Jessen M, Kim K, Tollot-Wegner M
… +21 more, Cindric Vranesic A, Dönmez C, Junker C, Lehmann T, Khandelwal A, Kurlishchuk Y, Hünniger T, Ritter C, Di Napoli E, Murali S, Bücking K, Haug V, Muth S, Tang TT, Rosenwald A, Radsak M, Inverso D, Deckert-Gaudig T, Deckert V, Paciello O, von Eyss B
YAP and TAZ, key effectors of the Hippo pathway, are often hyperactivated in cancer, promoting tumor progression and therapy resistance. Their oncogenic role depends on interaction with TEAD transcription factors, making...YAP and TAZ, key effectors of the Hippo pathway, are often hyperactivated in cancer, promoting tumor progression and therapy resistance. Their oncogenic role depends on interaction with TEAD transcription factors, making the TEAD-YAP/TAZ complex a promising therapeutic target. Using translational mouse models, we showed here that sustained systemic YAP/TAZ depletion caused severe side effects. These could be avoided through pulsed inhibition, which effectively suppressed tumor growth, even at advanced stages. We identified Tgfb2 as a critical YAP/TAZ target gene for tumor formation and demonstrated that YAP/TAZ drove T cell exclusion via activation of tissue remodeling genes. Consequently, YAP/TAZ inhibition enhanced immune cell infiltration. However, infiltrating T cells rapidly underwent exhaustion. Combining YAP/TAZ inhibition with immune checkpoint blockade (ICB) reversed this exhaustion and sensitized resistant tumors to immunotherapy. This combination reshaped the tumor microenvironment to support immune cell infiltration and activation, representing a therapeutic strategy that maximizes anti-tumor immunity while minimizing toxicity.
Pancreatic cancer remains a devastating disease with limited therapeutic options. Accumulating evidence has shown that cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs), the predominant cells i...Pancreatic cancer remains a devastating disease with limited therapeutic options. Accumulating evidence has shown that cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs), the predominant cells in the pancreatic cancer (PDAC) tumor microenvironment (TME), hinder anti-tumor immunity. However, the role of extracellular vesicles (EVs) in such process is poorly understood. In this study, using human bone-marrow-derived monocytes and PDAC tumor cells, we show that tumor cell-derived EVs (TC-EVs) induced monocyte differentiation towards M2-like immunosuppressive CD200R+/PD-L1+/HLA-DR- macrophages that express ALOX15b, that we identify as an independent PDAC poor-prognosis biomarker using a human pancreatic cancer metacohort. We also demonstrate that TC-EVs reprogram human primary PDAC CAFs, causing a fibronectin network reorganization associated with changes in extracellular matrix (ECM) composition, including alterations of the Wnt pathway elements such as SFRP1 enrichment. We further reveal that monocytes cultured on rSFRP1-enriched ECM differentiate also into M2-like immunosuppressive macrophages. Lastly, we demonstrate that both directly and indirectly TC-EVs, or rSFRP1-enriched ECM, driven differentiated macrophages hindered T-cell activation and subsequent anti-tumor activity. Our findings highlight novel, dual mechanisms of TC-EVs-mediated crosstalk, involving Alox15b+-Macrophages and SFRP1+-CAFs, that simultaneously contribute to foster the immunosuppressive ecosystem of pancreatic cancer.
