Pathophysiology : the official journal of the International Society for Pathophysiology最新文献

{"title":"Hyperbaric Oxygen Therapy in Experimental Autoimmune Myocarditis: Insights from Preclinical Models to Translational Perspectives.","authors":"Bozidar Pindovic, Vladimir Zivkovic, Radisa Pavlovic, Djurdjina Petrovic, Maja Muric, Ivan Srejovic, Dmitry Kolesov, Marina Kolotilova, Sergey Bolevich, Zarko Finderle, Vladimir Jakovljevic, Aleksandra Stojanovic","doi":"10.3390/pathophysiology33010018","DOIUrl":"10.3390/pathophysiology33010018","url":null,"abstract":"<p><p>Myocarditis is still a major global health issue that frequently manifests due to oxidative stress, immune-mediated myocardial damage, and unpredictable clinical progression. Experiments with autoimmune myocarditis (EAM) models have shown different ways that T-cell subsets, proinflammatory cytokines, macrophage polarization, and mitochondrial dysfunction are all connected and play a part in both acute inflammation and chronic remodeling of the heart. As a possible multimodal intervention that could affect several of these disease-causing pathways, hyperbaric oxygen therapy (HBOT) has become popular. This therapy delivers 100% oxygen to different tissues at higher atmospheric pressures. Early research shows that HBOT improves the delivery of oxygen to the inflamed myocardium, suppress the activation of NF-κB and NLRP3 inflammasomes, lowers oxidative stress, protects mitochondrial function, and boosts immune-regulatory T-cell responses. Despite these potentially promising findings, there are still a number of important translational obstacles to overcome, such as inconsistent protocols, a lack of long-term outcome data, insufficient mechanistic profiling, and doubts about the best protocol length and patient selection. To assess safety and effectiveness in human myocarditis, future studies should aim to integrate multi-omics analyses, HBOT regimens that are already standardized, sophisticated imaging, and carefully planned early-phase clinical trials. Overall, the currently available evidence supports HBOT as a biologically plausible and potentially valuable adjunct therapy for autoimmune myocarditis, expressing the need for further mechanistic and clinical investigation.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12921730/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146260690","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":"Pathophysiology Annual Report Card 2025.","authors":"Jonathan Steven Alexander","doi":"10.3390/pathophysiology33010017","DOIUrl":"10.3390/pathophysiology33010017","url":null,"abstract":"<p><p>As the Year of the Snake draws to a close and we 'gallop' into the Year of the Horse, we find a fitting metaphor for the work of science: continued effort, coordination, and progress that depends as much on balance in the saddle as on speed [...].</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12921829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146260692","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":"Do LRG1-SERPINA1 Interactions Modulate Fibrotic and Inflammatory Signatures in Rheumatoid Arthritis? A Proteomic and In Silico Investigation.","authors":"Talib Hussain, Monika Verma, Sagarika Biswas","doi":"10.3390/pathophysiology33010016","DOIUrl":"10.3390/pathophysiology33010016","url":null,"abstract":"<p><p><b>Background:</b> Rheumatoid arthritis (RA) is a systemic, pro-inflammatory, autoimmune disease that mainly affects the joints in a symmetrical manner. Differential proteomic profiling through Sequential Window Acquisition of all Theoretical Fragment Ion Mass Spectra (SWATH-MS/MS) helps in a better understanding of the RA pathogenesis. In this study, we compared the differentially upregulated proteins with those associated with fibrosis to gain a deeper understanding of the fibrotic aspect of RA. <b>Methods:</b> We analyzed plasma proteomics data, previously obtained by SWATH-MS/MS. Our focus was on proteins associated with Leucine Rich Alpha2glycoprotein1 (LRG1) and we employed an in silico method. <b>Results:</b> We identified common proteins between RA and fibrosis. Among them, LRG1 and Serine Protease Inhibitor Clade A, Member 1 (SERPINA1) showed a high co-expression score in the gene clusters. LRG1 is both pro-inflammatory and pro-fibrotic, while SERPINA1 is an anti-inflammatory protein that inhibits pro-inflammatory and pro-fibrotic molecules (Elastase). Further, docking studies and a simulation study of the docked complexes with the analysis of Hydrogen bonds, Solvent Accessible Surface Area (SASA), Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF) and Radius of gyration (Rg), suggested a strong interaction between the two partners, LRG1 and SERPINA1. <b>Conclusions</b>: Our study suggests that LRG1 may inhibit SERPINA1 and promote inflammation and fibrotic processes by disrupting SERPINA1's primary function.