Journal of molecular medicine (Berlin, Germany)最新文献

{"title":"High mobility group motif proteins' role in fibrosis, inflammation, and vascular injury in systemic sclerosis.","authors":"Fabian A Mendoza, Sonsoles Piera-Velazquez, Sergio A Jimenez","doi":"10.1007/s00109-026-02679-5","DOIUrl":"10.1007/s00109-026-02679-5","url":null,"abstract":"<p><p>Systemic Sclerosis (SSc) is an idiopathic systemic autoimmune disease characterized by progressive cutaneous and systemic fibrosis, severe vasculopathy, and multiple humoral and cellular immunological alterations. The pathogenesis of SSc is highly complex and remains incompletely elucidated. The fibrotic process is a crucial component of SSc and is responsible for organ failure and high mortality. Although an increasing understanding of the fibrotic process has enabled the clinical development of antifibrotic therapeutic agents, these agents have limited clinical efficacy. Recently, the potential role of a group of transcription factors containing a High Mobility Group (HMG) motif, in the development and pathological manifestations of SSc has been postulated. HMG proteins (notably HMGB1 and SOX9) act as profibrotic and proinflammatory transcription factors; however, HMG proteins can also function as damage-associated molecular patterns, amplifying Toll-like receptors and RAGE signaling, promoting endothelial activation, leukocyte recruitment, and stimulating the production of profibrotic cytokines. This convergent role of HMG proteins across various aspects of SSc pathogenesis, including immune dysregulation, vasculopathy, and fibrosis, makes them among the most attractive novel regulators and a desirable therapeutic target for SSc. Here, we review the recent evidence on the role of HMG proteins in SSc pathogenesis and explore the potential role of inhibiting their function.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13249760/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148213954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: a novel tsRNA, tRF-33-6978WPRLXN4V0O inhibits breast cancer development via regulating PTEN/AKT pathway in BHLHA15 mediated manner.","authors":"Ji Dai, Haoqiang Ji, Huihui Bai, Qilong Zhong, Haohang Sun, Mengze Chen, Qi Chen, Meidi Yan, Dandan Zhang, Shuangshuang Zhang","doi":"10.1007/s00109-026-02689-3","DOIUrl":"https://doi.org/10.1007/s00109-026-02689-3","url":null,"abstract":"","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148166637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SIRT1 regulates CaOx crystal-induced exacerbation of renal mitochondrial dysfunction and fibrosis through PPAR-α in aged mice.","authors":"Yuexian Xu, Kaiguo Xia, Xike Mao, Junfeng Yao, Bingbing Hou, Wei Wang, Zongyao Hao","doi":"10.1007/s00109-026-02687-5","DOIUrl":"10.1007/s00109-026-02687-5","url":null,"abstract":"<p><p>The present study investigates how Sirtuin 1 (SIRT1) regulates the worsening of calcium oxalate (CaOx) crystal-induced mitochondrial dysfunction and fibrosis in the kidneys with age. To establish a CaOx crystal deposition model, glyoxylic acid (Gly) was injected intraperitoneally into both young and aged mice. Additionally, an in vitro model was created by stimulating human renal tubular epithelial (HK2) cells with D-galactose (D-gal) and calcium oxalate monohydrate (COM). Lipid deposition, mitochondrial function, and fibrosis levels were assessed using various techniques, including western blotting (WB), polymerase chain reaction (PCR), immunohistochemistry, immunofluorescence, and specific staining methods. The effects on lipid deposition, mitochondrial function, and fibrosis were further analyzed by manipulating the expression of SIRT1 and peroxisome proliferator-activated receptor (PPAR-α), both in vitro and in vivo. Aging exacerbates the kidney mitochondrial dysfunction and fibrosis induced by CaOx crystals, with SIRT1 playing a crucial regulatory role in this process. SIRT1 regulates lipid metabolism via PPARα, intensifying the aging-related kidney mitochondrial damage and fibrosis induced by CaOx crystals.