Ananthapadmanabhan V, Bruno S, Vonk L
… +18 more, Cheng YC, Teshager A, Eschle BK, Howarth CL, Rodrigues JS, Schnabel J, Kodali A, Gokhale PC, Kshirsagar R, Breitkopf SB, Sharma K, Paulo JA, Li Y, Cherniack AD, Michor F, Chutake Y, Dey J, DeCaprio JA
J Clin Invest
· 2026 Jul · PMID 42383359
·
Full text
MDM2 is transcriptionally activated by the ST-MYCL-Tip60 complex in virus-positive Merkel cell carcinoma (MCC). MDM2 suppresses p53 and is a rational therapeutic target. MDM2 inhibitors face an intrinsic limitation: p53...MDM2 is transcriptionally activated by the ST-MYCL-Tip60 complex in virus-positive Merkel cell carcinoma (MCC). MDM2 suppresses p53 and is a rational therapeutic target. MDM2 inhibitors face an intrinsic limitation: p53 activation induces MDM2 transcription, creating a feedback loop that blunts inhibitor efficacy. We demonstrate that MDM2 degraders KTX-049 and KT-253 overcome this limitation by collapsing the p53/MDM2 negative feedback loop. KTX-049 was >100-fold more potent than the MDM2 inhibitor DS-3032 across WT p53 MCC cell lines, and this superior potency was quantitatively supported by mechanistic mathematical modeling. In vivo, KT-253 produced deep and durable tumor regressions, including complete responses in patient-derived xenograft models. Acquired resistance was strongly associated with acquisition of TP53 mutations, confirming on-target pathway pressure. These findings establish feedback architecture as a critical determinant of therapeutic response and position MDM2 degradation as a qualitatively distinct strategy that produces more durable pathway engagement than MDM2 inhibition, providing a preclinical rationale for prioritizing MDM2 degraders in WT TP53 MCC.
Abdualkader AM, Li X, Yin Y
… +6 more, Bai C, Pourfarziani P, Guan J, Kwon S, Kim KH, Al Batran R
J Clin Invest
· 2026 Jul · PMID 42383358
·
Full text
SGLT2 inhibitors boost ketone production by directly activating a liver enzyme, revealing a new mechanism that may contribute to their heart and kidney benefits.SGLT2 inhibitors boost ketone production by directly activating a liver enzyme, revealing a new mechanism that may contribute to their heart and kidney benefits.
J Clin Invest
· 2026 Jul · PMID 42383356
·
Full text
Metabolic dysfunction-associated steatohepatitis (MASH) is increasingly linked to disruptions of the gut/liver axis, yet the microbial mechanisms driving disease progression remain incompletely defined. Here, Qu et al. h...Metabolic dysfunction-associated steatohepatitis (MASH) is increasingly linked to disruptions of the gut/liver axis, yet the microbial mechanisms driving disease progression remain incompletely defined. Here, Qu et al. have identified ileal microbial ammonia production by Clostridium perfringens as a mechanistic driver of epithelial barrier dysfunction and hepatic CD8+ T cell remodeling in MASH. In nonhuman primate and mouse models of MASH, the authors demonstrated that the glycine-based tripeptide DT-109 restored gut barrier integrity and attenuated FosB-mediated CCL5 expression in CD8+ T cells via inhibition of bacterial nitrite reductase A-mediated microbial ammonia production. These findings position microbial nitrogen metabolism as a tractable therapeutic target and highlight metabolite-focused microbiome interventions as a potential MASH intervention.
J Clin Invest
· 2026 Jul · PMID 42383355
·
Full text
The cGAS/STING pathway enables cells to sense cytosolic DNA and mount rapid innate immune responses to infection, cellular stress, and tissue damage. While essential for host defense and immune surveillance, inappropriat...The cGAS/STING pathway enables cells to sense cytosolic DNA and mount rapid innate immune responses to infection, cellular stress, and tissue damage. While essential for host defense and immune surveillance, inappropriate or sustained activation of this pathway can drive chronic inflammation, autoimmunity, and disease-associated immune dysfunction, which can promote cancer growth. Effective immunity therefore depends on precise regulatory control that restrains cGAS/STING activity under homeostatic conditions while preserving the capacity for swift and robust responses to diverse danger signals. In this Review, we synthesize emerging principles that regulate cGAS/STING signaling across cellular contexts to control signal initiation, amplification, and termination. We discuss how disruption, persistence, or pathological rewiring of these regulatory processes contributes to immune imbalance across health and disease, promoting chronic inflammation, immunosuppression, and tissue pathology, with particular relevance to tumor progression and therapeutic resistance. Finally, we consider how restoring appropriate cGAS/STING regulation, rather than simply enhancing or inhibiting pathway activity, may reestablish immune homeostasis and improve therapeutic outcomes in cancer and other inflammatory diseases, framing the pathway as a dynamic regulatory circuit rather than a simple linear signaling cascade.