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12922013/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146260697","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":"Vitamin D Reprograms Non-Coding RNA Networks to Block Zika Virus in Human Macrophages.","authors":"Julieta M Ramírez-Mejía, Geysson Javier Fernandez, Silvio Urcuqui-Inchima","doi":"10.3390/pathophysiology33010015","DOIUrl":"10.3390/pathophysiology33010015","url":null,"abstract":"<p><p><b>Background:</b> Zika virus (ZIKV), a mosquito-borne flavivirus, is associated with congenital malformations and neuroinflammatory disorders, highlighting the need to identify host factors that shape infection outcomes. Macrophages, key targets and reservoirs of ZIKV, orchestrate both antiviral and inflammatory responses. <b>Methods:</b> Vitamin D (VitD) has emerged as a potent immunomodulator that enhances macrophage antimicrobial activity and regulates inflammation. To investigate how VitD shapes macrophage responses to ZIKV, we reanalyzed publicly available RNA-seq and miRNA-seq datasets from monocyte-derived macrophages (MDMs) of four donors, differentiated with or without VitD and subsequently infected with ZIKV. <b>Results:</b> Differential expression analysis identified long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and mRNAs integrated into competing endogenous RNA (ceRNA) networks. In VitD-conditioned and ZIKV-infected MDMs, 65 lncRNAs and 23 miRNAs were significantly modulated. Notably, lncRNAs such as HSD11B1-AS1, Lnc-FOSL2, SPIRE-AS1, and PCAT7 were predicted to regulate immune and metabolic genes, including G0S2, FOSL2, PRELID3A, and FBP1. Among the miRNAs, let-7a and miR-494 were downregulated, while miR-146a, miR-708, and miR-378 were upregulated, all of which have been previously implicated in antiviral immunity. Functional enrichment analysis revealed pathways linked to metabolism, stress responses, and cell migration. ceRNA network analysis suggested that SOX2-OT and SLC9A3-AS1 may act as molecular sponges, modulating regulatory axes relevant to immune control and viral response. <b>Conclusions:</b> Despite limitations in sample size and experimental validation, this study provides an exploratory map of ncRNA-mRNA networks shaped by VitD during ZIKV infection, highlighting candidate molecules and pathways for further studies on host-virus interactions and VitD-mediated immune regulation.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12921728/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146260693","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":"Amyloid Beta Oligomers as Early Triggers of Neuronal Cytoskeleton Dysfunction in Alzheimer's Disease.","authors":"Yadira Gasca-Martínez, Miguel Angel Ontiveros-Torres, Isaías López-Gallegos, José Jaime Jarero-Basulto","doi":"10.3390/pathophysiology33010014","DOIUrl":"10.3390/pathophysiology33010014","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is characterized by progressive cognitive decline, with amyloid beta oligomers (AβOs) emerging as the most neurotoxic species and acting as early triggers of cellular alterations. Before the appearance of other protein aggregates, AβOs disrupt the dynamics and stability of the neuronal cytoskeleton, a structure essential for maintaining neuronal morphology, axonal transport, and synaptic plasticity. Experimental evidence demonstrates that AβOs promote microtubule disassembly, Tau hyperphosphorylation, reduced kinesin levels, impaired axonal transport, and alterations in actin dynamics through the LIMK-cofilin signaling pathway. In addition, increased levels of neurofilament light chain have been identified as an early biomarker of axonal damage. Notably, these cytoskeletal disturbances arise in the absence of extensive neuronal death, underscoring the cytoskeleton as a critical early target in AD pathogenesis. In this review, we analyze cytoskeletal alterations induced by AβOs in neurons and discuss how these changes may contribute to disrupted neuronal communication, a defining early hallmark of AD pathology.