搜索结果：Cellular & molecular immunology

Aging affects lung function, predisposing older adults to respiratory diseases; however, the cellular and molecular mechanisms of lung aging are not fully understood. Leveraging single-cell and spatial transcriptomics data from 184 and 70 lung parenchyma samples, respectively, we present an analytical platform to dissect the cell composition, gene expression modules, and regulatory changes linked to multiple hallmarks of lung aging. Our findings show cell type-specific age-association of senescence markers and a decline in alveolar cell proliferation, autocrine WNT signaling, and stemness indicators with advancing age. Analysis of myeloid cells reveals a global reduction in macrophage subsets and a surge in mitochondrial dysfunction and inflammatory signaling. In contrast, lung parenchyma T cells expand with age and exhibit heightened interferon gamma expression, cytotoxic activity, and exhaustion in older lung and blood samples, indicative of age-related immune dysfunction. Cell interaction and spatial analysis demonstrate aberrant myeloid-T cell cross-talk, leading to an increase in T cell chemotaxis and activation. Lastly, we use machine learning to predict lung biological age and identify putative biomarkers of lung aging and disease risk.

Acquired resistance to epidermal growth factor receptor (EGFR)-targeted therapies remain a major challenge in non-small cell lung cancer (NSCLC), particularly in patients with malignant pleural effusion (MPE). The MPE microenvironment, characterized by acidic, cytokine- and metabolite-rich conditions, promotes the emergence of osimertinib-tolerant persister cells (OTPCs), contributing to disease relapse. In this study, we investigated the role of MPE in driving OTPC formation and identified key molecular regulators underlying this adaptive phenotype. MPE samples from advanced EGFR-mutant NSCLC were used to generate OTPCs through coculture with PC9 and H1975 cell lines. In contrast, non-malignant pleural effusions induced only limited tolerance. Transcriptomic profiling revealed extensive reprogramming in OTPCs, with PLCG1 and RAC1 among the most significantly upregulated genes, enriched in pathways related to glycolysis, hypoxia, and epithelial-mesenchymal transition. Functional analyses demonstrated that OTPCs exhibit enhanced macropinocytosis, metabolic flexibility, and invasive capacity. Mechanistically, PLCG1 and RAC1 formed a co-dependent signaling network, as supported by reciprocal knockdown and protein interaction studies. Inhibition of PLCG1 significantly impaired both mitochondrial respiration and glycolytic activity, reduced mesenchymal marker expression, and decreased OTPC viability by more than 60%, thereby restoring sensitivity to osimertinib. In vivo, combined inhibition of EGFR and PLCG1 resulted in sustained tumor suppression and improved survival without detectable toxicity. Collectively, these findings identify a co-dependent PLCG1-RAC1 signaling network that integrates metabolic adaptation and phenotypic plasticity to sustain drug tolerance in MPE-associated NSCLC. Targeting this pathway represents a promising strategy to overcome resistance to EGFR-directed therapies.

Postherpetic neuralgia (PHN), the most frequent and recalcitrant sequela of herpes zoster, arises from a complex interplay between inflammatory cascades and programmed cell death. Emerging evidence indicates that pyroptosis-a form of inflammatory cell death mediated by the NLRP3/Caspase-1/GSDMD axis-drives both the onset and chronicity of PHN. This review outlines the mechanism of action of pyroptosis and its divergent effects in the peripheral versus the central nervous system. Varicella-zoster virus reactivation triggers initial inflammation, promoting NLRP3 inflammasome assembly and Caspase-1 activation. Activated Caspase-1 cleaves GSDMD, resulting in the formation of membrane pores and the release of pro-inflammatory mediators such as IL-1β and IL-18. Peripherally, pyroptosis of satellite glial cells sensitizes sensory neurons through paracrine signaling, leading to peripheral sensitization. Centrally, microglial and astrocytic pyroptosis amplifies neuroinflammation, with the resulting accumulation of reactive oxygen species inducing pyroptosis of GABAergic neurons. The loss of these inhibitory interneurons disrupts the excitatory-inhibitory balance, causing central sensitization. These interconnected processes establish a self-reinforcing inflammation-pyroptosis-pain cycle. Consequently, interventions targeting key pyroptosis nodes-including NLRP3, Caspase-1, GSDMD, and P2X7R-via small-molecule inhibitors, natural compounds, or non-pharmacological approaches such as electroacupuncture, hold significant therapeutic promise for PHN. This review systematically delineates the multifaceted mechanisms underlying the role of pyroptosis in this condition and highlights the therapeutic potential of blocking this pathway to counteract peripheral and central sensitization, thereby offering a novel framework and precision targets for PHN management.