J Clin Invest
· 2026 Jul · PMID 42383354
·
Full text
Cells use plasticity programs to change lineages, which aids in tissue regeneration and remodeling but also allows aberrant cells to become cancerous and escape therapy. For example, tumor cells in invasive mucinous aden...Cells use plasticity programs to change lineages, which aids in tissue regeneration and remodeling but also allows aberrant cells to become cancerous and escape therapy. For example, tumor cells in invasive mucinous adenocarcinoma (IMA) emerge from lung epithelial cells by a plasticity program that reprograms them into gastric epithelium-like cells. In this issue of the JCI, Dadzie et al. show that hepatocyte nuclear factor 4 α (HNF4α) promotes gastric identity in lung epithelial cells via a mechanism involving restriction of FOXA1 and FOXA2 transcription factors to gastric gene enhancer loci. HNF4α also promotes resistance to KRAS inhibition by increasing nuclear factor erythroid 2-related factor 2 (NRF2) activity. These findings may advance therapeutic avenues in IMA.
J Clin Invest
· 2026 Jul · PMID 42383353
·
Full text
Advances in antigen discovery and autoantibody profiling have reshaped the classification of autoimmune kidney diseases, moving beyond purely histologic definitions. The identification of podocyte-targeting autoantibodie...Advances in antigen discovery and autoantibody profiling have reshaped the classification of autoimmune kidney diseases, moving beyond purely histologic definitions. The identification of podocyte-targeting autoantibodies has transformed the understanding of nephrotic syndrome, prompting renewed interest in autoimmune mechanisms underlying podocytopathies. Recent reports of nephrin autoantibodies in minimal change disease, the most common cause of nephrotic syndrome in children, suggested a potential antigen-defined subset, but findings have been inconsistent. In this issue of the JCI, Pecoraro and colleagues advance the field by systematically interrogating anti-nephrin antibodies across a diverse nephrotic syndrome cohort using human-based and orthogonal approaches. Their results highlight critical limitations in assay specificity and cohort heterogeneity while raising the question of the clinical utility of anti-nephrin antibodies in the care of patients with minimal change disease. More broadly, this study underscores the need for collaboration to establish standardized assays and rigorously phenotyped cohorts.
Mahajan AS, Forsyth CM, Phung CD
… +3 more, Shen X, Jarvis R, Stegh AH
J Clin Invest
· 2026 Jul · PMID 42383352
·
Full text
The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a central regulator of innate immunity that links cytosolic DNA sensing to type I IFN and inflammatory responses. While initially viewed...The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a central regulator of innate immunity that links cytosolic DNA sensing to type I IFN and inflammatory responses. While initially viewed as a uniformly beneficial antiviral and antitumor signaling axis, emerging evidence reveals that cGAS-STING functions as a context-dependent immune rheostat whose impact is dictated by signal magnitude, timing, cellular origin, subcellular localization of signaling components, and tissue context. These parameters explain why pathway activation can promote tumor rejection, vaccine efficacy, and host defense in some settings yet drive immune suppression, metastasis, neuroinflammation, or autoinflammatory disease in others. In this Review, we synthesize mechanistic and clinical insights across agonist and antagonist strategies targeting the cGAS-STING pathway in cancer, infectious disease, neurodegeneration, and interferonopathies. We highlight why first-generation STING agonists have underperformed clinically and how next-generation delivery systems and cGAS-directed approaches may overcome these limitations. We propose a disease-centric framework that integrates spatial delivery, dosing architecture, and pharmacodynamic biomarker discovery to enable rational modulation of cGAS-STING, repositioning the pathway as a tunable immunologic control node for precision therapy rather than a binary on/off switch.