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148059344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MEK inhibitor cobimetinib increases calreticulin and induces immune modulation in TNBC.","authors":"Ling-Ming Tseng, Ka-Yi Lau, Ji-Lin Chen, Pei-Yi Chu, Chun-Teng Huang, Wan-Lun Wang, Yuan-Ya Chang, Jiun-I Lai, Chi-Cheng Huang, Ming-Shen Dai, Chun-Yu Liu","doi":"10.1007/s00109-026-02684-8","DOIUrl":"10.1007/s00109-026-02684-8","url":null,"abstract":"<p><p>Immunogenic cell death (ICD) can activate immune cells and potentiate the response to immunotherapy. The mitogen-activated protein kinase (MAPK) signaling pathway regulates the immune response and mediates T-cell receptor signaling. Activation of the MAPK signaling pathway decreases the levels of tumor-infiltrating lymphocytes in triple-negative breast cancer (TNBC) and is associated with worse survival. Here, we investigated the potential of the MEK inhibitor cobimetinib as an ICD inducer in TNBC. We demonstrated that cobimetinib elicited hallmarks of ICD, including elevated levels of damage-associated molecular patterns. Ectopic ERK expression attenuated cobimetinib-induced CRT. Cobimetinib also evoked caspase-8 activation with increased Bax and Bak expression, while caspase inhibitor suppressed cobimetinib-induced CRT expression and apoptosis. In immunocompetent (BALB/c) mice bearing 4T1 tumors, cobimetinib exhibited stronger tumor growth inhibition than in immunodeficient (nude) mice, suggesting an immune-dependent antitumor effect. Furthermore, cobimetinib treatment increased the proportions of naïve CD8⁺ T cells and effector CD4⁺ T cells and decreases the proportion of myeloid-derived suppressor cells in immunocompetent mice bearing 4T1 tumors. Notably, we observed differential immunomodulatory effects of cobimetinib in tumor-bearing mice compared to non-tumor-bearing immunocompetent mice. Our findings indicate that MEK inhibition is associated with ICD-related molecular alterations, and that cobimetinib may contribute to immune modulation in TNBC.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13201367/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148020507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vasoactive intestinal peptide advances chondrogenesis and modulates pathogenic mediators in human osteoarthritis.","authors":"Karolina Tecza, Cristina Rodríguez-Hernández, Raúl Villanueva-Romero, David Castro-Vázquez, Alicia Cabrera-Martín, Paula Arribas-Castaño, Mar Carrión, Irene Gutiérrez-Cañas, Raquel Largo, Valentina Calamia, Francisco J Blanco, Rosa P Gomariz, Yasmina Juarranz, Carmen Martínez, Selene Pérez-García","doi":"10.1007/s00109-026-02683-9","DOIUrl":"10.1007/s00109-026-02683-9","url":null,"abstract":"<p><p>Current therapies for osteoarthritis (OA) focus on symptom management, rather than halting disease progression. Vasoactive intestinal peptide (VIP) has shown promising effects in musculoskeletal diseases, preserving joint integrity and modulating inflammation. This study investigates the potential of VIP to promote chondrogenic differentiation of human bone marrow mesenchymal stem cells (BM-hMSC) and to modulate inflammatory and cartilage extracellular matrix (ECM)-degrading mediators in human osteoarthritis articular chondrocytes (OA-hAC). BM-hMSC from healthy donors were cultured in 3D pellet sytems under chondrogenic conditions, with or without VIP, for up to 21 days. Chondrogenesis was evaluated through the expression of key markers (SOX9, COL2A1, and ACAN), hypertrophic markers (RUNX2, COL10A1, and MMP13), and glycosaminoglycans (GAG). VIP accelerated chondrogenic differentiation by inducing earlier mRNA and protein expression of chondrogenic markers and enhancing GAG production. In parallel, OA-hAC were cultured in 3D alginate microbeads and stimulated with fibronectin fragments (Fn-fs) in the presence and absence of VIP. We analysed the effects of VIP on cell proliferation, GAG production, and the modulation of complement components (C1R and C3) and matrix metalloproteinases (MMP1, MMP3, MMP9, and MMP13). VIP increased cell proliferation and GAG deposition while significantly reducing the production of complement component C1R and matrix metalloproteinases MMP1 and MMP13. Overall, these findings demonstrate that VIP advances chondrogenesis and exerts anti-inflammatory and anti-catabolic effects in 3D culture models. This study highlights the potential of VIP as a therapeutic agent and supports the combination of MSC-based approaches with VIP as a promising strategy to enhance cartilage regeneration and slow OA progression.