Syntaxin-4 (Stx4), a member of the Qa-SNARE protein family, is a pivotal regulator of membrane trafficking. Stx4 is predominantly localized at the postsynaptic membrane of neurons and in glial cells, where it is essential for synaptic plasticity and the maintenance of neuronal homeostasis. Stx4 facilitates the activity-dependent exocytosis of glutamatergic receptors, thereby governing the balance between Long-Term Potentiation (LTP) and Long-Term Depression (LTD). Emerging evidence suggests that dysregulation of Stx4 is intricately linked to the pathogenesis of neurodegenerative diseases. In Alzheimer's disease, Stx4 is involved in synaptic dysfunction and cognitive impairment through its interactions with amyloid-β (Aβ) and tau pathologies, affecting receptor recruitment at dendritic spines. In Parkinson's Disease (PD), Stx4 contributes to α-synuclein proteostasis, dopaminergic signaling, neuroinflammation, and the maintenance of blood-brain barrier integrity. While its presence in cerebrospinal fluid highlights its potential as a candidate biomarker for these diseases, further validation is required to establish clinical utility. This review summarizes current mechanistic insights into Stx4's multifaceted roles in the neurodegenerative disorders and explores the therapeutic prospects of targeting Stx4-mediated pathways due to its translational potential.

Epstein-Barr virus (EBV) is an oncogenic herpesvirus associated with multiple lymphoid and epithelial malignancies. Despite extensive investigation of EBV vaccine strategies, effective therapeutic approaches capable of targeting established EBV-associated cancers remain limited. In this study, we developed an integrated immunoinformatics and structure-guided framework for the design and prioritization of therapeutic multi-epitope vaccine candidates targeting both structural glycoproteins (gp350, gB, gH/gL, and gp42) and latency-associated proteins (EBNA1, LMP1, LMP2, and BZLF1). Sixteen multi-epitope vaccine constructs were generated and evaluated through sequence validation, structural refinement, reverse vaccinology assessment, immune-response simulation, receptor interaction analysis, molecular dynamics simulations, and expression-readiness profiling. The prioritized epitope repertoire achieved projected global population coverage exceeding 98% for both MHC class I and II pathways. Structural refinement improved model quality across vaccine constructs, while immunological and safety assessments supported favorable predicted antigenicity, non-allergenic potential, non-toxicity, and developability properties. Immune simulations predicted coordinated innate, humoral, and cellular responses, with several constructs demonstrating strong predicted immunogenic profiles. Molecular docking and molecular dynamics analyses further supported predicted structural compatibility and interaction stability with immune-associated receptors under simulated conditions. Integrated multi-parameter evaluation identified Constructs 4, 7, 10, 8, and 12 as the most promising candidates, with Construct 4 exhibiting the most balanced profile across immunological, structural, safety, and expression-related properties. Collectively, this study provides a comprehensive computational framework for therapeutic EBV vaccine development and identifies prioritized vaccine candidates for experimental validation. The proposed strategy offers a scalable approach for accelerating the development of multi-epitope vaccines targeting persistent viral infections and virus-associated malignancies.

Acute myeloid leukemia (AML) is a malignant clonal expansion of myeloid progenitor cells that impedes normal hematopoiesis and culminates in bone marrow failure and death. The development of chemoresistant disease in response to first-line chemotherapies is common and indicates a need for new therapies. Tumor-specific mRNA vaccines have emerged as potent inducers of cellular immunity against solid tumors, yet their utility in targeting AML and the specific mechanisms that govern their broader activity remain poorly defined. Here, we demonstrate that microRNA-155 (miR-155) within T cells is vital for host anti-leukemia responses at baseline, and for mRNA vaccine-elicited cellular responses against AML. Loss of miR-155 in T cells in conditional knockout (TCKO) mice (miR-155 fl/fl CD4+Cre) results in deficient antitumor immunity against syngeneic ovalbumin-expressing C1498 murine AML (C1498-OVA). T cell-intrinsic miR-155 is required for terminal differentiation of short-lived effector KLRG1+ CD8+ T cells, thereby providing protective immunity induced by a tumor Ag-specific mRNA vaccine against C1498-OVA AML. Single-cell RNA sequencing reveals distinct miR-155-dependent transcriptomic regulation during the mRNA vaccine response. including changes indicative of a failure to appropriately respond to IFN-γ signaling in miR-155 TCKO CD8+ T cells. Notably, we identify a subset of genes modulated by miR-155 in CD8+ T cells specific to response to mRNA vaccination, indicating a novel and context-specific role for miR-155 in regulating the immune response to mRNA-lipid nanoparticle therapeutics. Together, these data indicate T cell-expressed miR-155 is a master regulator of intrinsic cellular immunity to AML and promotes tumor-specific mRNA vaccine responses.