Saitoh W, Higashikuni Y, Bavuu O
… +2 more, Sata M, Fukuda D
J Clin Invest
· 2026 Jul · PMID 42383351
·
Full text
Cardiovascular diseases (CVDs) remain the leading cause of mortality and morbidity worldwide, highlighting the need for novel therapeutic approaches. Inflammation plays a key role in CVD pathogenesis, and accumulating ev...Cardiovascular diseases (CVDs) remain the leading cause of mortality and morbidity worldwide, highlighting the need for novel therapeutic approaches. Inflammation plays a key role in CVD pathogenesis, and accumulating evidence has implicated the cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway in this process. The cGAS/STING pathway recognizes both non-self- and self-DNA, including mitochondrial and nuclear DNA, to activate its downstream proinflammatory signaling molecules, including TANK-binding kinase 1, IFN regulatory factor 3, and NF-κB. Various pathological stressors have been shown to induce self-DNA release into the cytosol and bloodstream from damaged cells in the cardiovascular system, indicating that circulating cell-free DNA is a useful biomarker of CVDs; however, how this contributes to the inflammatory signaling, cell death, and fibrosis that characterize CVDs remains unclear. Here, we discuss the current understanding on the roles of self-DNA and the cGAS/STING pathway in the pathophysiology of CVDs and the therapeutic potential of targeting this pathway.
Pang KL, Mehta V, Aitken C
… +14 more, Dobbins SE, Yu J, Bonetti G, Keen AN, Zhang F, Sabine A, Petrova TV, Riley PR, Jones EY, Michelini S, Bertelli M, Reader JS, Ostergaard P, Tzima E
J Clin Invest
· 2026 Jul · PMID 42383350
·
Full text
Lymphatic valves are essential for maintaining tissue fluid homeostasis, and their dysfunction leads to lymphedema, a morbid and disfiguring disease without a cure. Mechanical forces due to lymph flow are required for pr...Lymphatic valves are essential for maintaining tissue fluid homeostasis, and their dysfunction leads to lymphedema, a morbid and disfiguring disease without a cure. Mechanical forces due to lymph flow are required for proper lymphatic valve development, yet it remains unclear how lymphatic endothelial cells (LECs) sense and decode mechanical signals. In this study, we identify the cell guidance semaphorin receptor plexin D1 (PLXND1) as a lymphatic mechanosensor required for lymphatic valve morphogenesis. Conditional genetic ablation of Plxnd1 in LECs caused major defects in lymphatic valve development in 2 different lymphatic vascular beds. Mechanistically, PLXND1 acted as a mechanosensor within a lymphatic mechanocomplex, initiating distinct mechanical signals and activating the lymphatic valve transcriptional program through an unconventional pathway. Screening of patients with primary lymphedema identified PLXND1 missense variants, and functional analysis established 2 pathogenic variants that selectively disrupt the ligand versus mechanosensing functions of this receptor. Variants associated with lymphedema in members of the mechanocomplex disrupted its formation, underscoring the central role of this complex in lymphatic valve biology. Our work uncovers a mechanosensing mechanism guiding lymphatic valve development, and has profound implications for the understanding and treatment of primary lymphedema in humans.
J Clin Invest
· 2026 Jul · PMID 42383349
·
Full text
Immune checkpoint inhibitor-induced inflammatory arthritis (ICI-IA) is an immune-related adverse event (irAE) following treatment with PD-1, PD-L1, or CTLA-4 inhibitors in patients with cancer. In this issue of the JCI,...Immune checkpoint inhibitor-induced inflammatory arthritis (ICI-IA) is an immune-related adverse event (irAE) following treatment with PD-1, PD-L1, or CTLA-4 inhibitors in patients with cancer. In this issue of the JCI, Ma and colleagues identified a subset of regulatory T cells (Tregs) that coexpress CD137 and IL-6 receptor (IL6R), termed atypical Tregs (AtpTregs), which are selectively enriched in patients with ICI-IA. Functionally, AtpTregs exhibited reduced suppressive capacity and a Th17-like proinflammatory phenotype. Notably, these cells were associated with more severe arthritis, yet improved cancer outcomes, suggesting a potential role in tumor control. The anti-IL6R therapy tocilizumab, administered as an off-label intervention for ICI-IA, reduced AtpTreg abundance and alleviated arthritis while maintaining antitumor immunity in a small cohort of patients with new-onset ICI-IA. Thus, anti-IL6R could be a targeted approach to manage ICI-IA and potentially other irAEs involving AtpTregs.
