoids increases sensitivity to CD8 + T cell-mediated killing in the co-culture systems. Phosphoproteomic data analysis reveals YAP1 activation impairs immunotherapy efficacy. Inhibiting YAP1 or increasing mitochondrial complex I levels bolsters immunotherapy effectiveness in ESCC allograft tumors. Finally, we develop a highly accurate predictive model (AUC ≥ 0.90) by the signatures of mitochondrial complex I-mediated anti-tumor immune response and validate it in independent cohorts. This study provides a rich resource for investigating the mechanisms and indicators of immunotherapy in ESCC.
Huang Y, Ye Y, Zhu X
… +7 more, Liang D, Cui R, Yuan X, Li X, Zou Q, Li H, Huang W
EMBO Mol Med
· 2026 May · PMID 41963642
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The limitations of existing drugs and the development of drug resistance make it urgent to develop new drugs against methicillin-resistant Staphylococcus aureus (MRSA). The re-development of the antibacterial activity of...The limitations of existing drugs and the development of drug resistance make it urgent to develop new drugs against methicillin-resistant Staphylococcus aureus (MRSA). The re-development of the antibacterial activity of drugs that have already been proven safe for human use is an effective way. In this study, we discovered that the Src homology region 2 domain-containing phosphatase-1 (SHP-1) agonist SC-43, exhibits potent activity against Gram-positive bacteria, including MRSA. The mode of action studies revealed that SC-43 inhibits the key enzyme coproporphyrin ferrochelatase (CpfC) of the coproporphyrin-dependent (CPD) heme synthesis pathway and interferes with the bacterial porphyrin metabolism. The determination of the structure of CpfC derived from S. aureus (SA) in this study allowed us to reveal the inhibitory effect of SC-43 at the molecular level. Animal experiments showed that SC-43 has the potential to become a new anti-MRSA drug. In conclusion, this study discovered a new anti-MRSA activity of a drug currently undergoing clinical trials and simultaneously verified the feasibility of developing new anti-Gram-positive bacteria drugs by inhibiting the CPD pathway.
Len-Tayon K, Gantzer J, Dariane C
… +9 more, Fogel O, Friedrich V, Rovito D, Lindner V, Gilbart V, Yanushko D, Henri S, Metzger D, Laverny G
EMBO Mol Med
· 2026 May · PMID 41957119
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Prostate cancer (PCa)-related deaths are mainly due to metastasis. The increase in de novo metastatic hormone-naive PCa (mHNPCs) highlights the urgent need for biomarkers and treatment strategies. We report in a cohort o...Prostate cancer (PCa)-related deaths are mainly due to metastasis. The increase in de novo metastatic hormone-naive PCa (mHNPCs) highlights the urgent need for biomarkers and treatment strategies. We report in a cohort of French PCa patients that the levels of vitamin D and of prostate-specific antigen, the progression biomarker used clinically, are negatively associated. However, the impact of vitamin D receptor (VDR) signaling on prostate tumorigenesis remains unclear. Mice with PTEN inactivation in prostatic epithelial cells (PECs) at adulthood (Pten mice) faithfully recapitulate the human disease. We showed that inactivation of PTEN and VDR in PECs promotes tumor aggressiveness. We demonstrate that VDR loss induces oxidative stress, which in turn enhances PECs proliferation. Moreover, CXCL5 overexpression in PTEN- and VDR-deficient PECs promotes neutrophil infiltration. Importantly, our data highlight elevated circulating neutrophil levels as a biomarker of PCa dissemination and show the potency of targeting neutrophil chemotaxis to reduce liver micrometastases. Overall, this work provides major insights into how vitamin D signaling slows down tumorigenesis and opens new avenues for therapeutic and diagnostic strategies for mHNPC.