Interleukin-18 (IL-18) is a pleiotropic cytokine of the IL-1 family that has an important role in antitumour and antiviral immunity. Growing interest in its therapeutic potential has led researchers to explore strategies that harness IL-18 to modulate the tumour microenvironment. For example, engineered T cells are being armoured with IL-18 to enhance adoptive cell therapies and strengthen other immunotherapy approaches. As these strategies move towards clinical application, a key translational challenge is identifying the molecular mechanisms that influence treatment response and resistance, crucial for guiding trial design and patient selection across tumour types. This Review revisits the fundamental biology of IL-18, including its origins, cellular sources and regulatory networks, particularly those involving IL-18 binding protein (IL-18BP) and IL-37. We discuss how IL-18 promotes interferon-γ (IFNγ) production within the tumour microenvironment, supporting M1-like macrophage polarization, CD8+ cytotoxic T cell and CD4+ T helper 1 cell responses, natural killer cell activity and durable T cell memory. We also discuss preclinical models of IL-18 delivery, including dendritic cell platforms and cellular therapies, and highlight emerging strategies such as IL-18BP blockade and IL-18-secreting CAR T cells. Finally, we review results from early clinical studies and outline key challenges for translation, including the dual protumour and antitumour roles of IL-18.

Macrophages are essential for both, to clear pathogens and preserve tissue homeostasis, yet the molecular regulators of this equilibrium remain incompletely defined. Here, we identify SAILR (survival associated immune-regulatory RNA), a primate-specific long noncoding RNA (lncRNA), as a critical modulator of macrophage viability under infection conditions. SAILR is induced during monocyte-to-macrophage differentiation, but rapidly downregulated upon bacterial challenge in a nuclear factor kappa B (NF-κB) dependent manner. In both naïve and immune-activated macrophages, SAILR dampens the expression of adhesion, phagocytosis, and invasion factors, which include SIGLEC1 and MMP7. During infection with Salmonella Typhimurium, depletion of SAILR sensitizes macrophages to apoptosis, resulting in loss of intracellular replication niches and reduced bacterial recovery. Conversely, enforced SAILR expression promotes macrophage survival and increases intracellular pathogen burden. Mechanistically, SAILR interacts with the antiapoptotic adaptor protein 14-3-3β to support macrophage survival. Notably, downregulation of SAILR is mirrored in circulating immune cells from patients with severe COVID-19 and sepsis. Together, our findings position SAILR as a central regulator in linking macrophage survival to host-pathogen interaction and disease pathophysiology.

Hypothyroidism is a prevalent endocrine disorder characterized by insufficient thyroid hormone (T3T4) production. Thyroglobulin (Tg) serves as the prohormone for T3 and T4 production, with many variants of uncertain clinical significance due to genetic diversity in the Tg gene. We leveraged the large-scale All of Us biobank to investigate the disease association of prevalent yet undercharacterized Tg variants. We related variant presence to thyroid-stimulating hormone levels and levothyroxine (LT4) usage as proxies for thyroid function. This identified R152H, Q870H, A993T, P1012L, and P1494L variants linked to increased LT4 usage and decreased thyroid function, while the R320C variant was associated with decreased thyroid function. Molecular characterization in Fisher rat thyroid cells revealed decreased secretion efficiency of R152H, Q870H, and R320C variants. Affinity purification-mass spectrometry demonstrated that secretion-deficient variants showed higher engagement with the protein homeostasis network, indicating protein quality control defects as the pathophysiology mechanism. In contrast, secretion-competent A993T and P1494L variants showed elevated interactions with degradation and antigen-presentation pathways, suggesting an alternative pathophysiology possibly linked to Hashimoto's disease, an autoimmune condition with overproduction of autoantibodies that target thyroid proteins. In support, participants carrying the A993T or P1494L variants had elevated anti-thyroidperoxidase (TPO) antibody levels. We estimate ∼115,000 US individuals currently taking levothyroxine could benefit from precision medicine targeting these variants, with ∼85,000 carrying Q870H. Our findings highlight the power of combining large public biobank data with molecular characterization to understand Tg genotype-to-phenotype relationships. Q870H represents a candidate for molecular therapies to restore secretion, offering precision medicine beyond LT4 replacement therapy.