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12921916/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146260695","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":"Zinc Depletion Increases Susceptibility to AMPK-Induced Atrophic Responses in C2C12 Myotubes.","authors":"Taishi Imoto, Junpei Ishizaka, Yukinori Tamura","doi":"10.3390/pathophysiology33010012","DOIUrl":"10.3390/pathophysiology33010012","url":null,"abstract":"<p><p><b>Background</b>: AMP-activated protein kinase (AMPK) acts as a key energy sensor that negatively regulates skeletal muscle mass. Zinc is an essential trace element that is required for myogenic differentiation and protein synthesis, while zinc deficiency has been associated with muscle atrophy in vivo. However, how zinc status modulates AMPK activation itself or alters downstream responses to AMPK signaling in muscle cells remains unclear. <b>Methods</b>: C2C12 myotubes were cultured under zinc-depleted (ZnD), zinc-sufficient (20 μM; Zn20), or zinc-supplemented (40 μM; Zn40) conditions. AMPK was activated by AICAR, and zinc status-dependent responses were evaluated using molecular and morphological analyses. <b>Results</b>: AICAR increased intracellular zinc levels in Zn20 and Zn40 but not in ZnD. Zinc transporter expression exhibited gene-specific regulation: <i>Zip3</i> was upregulated across all zinc conditions, <i>Zip14</i> was significantly induced in ZnD and Zn40, and <i>Zip10</i> was selectively upregulated in Zn40. AICAR induced myotube atrophy in all groups; however, the reduction in myotube diameter was significantly greater under zinc-depleted conditions. Zinc depletion was associated with transcriptional upregulation of FoxO1, FoxO3, Atrogin-1, and MuRF1 in response to AICAR, while AMPK activation and suppression of S6K1 phosphorylation occurred to a similar extent regardless of zinc status. <b>Conclusions</b>: These findings indicate that zinc availability does not alter AMPK activation itself but modulates downstream atrophic responses to AMPK signaling. Under conditions of AMPK activation, adequate zinc availability is accompanied by increased intracellular zinc levels and stress-responsive ZIP regulation, which may limit excessive atrophic gene induction, whereas zinc depletion increases susceptibility to AMPK-induced atrophic responses in skeletal muscle cells.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12922060/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146260687","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":"Bioinformatic Analysis of Contrasting Expression Patterns and Molecular Interactions of TIMPs in Breast Cancer: Implications for Tumor Progression and Survival.","authors":"Lorena Cayetano-Salazar, Jhactcidi Jackeline García-López, Dania A Nava-Tapia, Eymard Hernández-López, Caroline Weinstein-Oppenheimer, Julio Ortiz-Ortiz, Marco Antonio Leyva-Vázquez, Miguel Ángel Mendoza-Catalán, Adán Arizmendi-Izazaga, Napoleón Navarro-Tito","doi":"10.3390/pathophysiology33010013","DOIUrl":"10.3390/pathophysiology33010013","url":null,"abstract":"<p><p><b>Background/Objectives:</b> Although tissue inhibitors of metalloproteinases (TIMPs) are key regulators in breast cancer, their differential expression, clinical relevance, and molecular roles remain unclear. This study aimed to compare the expression patterns of the four TIMPs in breast cancer and evaluate their molecular interactions and associated pathways through an integrated bioinformatic analysis. <b>Methods:</b> The expression of TIMPs and their correlations with MMPs were analyzed using the TCGA PanCancer, cBioPortal, and GEO datasets. Associations between TIMP expression and overall survival were assessed in the TCGA Breast Invasive Carcinoma PanCancer cohort. Pathway enrichment analysis was performed using GO, KEGG, and DAVID. The relationships between immune cell infiltration, stromal cells, and TIMP expression were assessed using the EPIC algorithm. Statistical analyses