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148020497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of PANoptosis in intestinal diseases and its therapeutic implications.","authors":"Can Yu, Yihang Huang, Bohao Han, Fengqi Duan, Bing Liu, Cheng Zeng","doi":"10.1007/s00109-026-02685-7","DOIUrl":"10.1007/s00109-026-02685-7","url":null,"abstract":"<p><p>PANoptosis is a novel programmed inflammatory cell death pathway. It integrates pyroptosis, apoptosis, and necroptosis components via a unified molecular platform termed PANoptosome. Unlike single classical cell death pathway, PANoptosis is tightly regulated by key regulators such as ZBP1, RIPK3, caspase-8, and ASC, resulting in a highly inflammatory and immunogenic form of cell death. While its pathological relevance has been widely investigated in cancer, microbial infections, and systemic inflammatory syndromes, its role in intestinal diseases has not been comprehensively explored. In this review, we summarize emerging evidence highlighting its key role in intestinal diseases, including Crohn's disease, ulcerative colitis, colorectal cancer, intestinal ischemia/reperfusion injury, necrotizing enterocolitis, celiac disease, and immune checkpoint inhibitors-induced colitis. We further summarize recent advances in PANoptosis mechanisms and immunological regulation in intestinal diseases, highlight its intricate interplay with gut microbiota, and discuss the therapeutic potential of targeting PANoptosis to restore intestinal homeostasis and mitigate disease progression.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148008547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A proteomic atlas phenotyping Fabry disease identifies a precise cardiovascular risk signature that integrates mitochondrial and lysosomal pathways.","authors":"Gaetano Santulli, Shivangi Pande, Fahimeh Varzideh","doi":"10.1007/s00109-026-02682-w","DOIUrl":"10.1007/s00109-026-02682-w","url":null,"abstract":"<p><p>Fabry disease is an X-linked lysosomal storage disorder caused by α-galactosidase A deficiency, leading to progressive accumulation of Gb3 and lyso-Gb3 and a complex multisystem phenotype extending beyond substrate storage. Cardiovascular involvement remains the leading cause of morbidity and mortality, yet early detection and risk stratification remain challenging. In this context, a new proteomic study leveraging high-throughput proximity extension assays and machine learning has defined a cardiovascular risk signature in Fabry disease. Differential expression analysis identified widespread proteomic remodeling involving inflammatory signaling, extracellular matrix organization, angiogenesis, and metabolic pathways, supporting a systems-level view of disease pathogenesis. A 10-protein biosignature integrating markers of mitochondrial stress, lysosomal function, vascular remodeling, and immune activation demonstrated the ability to discriminate patients with cardiovascular involvement. Notably, proteins such as GDF15, NT-proBNP, NOS1, CTSF, and TNFRSF11B highlight the interplay between mitochondrial dysfunction, lysosomal impairment, and vascular inflammation. These findings suggest that Fabry cardiomyopathy reflects coordinated dysregulation across metabolic and inflammatory networks and that multi-protein signatures may improve precision phenotyping and cardiovascular risk prediction beyond conventional biomarkers.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147990735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The mechanism of the JNK signaling pathway in drug addiction : Author list.","authors":"Shuang Han, Hongming Ye, Min Li, Yuzhu Wang, Yue Chen, Xiaohong Zhou, Zicheng Li","doi":"10.1007/s00109-026-02686-6","DOIUrl":"10.1007/s00109-026-02686-6","url":null,"abstract":"<p><p>Drug addiction is a multifactorial neurofunctional disorder influenced by a complex interplay of environmental, biological, and genetic factors. Recent studies have demonstrated that aberrant activation of the c-Jun N-terminal kinase (JNK) signaling pathway plays a critical role in the development of drug addiction. JNK, a member of the mitogen-activated protein kinase (MAPK) family, participates in neural development during embryogenesis and regulates neuronal proliferation and differentiation in adulthood, thereby maintaining the functional integrity of neural stem and progenitor cells and preserving appropriate brain plasticity and homeostasis. By modulating key biological processes such as inflammation, oxidative stress, autophagy, and apoptosis, the JNK signaling pathway regulates neuronal homeostasis and synaptic plasticity and contributes to the molecular mechanisms underlying drug addiction. In addition, JNK signaling influences addiction-related epigenetic regulation by modulating DNA methylation. This review comprehensively analyzes the involvement of the JNK signaling pathway in drug addiction, to broaden current perspectives on addiction research and inform the development of novel therapeutic strategies.