Long non-coding RNAs (lncRNAs) are known to play a vital role in regulating tumorigenesis. Previous studies have shown that long non-coding RNA modulated by transforming growth factor-beta (lncRNA-ATB) is overexpressed in non-small-cell lung cancer (NSCLC); however, the underlying mechanism of lncRNA-ATB as an oncogenic regulator remains elusive. This study elucidates the effect of lncRNA-ATB on cell proliferation, migration, and invasion of NSCLC cell lines (A549 and H522) and triggers cellular immune responses. The tumor microenvironment was simulated in BALB/c mice, and the in vivo pro-tumor effect of lncRNA-ATB was discovered. This study further explores the molecular mechanisms of lncRNA-ATB-mediated effects. The interaction of lncRNA-ATB with insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs) has been found, and IGF2BP2 can play a role in tumor immune cell infiltration and tumor cell proliferation by stabilizing lncRNA-ATB. In conclusion, lncRNA-ATB plays a complex regulatory role in the progression of NSCLC and may serve as a potential target for future treatment. This study provides valuable insights into the complex interactions of lncRNAs in the pathogenesis of NSCLC, and the robust methodology and comprehensive analysis presented in this study contribute to advancing our understanding of the molecular mechanisms underlying NSCLC progression.

The extent to which the cerebrovasculature is affected in various brain disorders is still not well understood. To address this, we established a transcriptomic repository of major vascular cell types and microglia to compare the global transcriptomic response in mouse models of three human brain disorders linked to neuroinflammation and associated vascular reactivity: Alzheimer's disease (AD), traumatic brain injury (TBI), and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Single-cell analysis of >250,000 cells at different disease stages led to identification of two previously unknown vascular cell subtypes, expanded the endothelial zonation spectrum and allowed for a detailed analysis of the cellular and molecular responses. Surprisingly, most vascular cell types lacked major transcriptomic changes across the three conditions, while microglia exhibited significant, disease-specific transcriptional changes. Notably, microglial responses converged between late-stage TBI and AD, offering insights into the predisposition for neurodegeneration following TBI.

Sepsis-associated acute respiratory distress syndrome (ARDS) is driven by metabolic reprogramming and immune dysregulation, but the molecular link between them remains unclear. Lactylation, a lactate-derived post-translational modification, couples metabolic state to transcriptional and functional outcomes in immune and parenchymal cells as an epigenetic reader of glycolytic flux. Recent evidence demonstrates that lactylation regulates macrophage polarization, neutrophil extracellular trap formation, myeloid derived suppressor cell function, and T cell differentiation, while also controlling ferroptosis, autophagy, and endothelial injury in the septic lung. Clinical studies have identified histone H3K18 lactylation as a potential biomarker for sepsis severity and prognosis. This review establishes lactylation as a novel epigenetic bridge connecting metabolic reprogramming and immune dysregulation in sepsis associated ARDS and highlights therapeutic opportunities targeting this modification.

Recurrent spontaneous abortion (RSA) is closely associated with disruption of both immune homeostasis and vascular development at the maternal-fetal interface. To decode the underlying cellular defects, we performed single-cell RNA sequencing (scRNA-seq) on human decidual tissues, revealing a profound imbalance in macrophage polarization and impaired efferocytosis in RSA patients. Through transcriptomic screening and clinical validation, we pinpointed the Fgr proto-oncogene, Src family tyrosine kinase (Fgr) as a key pathological driver overexpressed in RSA macrophages, acting as a molecular brake on the pro-healing M2 phenotype. Seeking a targeted intervention, we demonstrated that the natural flavonoid Apigenin (Api) directly binds and inhibits the Fgr kinase domain, which essentially triggers robust Interleukin 10 (IL10) secretion. Crucially, this Api-mediated Fgr/IL10 signaling axis not only restores M2 polarization and enhances apoptotic cell clearance, but also rescues pro-angiogenic crosstalk with endothelial cells in a vascular endothelial growth factor (VEGF) -dependent manner. Furthermore, in a lipopolysaccharide (LPS)-induced murine miscarriage model, Api administration effectively reduced embryo resorption and rescued pregnancy loss. Collectively, our study highlights the Fgr/IL10 axis as a critical determinant of decidual homeostasis and establishes Api as a promising therapeutic strategy for RSA.