BACKGROUND: Rheumatoid factor (RF) autoantibodies are highly prevalent, yet the molecular determinants of RF development and its progression to rheumatoid arthritis (RA) remain poorly understood. Here, we define the gene...BACKGROUND: Rheumatoid factor (RF) autoantibodies are highly prevalent, yet the molecular determinants of RF development and its progression to rheumatoid arthritis (RA) remain poorly understood. Here, we define the genetic, phenotypic, and molecular architecture of RF and its progression to RA. METHODS: 469,036 UK Biobank participants with RF testing and 76 ALTRA cohort individuals were studied. Phenome-wide (PheWAS), genome-wide (GWAS), and proteome-wide association studies compared RF-positive individuals without autoimmune disease to RF-negative controls. Single-cell RNA sequencing enabled pseudobulk differential expression and cytokine signature enrichment analyses. RESULTS: RF seroprevalence was 9.3% and longitudinally stable in 94.5% of individuals. PheWAS identified 48 significant associations, led by chronic viral hepatitis (OR 4.8), hypersensitivity pneumonitis (OR 3.6), bronchiectasis (OR 1.9), and COPD (OR 1.4). GWAS of 24,216 RF-positive individuals revealed 29 independent loci; the strongest signal was in the extended HLA region (OR 1.45, P-value=5.4×10-221). Non-HLA loci converged on B cell homeostasis genes (ETS1, BACH2, PAX5, TNFRSF13B, FCGR2A). RF-positive individuals did not carry elevated RA polygenic risk. Proteomic profiling identified 153 differentially abundant proteins enriched for humoral immunity and interferon-induced chemokines, with 79% showing dose-response relationships across titers. Progression to RA involved a shift toward activating tissue-damaging inflammatory pathways rather than amplification of the RF signature. Single-cell transcriptomics of RF-positive individuals without RA localized dysregulation to memory B cells, with downregulation of inhibitory genes (FCGR2B, BACH2, FOXP1) and upregulation of activation markers. CONCLUSION: RF production is governed by HLA class II and B cell regulatory loci, associated with mucosal inflammation, and is genetically and molecularly distinct from RA.
Saha S, Zhang Y, Gibert MK
… +30 more, Dube C, Hanif F, Mulcahy EQX, Bednarek S, Sun Y, Marcinkiewicz P, Wang X, Kwak G, Polash AH, Li H, Hudson K, Dinda M, Saha T, McCord M, Guessous F, Cruickshanks N, Rivera Colon R, Dell'Olio L, Anbu R, Liu W, Choi S, Kefas B, Kumar P, Klibanov AL, Schiff D, Suk JS, Hanes J, Mata J, Hafner M, Abounader R
Glioblastoma is a fatal primary malignant brain tumor, with an average survival of 15 months despite surgical resection, chemotherapy, and radiation therapy. Due to the concurrent deregulation of numerous genes in gliobl...Glioblastoma is a fatal primary malignant brain tumor, with an average survival of 15 months despite surgical resection, chemotherapy, and radiation therapy. Due to the concurrent deregulation of numerous genes in glioblastoma, molecular monotherapies have not improved clinical outcomes. Evidence suggests that targeting multiple deregulated molecules is essential for better therapies; however, this is limited by the lack of suitable drugs and increased toxicity of combination therapies. To address this, we hypothesized that miRNAs, small gene-regulatory RNAs that suppress mRNA, could simultaneously inhibit multiple deregulated genes in glioblastoma, and be used for more effective therapies. We identified regulatory miRNAs - those that target several deregulated genes in glioblastoma - using a combination of PAR-CLIP screening, TCGA data analyses and an algorithm to rank target importance and miRNA therapeutic potential. We selected two tumor suppressor miRNAs, miR-340 and miR-382, and one oncogenic miRNA, miR-17 and showed that they target critical glioblastoma pathways and alter cell growth, survival, invasion, and in vivo tumor growth. We developed and successfully applied a miRNA therapeutic delivery approach using Brain Penetrating Nanoparticles combined with MRI-guided focused ultrasound and microbubbles, to inhibit established tumor growth and to extend animal survival. This strategy offers a promising approach for translating miRNA-based therapies into clinical trials for glioblastoma and other cancers.