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147990754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Melatonin protects liver and periodontal tissues from inflammation exacerbated by metabolic syndrome-periodontitis association.","authors":"Ana Paula Vázquez Mosquera, Facundo Mateo Martín, Graciela Del Valle Castillo, Estela Maris Muñoz, María Elena Peralta López, Agata Rita Carpentieri","doi":"10.1007/s00109-026-02681-x","DOIUrl":"10.1007/s00109-026-02681-x","url":null,"abstract":"<p><p>Metabolic syndrome (MetS) and periodontal disease (PD) are prevalent inflammatory conditions with global health implications. Their bidirectional interaction amplifies systemic and metabolic inflammation, worsening periodontal destruction while PD exacerbates metabolic disturbances. This study evaluates the combined impact of MetS and PD on periodontal and hepatic health and examines melatonin (MEL) as a therapeutic agent. Male Wistar rats were assigned to Control, MetS, PD, MetS + PD, and MetS + PD + MEL groups. MetS was induced with 10% fructose intake for 35 days and PD by ligature placement for 4 days. MEL (10 mg/kg) was administered to assess its anti-inflammatory effects. Body weight, glycemia, lipid profile, and liver enzymes were measured. Radiographic and histomorphometric analyses were performed on the jaw, and NLRP3 and IL-10 expression assessed by immunohistochemistry in jaw and liver. MetS + PD animals showed aggravated hyperglycemia, dyslipidemia, hepatic injury, and severe periodontal destruction, with increased NLRP3 and reduced IL-10 levels. MEL attenuated these alterations, improving metabolic outcomes, preserving periodontal bone, restoring hepatic histology and enzyme levels, and modulating inflammation by decreasing NLRP3 and increasing IL-10. These findings indicate that MetS and PD synergistically intensify inflammatory and metabolic disturbances, and that MEL counteracts this exacerbated inflammatory burden, emerging as a promising adjunct therapeutic candidate for systemic-oral inflammatory conditions. KEY MESSAGES: Metabolic syndrome and periodontitis synergistically exacerbate liver and periodontal damage. Melatonin mitigates these combined metabolic and inflammatory alterations. Melatonin protective effect is associated with reduced NLRP3 activation and restored IL-10 expression.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147978216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Platelet-neutrophil niches associate with epidermal immune activation and systemic inflammation in psoriatic disease.","authors":"Caio Santos Bonilha","doi":"10.1007/s00109-026-02680-y","DOIUrl":"10.1007/s00109-026-02680-y","url":null,"abstract":"<p><p>Platelets are increasingly recognised as inflammatory mediators that influence leukocyte behaviour, yet their spatial organisation and contribution to psoriatic skin inflammation remain incompletely understood. Here, spatial transcriptomics was used to map platelet-leukocyte niches (PLNi) across inflammatory skin diseases, contrasting psoriasis (PsO) with atopic dermatitis (AD). PLNi were selectively expanded in PsO lesions, where platelet-neutrophil co-localisation defined transcriptionally active regions enriched for stress and inflammatory mediators. PsO and psoriatic arthritis (PsA) shared a convergent cellular profile in which platelet association occurred across immune lineages but was markedly increased in neutrophils, particularly within the epidermis. Epidermal PLNi showed coordinated spatial patterns of dendritic and T cell enrichment, with neutrophil-platelet niches correlating with both. Neutrophil-platelet regions displayed enhanced inflammatory activity and stronger dendritic- and T-cell activation signatures, becoming more frequent with disease severity and pointing to a role for epidermal platelet-neutrophil associations in amplifying psoriatic immune responses. Peripheral multiomic analysis revealed enhanced platelet-neutrophil coupling and increased neutrophil activation in PsA, consistent with the higher systemic inflammatory burden of the arthritic form of the disease. Altogether, these results establish platelet-neutrophil niches as spatial features linked to immune activation in psoriatic disease, with consistent platelet-neutrophil aggregation patterns in circulation. KEY MESSAGES: Platelet-neutrophil niches expand selectively in psoriatic lesions Epidermal niches align with dendritic and T-cell activation programs syndrome Niche prevalence correlates with psoriasis clinical severity Psoriatic arthritis shows systemic platelet-neutrophil coupling Findings outline a platelet-associated inflammatory axis in autoimmunity.</p>","PeriodicalId":520678,"journal":{"name":"Journal of molecular medicine (Berlin, Germany)","volume":"104 1","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147966909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}