Transposons, also known as jumping genes, are DNA sequences capable of relocating within or between chromosomes. Long interspersed element-1 (LINE-1), the only autonomously active retrotransposon in the human genome, plays a critical role in maintaining genomic stability through its dynamic regulation. Under normal physiological conditions, the host employs epigenetic and other mechanisms to maintain LINE-1 in a silenced state. However, when this precise regulatory control is disrupted, aberrant LINE-1 activation can lead to insertional mutations, resulting in genomic instability and the development of various genetic disorders and malignant tumors. Recent evidence has demonstrated elevated LINE-1 expression in multiple cancers, such as breast, esophageal, lung, and colorectal cancer, suggesting a close association between LINE-1 dysregulation and tumorigenesis. This review summarizes the multi-layered regulatory network governing LINE-1, encompassing epigenetic modifications, non-coding RNAs, and various host restriction factors. It also explores the molecular mechanisms underlying LINE-1 aberrant activation in the tumor microenvironment and outlines the diverse pathways through which LINE-1 influences tumor development, such as compromising genomic stability, triggering inflammation and immune responses, and participating in cellular immortalization. This review not only provides a theoretical foundation for utilizing LINE-1 as a molecular biomarker in cancer diagnosis but also offers new perspectives for developing novel anti-tumor therapeutic strategies based on LINE-1 regulation. 转座子又称跳跃基因，是一段能够在染色体内或不同染色体之间改变自身位置的DNA序列。长散在核元件-1 (long interspersed element 1，LINE-1)作为人类基因组中唯一具有自主逆转座活性的转座子，其动态调控对维持基因组稳定性具有重要的意义。在正常生理状态下，宿主通过表观遗传等机制使LINE-1处于沉默状态，但当这种精密调控被打破时，LINE-1异常激活介导的插入突变会引发基因组不稳定，进而诱发多种遗传性疾病和恶性肿瘤。近年来的研究证据表明，在乳腺癌、食管癌、肺癌以及结直肠癌等多种肿瘤中存在LINE-1的高表达，提示LINE-1的异常激活与肿瘤发生发展存在密切关联。本文综述了宿主对LINE-1多层次的调控网络，包括表观遗传修饰、非编码RNA以及多种宿主限制因子；探讨了LINE-1在肿瘤微环境中异常激活的分子机制，并总结了LINE-1影响肿瘤发生发展的多种途径，例如影响基因组稳定性、引发炎症和免疫反应以及参与细胞永生化过程。本文不仅为LINE-1作为肿瘤分子诊断标志物提供了理论依据，同时为基于LINE-1调控的新型抗肿瘤治疗策略提供了新的视角。.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is initiated by ectopic lipid accumulation, but the precise mechanochemical transducers driving its progression to metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis remain incompletely understood. This review comprehensively elucidates the central pathogenic role of intracellular calcium signaling dysregulation in MASLD. We detail how the metabolically toxic microenvironment induces pathological biophysical remodeling of lipid rafts and key calcium transporters across the plasma membrane (PM), endoplasmic reticulum (ER), and mitochondria. This pervasive transmembrane and inter-organellar calcium imbalance precipitates severe organelle network collapse, characterized by calcium depletion-driven ER stress, mitochondrial dysfunction, and the structural derangement of mitochondria-associated ER membranes (MAMs). Aberrant calcium fluxes function as critical secondary messengers that dictate hepatic immune microenvironment remodeling, at the cellular level driving Kupffer cell pro-inflammatory polarization, NLRP3 inflammasome assembly, and the amplification of damage-associated molecular patterns (DAMPs). These calcium-dependent immune-metabolic feedback loops synergistically trigger hepatic stellate cell (HSC) transdifferentiation and fibrogenesis. Finally, we highlight the latent calcium-regulatory mechanisms of current metabolic therapeutics and prospect the translational potential of targeted calcium modulators coupled with advanced nanodelivery systems, advocating for multi-targeted pharmacological strategies to arrest irreversible liver injury.