Reproductive aging is characterized by a progressive decline of reproductive function, with broad implications for overall health and longevity. Environmental factors, including assisted reproductive technologies (ART),...Reproductive aging is characterized by a progressive decline of reproductive function, with broad implications for overall health and longevity. Environmental factors, including assisted reproductive technologies (ART), can accelerate reproductive aging by promoting premature ovarian failure in females. In vitro fertilization (IVF) though widely used and generally considered safe, has been associated with lasting effects on offspring health. Using a mouse model that closely approximates human IVF, we demonstrated that IVF accelerates reproductive aging in female offspring by inducing premature ovarian failure. IVF-conceived females exhibited altered ovarian function, reduced follicle reserve, disrupted endocrine profiles, and transcriptomic and epigenetic changes consistent with premature reproductive decline. These findings reveal long-term consequences of IVF on female reproductive health and highlight the need to understand how early-life interventions influence reproductive longevity.
Gu T, Chen Z, Tang B
… +17 more, Wang T, Yang Q, Liu H, Liang Z, Wang Q, Zhang Y, Sun Y, Di M, Yuan T, Qiu Y, Du Y, Song L, Wu S, Wang W, Xu X, Dong Y, Kang L
BACKGROUND: B cell maturation antigen (BCMA) is a key therapeutic target in multiple myeloma (MM), yet its whole-body in vivo distribution and role in disease assessment remain incompletely defined. We aimed to evaluate...BACKGROUND: B cell maturation antigen (BCMA) is a key therapeutic target in multiple myeloma (MM), yet its whole-body in vivo distribution and role in disease assessment remain incompletely defined. We aimed to evaluate the safety, diagnostic performance, and clinical utility of a novel BCMA-targeted PET tracer, 68Ga-PFBC01, in patients with plasma cell disorders. METHODS: We conducted a single-center, prospective, single-arm phase I trial (ClinicalTrials.gov NCT06717113). Fifty patients underwent 68Ga-PFBC01 PET/CT, including 40 with paired 18F-FDG PET/CT for head-to-head comparison. Primary outcomes included diagnostic performance (sensitivity, specificity, PPV, NPV, and inter-reader agreement). Secondary outcomes included correlations with clinical biomarkers, treatment response assessment, impact on clinical decision-making, and safety. RESULTS: 68Ga-PFBC01 PET/CT demonstrated superior diagnostic performance compared with 18F-FDG PET/CT (sensitivity 96.9% vs 84.6%; specificity 71.4% vs 60.0%). Quantitative PET-derived tumor burden correlated with M protein (R = 0.325, P = 0.026), free light chains (R = 0.340-0.437, P ≤ 0.015), soluble BCMA (R = 0.433, P = 0.050), and bone marrow plasma cells (R = 0.682, P < 0.001). Imaging findings altered clinical management in multiple cases, enabling both therapy escalation and de-escalation. Blood-pool uptake strongly correlated with soluble BCMA (R = 0.899, P < 0.001) and overall disease burden (R = 0.736, P < 0.001). No serious tracer-related adverse events were observed; two patients (4%) experienced mild events. CONCLUSION: 68Ga-PFBC01 PET/CT provides biologically specific, whole-body assessment of MM, outperforming 18F-FDG and enabling integrated evaluation of tumor burden and systemic disease activity, with direct implications for clinical decision-making. CLINICALTRIALS: gov NCT06717113. FUNDING: National Natural Science Foundation of China (82472018, 82402320) to Prof. Lei Kang, 82402320 to Dr. Tianyao Wang); Beijing Nova Program (20240484725) to Prof. Lei Kang; National High Level Hospital Clinical Research Funding (Interdisciplinary Research Project of Peking University First Hospital, 2024IR07, Scientific and Technological Achievements Transformation Incubation Guidance Fund Project of Peking University First Hospital, 2025CX38, 2024CX18) to Prof. Lei Kang.