were performed using R. <b>Results:</b><i>TIMP1</i> was the only inhibitor overexpressed in breast tumors and showed significant associations with the Luminal B, HER2, TNBC, and normal-like subtypes, along with a modest increase across stages. <i>TIMP2</i>, <i>TIMP3</i>, and <i>TIMP4</i> were downregulated in tumors. High expression of <i>TIMP1</i> and <i>TIMP4</i> correlated with better overall survival. <i>TIMP1</i>-associated genes were enriched in NF-kappa and PI3K-Akt signaling and actin cytoskeleton components. <i>TIMP2</i> was linked to Hedgehog and MAPK pathways and actin-related elements. <i>TIMP3</i> correlated with Hedgehog and PI3K-Akt signaling, DNA damage response, and membrane components. TIMP4 was associated with VEGF, MAPK, PI3K-Akt, DNA damage pathways, and actin organization. <i>TIMP2</i> showed strong positive correlations with <i>MMP2</i> and <i>MMP14</i>, while <i>TIMP4</i> showed negative correlations with <i>MMP1</i> and <i>MMP9</i>. Interestingly, we found a strong positive correlation between <i>TIMP2</i> and <i>TIMP3</i> with <i>ADAM12</i>, as well as between <i>TIMP2</i> and <i>TIMP3</i> with <i>ADAM10</i>, and negative correlations with <i>ADAM15</i>. The differential expression of TIMPs favors greater infiltration of immune cells related to tumor progression and poor prognosis in breast cancer patients. <b>Conclusions:</b> TIMPs display contrasting expression profiles and distinct pathway associations in breast cancer. <i>TIMP1</i> emerges as the only consistently overexpressed inhibitor, while <i>TIMP4</i> appears as a promising prognostic marker with unique MMP correlations that may influence tumor behaviors.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12921991/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146260694","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":"The Paradoxical Effect of Cannabis Use on Cognition in Chronic Psychotic Disorders.","authors":"Fiorela Gorea, Martina Pelle, Federico Fiori Nastro, Carmine Gelormini, Fatime Elezi, Michele Ribolsi, Giorgio Di Lorenzo","doi":"10.3390/pathophysiology33010011","DOIUrl":"10.3390/pathophysiology33010011","url":null,"abstract":"<p><strong>Background/objectives: </strong>Cannabis use has a particularly high prevalence in individuals with psychotic disorders. Although cannabis use is generally associated with cognitive impairments in the general population, its impact on cognition in psychosis remains controversial. This study aimed to investigate the association between cannabis use and cognitive performance in a cohort of individuals affected by psychotic disorders.</p><p><strong>Methods: </strong>A total of 105 inpatients with psychotic disorders (mean age: 40.3 years; 34 females) were recruited from the University Hospital Center \"Mother Teresa\" in Tirana. Data collection included socio-demographic and clinical variables. Cognitive functioning was evaluated using the Montreal Cognitive Assessment (MoCA), while psychopathology was assessed with the Brief Negative Symptom Scale (BNSS), the Calgary Depression Scale for Schizophrenia (CDSS), the Psychotic Symptom Rating Scales (PSYRATS), and the Scale for the Assessment of Thought, Language, and Communication (TLC).</p><p><strong>Results: </strong>Cannabis users (CU) were more frequently male, younger, and exhibited an earlier onset of psychosis compared to non-users (No-CU). Importantly, CU demonstrated higher MoCA scores, with the most favorable outcomes observed among daily users.</p><p><strong>Conclusions: </strong>Contrary to the prevailing assumption that cannabis use exacerbates cognitive decline, our findings indicate an unexpected association between cannabis use and preserved cognitive functioning in psychosis. These results underscore the need to consider dosage, frequency, and cannabinoid composition (THC/CBD ratio) when interpreting cannabis-related cognitive outcomes in psychotic disorders.