Chronic obstructive pulmonary disease (COPD) exacerbation is a common respiratory condition, particularly when accompanied by eosinophilia, which mediates inflammatory responses that significantly impair the integrity of the airway mucosal barrier. This study aims to elucidate the roles of interleukin-24 (IL-24) and eosinophils (EOS) in COPD-associated tissue remodeling, focusing on their effects on the expression of pro-inflammatory mediators and extracellular matrix (ECM) components in pulmonary fibroblasts, as well as the underlying molecular mechanisms. Based on the differential expression of IL-24 between healthy individuals and COPD patients and its correlation with EOS, we differentiated EOL-1 cells into EOS using butyrate and established a co-culture system with pulmonary fibroblasts. Concurrently, groups of fibroblasts were stimulated with varying concentrations of IL-24 alone. The regulatory effects on pro-inflammatory mediators and ECM expression were systematically analyzed using flow cytometry, real-time quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, immunofluorescence, and Western blotting. Under the present experimental conditions, IL-24 treatment was associated with enhanced fibrotic responses in pulmonary fibroblasts. Furthermore, compared with butyrate treatment alone, the combination of IL-24 and butyrate further increased the differentiation rate of EOL-1 cells into EOS cells. Differentiated EOS further stimulated pulmonary fibroblasts to secrete pro-inflammatory factors IL-6 and IL-8, as well as the tissue remodeling-related factor vascular endothelial growth factor (VEGF), thereby exacerbating the fibrotic process. This study confirms that IL-24 promotes the maturation and differentiation of EOL-1 cells and can induce a fibrotic phenotypic transformation in pulmonary fibroblasts. This interaction participates in regulating inflammatory responses and tissue remodeling during COPD progression, highlighting the critical role of eosinophil-fibroblast crosstalk in the pathological mechanisms of the disease.

Human pluripotent stem cell (hPSC) manufacturing workflows frequently rely on suspension aggregation, yet inter-line and batch-to-batch variability in aggregate formation can compromise process consistency and downstream differentiation performance. We evaluated whether a short exposure to HA-100, a small-molecule inhibitor of protein kinase A and protein kinase C signaling, could be used as an upstream process intervention to improve aggregate uniformity without compromising hPSC identity or developmental competence. Nine hPSC lines, including human embryonic stem cell and induced pluripotent stem cell lines, were examined in suspension culture. HA-100 was applied during the first 24 h of aggregation. Aggregate morphology and size distribution were assessed across lines. To investigate the cellular basis of this effect, we generated an mCherry-TJP1 reporter hESC line, which enabled live visualization of junction dynamics, including responses under calcium-depleted conditions and recovery of transepithelial electrical resistance. HA-100 treatment promoted more compact and spherical aggregates, increased aggregate size into a narrower range across lines, and reduced overall variability relative to medium alone. Across the nine-line panel, HA-100-treated aggregates fell within an empirically definesd size range of 25.37-33.95 x 10^-4 mm^3 after 24 h of suspension culture, providing a practical benchmark for process monitoring. In calcium-depleted conditions, HA-100 delayed disruption of intercellular contacts and accelerated recovery of transepithelial electrical resistance, consistent with improved junctional resilience. Transient exposure to HA-100 did not abolish pluripotency marker expression or tri-lineage differentiation capacity. These data support HA-100 as a practical upstream intervention to reduce aggregate heterogeneity in suspension hPSC cultures and improve reproducibility in manufacturing-oriented workflows requiring consistent aggregation.