Sun S, Yan XY, Dong YH
… +18 more, You JM, Guo ZY, Lv DX, Xie SS, Hou R, Li XY, Yu JT, Shen XY, Wei J, Song ZY, Chen ZQ, Zhu YL, Xu XX, Jin J, Wen JG, Wang H, Meng XM, Wang W
The inflammatory response resulting from the abnormal accumulation of metabolites has been implicated in the pathogenesis of organ fibrosis; however, its role and underlying mechanisms in renal fibrosis remain unclear. I...The inflammatory response resulting from the abnormal accumulation of metabolites has been implicated in the pathogenesis of organ fibrosis; however, its role and underlying mechanisms in renal fibrosis remain unclear. In this study, we observed a negative correlation between fumarate hydratase (FH) expression and the degree of renal fibrosis. Loss of FH function was associated with heightened inflammation and exacerbated tubulointerstitial damage in the kidney. Moreover, FH deficiency aggravated fibrosis in both the liver and lungs. Mechanistically, the depletion of FH in renal tubular cells led to fumarate accumulation. Fumarate directly succinated A-kinase anchoring protein 12 at cysteine 670, thereby diminishing its capacity to inhibit the activity of protein kinase Cζ (PKCζ). This process exacerbated renal inflammation and fibrosis by activating the downstream PKCζ/NF-κB and PKCζ/β-catenin pathways. Additionally, the upregulation of FH through adeno-associated virus 2/9-mediated FH overexpression markedly mitigated renal inflammation and fibrosis. These findings highlighted the important role of fumarate accumulation in the advancement of renal fibrosis, supporting FH as a potential therapeutic target in renal fibrosis.
Liang H, Zhu D, Du Z
… +18 more, Li X, Shi R, Lei J, Tong B, Xu H, Wu D, Zhou X, Du Y, Ou Z, Wei J, Peng S, Ke W, Liao Z, Wang B, Wang K, Feng X, Song Y, Yang C
Intervertebral disc degeneration (IVDD) is a leading cause of low back pain, yet clinically, there remains no effective therapeutic approach to reverse its progression, imposing a substantial socioeconomic burden. While...Intervertebral disc degeneration (IVDD) is a leading cause of low back pain, yet clinically, there remains no effective therapeutic approach to reverse its progression, imposing a substantial socioeconomic burden. While multiple factors contribute to IVDD pathogenesis, cellular senescence has emerged as a critical risk factor associated with both the incidence and progression of IVDD. Ageing and other damage factors drive nucleus pulposus cells (NPCs) towards a senescent phenotype characterized by increased secretion of proinflammatory factors, resulting in NPC dysfunction and tissue degeneration, which are hallmarks of IVDD. In this study, we demonstrated that PRMT2 deficiency disrupted arginine methylation‒ubiquitination crosstalk, driving NPC inflammatory senescence and accelerating IVDD progression. Mechanistically, PRMT2 loss reduced FBXO7 methylation at Arg 504, promoting the FBXO7-MED12 interaction to facilitate MED12 ubiquitination and subsequent proteasomal degradation. MED12 deficiency induced pathological R-loop accumulation, which activated the cytosolic DNA-sensing cGAS-STING axis, triggering inflammatory response cascades. Notably, engineered extracellular vesicles (EVs) delivering MED12-overexpressing plasmids effectively inhibited NP cell senescence and attenuated IVDD progression. Together, our findings establish that dysregulated methylation‒ubiquitination crosstalk critically drives IVDD progression and reveal MED12 as a promising therapeutic target for ameliorating the impact of IVDD.