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12921724/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146260696","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":"Bridging the Gap Between Static Histology and Dynamic Organ-on-a-Chip Models.","authors":"Zheyi Wang, Keiji Naruse, Ken Takahashi","doi":"10.3390/pathophysiology33010010","DOIUrl":"10.3390/pathophysiology33010010","url":null,"abstract":"<p><p>For more than a century, pathology has served as a cornerstone of modern medicine, relying primarily on static microscopic assessment of tissue morphology-such as H&E staining-which remains the \"gold standard\" for disease diagnosis. However, this conventional paradigm provides only a snapshot of disease states and often fails to capture their dynamic evolution and complex functional mechanisms. Moreover, animal models are constrained by marked interspecies differences, creating a persistent gap in translational research. To overcome these limitations, we propose the concept of New Pathophysiology, a research framework that transcends purely morphological descriptions and aims to resolve functional dynamics in real time. This approach integrates Organ-on-a-Chip (OOC) technology, multi-omics analyses, and artificial intelligence to reconstruct the entire course of disease initiation and to enable personalized medicine. In this review, we first outline the foundations and limitations of traditional pathology and animal models. We then systematically summarize more than one hundred existing OOC disease models across multiple organs-including the kidney, liver, and brain. Finally, we elaborate on how OOC technologies are reshaping the study of key pathological processes such as inflammation, metabolic dysregulation, and fibrosis by converting them into dynamic, mechanistic disease models, and we propose future perspectives in the field. This review adopts a relatively uncommon classification strategy based on pathological mechanisms (mechanism-based), rather than organ-based categorization, allowing readers to recognize shared principles underlying different diseases. Moreover, the focus of this work is not on emphasizing iteration or replacement of existing approaches, but on preserving past achievements from a historical perspective, with an emphasis on overcoming current limitations and enabling new advances.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12922035/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146260688","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":"Novel Insights into the Enigmatic Genetics of Male Breast Cancer in China.","authors":"Guan-Tian Lang, Xiao-Ling Weng, Yun Liu, Xin Hu, Zhi-Ming Shao, Zhen Hu","doi":"10.3390/pathophysiology33010009","DOIUrl":"10.3390/pathophysiology33010009","url":null,"abstract":"<p><strong>Objectives: </strong>The molecular characterization of male breast cancer (MaBC) has long been understudied, primarily due to its rare occurrence. Clinical management of MaBC remains profoundly challenging, with current therapeutic strategies largely extrapolated from female breast cancer protocols.</p><p><strong>Methods: </strong>Through panel-based sequencing targeting <i>BRCA1</i>, <i>BRCA2</i>, and <i>PALB2</i> variants, we delineated the genomic landscape of 96 MaBC cases. Subsequent whole-exome sequencing (WES) of 84 <i>BRCA1/2</i>- and <i>PALB2</i>-mutation-negative MaBC patients, compared against 4480 healthy controls, revealed compelling findings.</p><p><strong>Results: </strong>Pathogenic variants in <i>BRCA1/2</i> and <i>PALB2</i> were identified in 14.6% (14/96) of MaBC cases, with <i>BRCA2</i> mutations predominating at 12.5% (<i>n</i> = 12). Notably, one patient harbored the <i>BRCA1</i> c.4015G > T stop-gained mutation, while another exhibited the <i>PALB2</i> c.481_482dupGA alteration. Our analysis further uncovered 170 pathogenic/likely pathogenic mutations, with <i>RAD50</i>, <i>DMD</i>, <i>ARSA</i>, and <i>ABCC6</i> demonstrating recurrent mutations in MaBC.</p><p><strong>Conclusions: </strong>As the inaugural germline genomic investigation of MaBC in a Han Chinese population, this work reveals clinically actionable alterations with diagnostic and therapeutic implications. These discoveries not only advance our understanding of MaBC's molecular architecture but also underscore the critical need for dedicated research into this malignancy.</p>","PeriodicalId":520741,"journal":{"name":"Pathophysiology : the official journal of the International Society for Pathophysiology","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12921874/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146260689","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}