Prostate cancer (PCa) remains a leading cause of cancer‑related mortality in men despite advances in screening and localized treatment. The clinical heterogeneity of PCa, ranging from indolent disease to aggressive, lethal phenotypes, underscores the urgent need for reliable biomarkers that improve diagnosis, prognostication and therapeutic decision‑making. While prostate‑specific antigen testing has reduced mortality, its limited specificity has resulted in overdiagnosis and overtreatment. The present review provides a comprehensive overview of contemporary and emerging biomarkers that support a precision‑medicine approach to PCa management. The present review summarizes established and novel diagnostic, prognostic and predictive biomarkers, including serum‑ and urine‑based assays, genomic and transcriptomic signatures and multiparametric imaging. Particular emphasis is placed on liquid biopsy technologies (circulating tumor cells, circulating tumor DNA and extracellular vesicles), which offer minimally invasive, real‑time insights into tumor burden, molecular evolution and treatment resistance, although their clinical implementation remains context‑dependent and is currently most established in advanced disease settings rather than routine early‑stage management. The present review discusses the strengths and limitations of these platforms, highlighting disease‑stage dependency, technical variability and sensitivity constraints. Beyond tumor‑intrinsic markers, tissue‑based immune biomarkers that capture the tumor immune microenvironment, including immune cell density, spatial organization, checkpoint expression and immune‑related gene signatures, are explored. Evidence indicates that 'immune‑hot' tumors characterized by CD8+ T‑cell infiltration and interferon‑γ signaling are associated with improved outcomes, whereas immunosuppressive macrophage‑ or regulatory T‑cell‑dominant profiles predict poor prognosis. However, these associations are not uniform across studies and PCa remains largely resistant to immunotherapy, underscoring the need to improve the understanding of immune evasion mechanisms and the contextual limitations of immune biomarkers. Furthermore, the present review examines the emerging role of germline human leukocyte antigen class I genotype as a prognostic and predictive biomarker, explicitly integrating it with tissue‑based immune contexture and liquid biopsy readouts by proposing immunoediting as a unifying mechanistic framework that links allele‑specific antigen presentation to immune infiltration. Finally, the present review highlights the prognostic significance of preexisting tumor‑antigen‑specific CD8+ T cells, which reflect an active antitumor immune response and predict a favorable progression‑free survival and responsiveness to immunotherapeutic strategies. Collectively, the present review underscores the need for standardized, multimodal biomarker integration and prospective validation to enable personalized, immune‑aware management of PCa.

Rheumatic heart disease (RHD) is a chronic sequel of acute rheumatic fever characterized by sustained inflammation, fibrosis, and valve degeneration; however, the underlying processes remain unclear. To identify dysregulated molecular pathways, we conducted LC-MS/MS-based proteomic profiling of RHD mitral valve tissue compared with ischemic controls and validated systemic inflammation in RHD patients through peripheral blood analysis. Proteomic analysis revealed upregulation of immune response proteins, TGFβ signaling, and extracellular matrix (ECM) regulators. Notably, proteins associated with innate immune activation and macrophage-related pro- and anti-inflammatory responses were found to be enriched. Peripheral blood analysis further confirmed elevated levels of IL6, TNFα, and TIMP1, indicating systemic inflammation. To investigate the underlying mechanisms, we isolated human valve interstitial cells (hVICs) and treated them with proinflammatory stimuli (TNFα, IFNγ) and profibrotic/ anti-inflammatory (TGFβ) stimulation. TGFβ induced morphological changes within 24 h, consistent with fibrotic transformation, and upregulated fibrotic markers (ACTA2, COL1A1, COL1A2, TIMP1, CTGF, MMP2, and TGFβ) along with increased collagen deposition. In contrast, TNFα and IFNγ suppressed fibrotic gene expression while upregulating TIMP1. Notably, TGFβ induced canonical Smad3 phosphorylation, whereas TNFα and IFNγ did not find, any change. Further, macrophage-hVIC interactions were evaluated using conditioned media from M1 [LPS (100 ng/ml) + TNFα (10 ng/ml)] and M2c [TGFβ (10 ng/ml)] polarized macrophages. M2c macrophage-conditioned media enhanced profibrotic gene expression, whereas M1-conditioned media suppressed it, highlighting the role of immune-fibrotic crosstalk in valvular fibrosis. Notably, the 5-HT₂B receptor antagonist SB204741 and tadalafil effectively inhibited TGFβ-induced Smad3 phosphorylation in hVICs, thereby reducing fibrotic signaling. In addition, tadalafil selectively suppressed ERK1/2-mediated non-canonical signaling, while no significant changes were observed in the STAT3, p38 MAPK and JNK pathways. Collectively, these findings identify immune-fibrotic crosstalk and selective activation of canonical TGFβ/Smad3 and ERK1/2-mediated non-canonical signaling pathways as important contributors to valvular fibrosis in rheumatic heart disease and suggest that targeting these pathways may provide potential therapeutic approaches to limit disease progression.