International Journal of Biological Sciences最新文献

Background: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) represents a prevalent urological disorder characterized by urinary symptoms, persistent pelvic or perineal discomfort accompanied by intraprostatic leukocyte infiltration. The C-X-C chemokine receptor type 4 (CXCR4) is critically involved in mediating inflammatory responses. Nevertheless, the specific involvement of CXCR4 in the immunoinflammatory mechanisms underlying CP/CPPS pathogenesis remains poorly characterized. Methods: The therapeutic efficacy of AMD3100, a CXCR4 antagonist, in CP/CPPS was evaluated in a murine model of experimental autoimmune prostatitis (EAP). The progression of EAP and T helper 17 (Th17) cell-mediated immune responses following AMD3100 intervention was assessed via HE staining, immunohistochemistry, immunofluorescence, quantitative polymerase chain reaction (qPCR), and flow cytometry. To unravel mechanistic insights into the role of CXCR4 in regulating Th17 cell differentiation, RNA sequencing, qPCR, and western blotting validation were conducted. In addition, histological staining, measurements of reactive oxygen species (ROS) and peroxidation markers, and co-culture assays were employed to assess the antioxidative effects of AMD3100 in prostate epithelial cells. Results: AMD3100 significantly alleviated a series of symptoms of prostatitis in EAP mice. Meanwhile, inhibition of CXCR4 by AMD3100 could significantly decrease the proportion of Th17 cells and downregulate the elevated expression of both pro-inflammatory and Th17-associated cytokines in these mice. However, administration of IL-17A partially reversed the therapeutic effects of AMD3100, elevating oxidative stress biomarkers and promoting the apoptosis of prostate epithelial cells. Mechanistically, CXCR4 inhibition suppresses NF-κB activation, thereby inhibiting Th17 cell differentiation. Furthermore, integrated findings from both in vitro and in vivo studies demonstrated that aberrant NF-κB activation not only counteracted AMD3100-mediated suppression of Th17 cell differentiation but also exacerbated prostatic epithelial cell damage through amplified inflammatory responses, oxidative stress, and apoptosis. Conclusions: CXCR4 presents a promising therapeutic target for CP/CPPS. Pharmacological blockade of CXCR4 with AMD3100 inhibits Th17 cell differentiation, consequently mitigating inflammatory infiltration and oxidative tissue injury in CP/CPPS.

Pulmonary Fibrosis (PF), an end-stage manifestation of interstitial lung diseases, is associated with largely unfavorable prognoses. Lung cancer (LC), a leading cause of nationally cancer-related mortality with progressively increasing incidence, exhibits pathological interconnections with PF. The chronic remodeling of the pulmonary microenvironment-including cellular components, extracellular matrix (ECM), inflammatory cytokine networks, and metabolic reprogramming-represents the core pathogenic mechanism underlying PF-LC comorbidity. This review systematically elaborates how the fibrotic microenvironment promotes malignant transformation of lung cancer via chronic inflammation, increased matrix stiffness, immunosuppressive regulation, and epigenetic modulation. Furthermore, we investigate the bidirectional crosstalk by which LC progression reciprocally modulates fibrotic processes. Finally, we integrate current clinical challenges and propose novel therapeutic strategies targeting the fibrotic microenvironment to address this lethal pathophysiological synergy.

Ferroptosis has been demonstrated to play pivotal roles in a spectrum of pathological processes, including multi-organ dysfunction, retinal degeneration, neurodegenerative disorders, autoimmune diseases, and tumorigenesis. Notably, its pivotal role in counteracting cancer drug resistance positions ferroptosis as a promising therapeutic target. The precise regulation of this cell death pathway is fundamentally dependent on the functional orchestration of associated proteins, where subtle modifications can exert profound effects on ferroptotic progression. Post-translational modifications (PTMs) serve as sophisticated molecular switches that dynamically regulate protein structure, activity, subcellular localization, and functional interactions through covalent attachment of biochemical groups or regulatory subunits. These modifications - including proteolytic processing, partial degradation, or complete protein turnover - significantly expand the functional repertoire of the proteome, thereby exerting crucial regulatory control over cellular survival decisions. This comprehensive review systematically examines the intricate crosstalk between ferroptosis and major PTM pathways, with particular emphasis on ubiquitination, phosphorylation, acetylation, SUMOylation, methylation, oxidative modifications, glycosylation, S-nitrosylation, lactylation, and lipidation. Through critical analysis of current research advances, we elucidate the mechanistic basis by which PTMs modulate ferroptotic pathways and discuss their therapeutic implications. Furthermore, we provide prospective insights into emerging research directions and potential clinical applications targeting PTM-mediated ferroptosis regulation.

In recent years, a growing number of evidence suggests that cancer is a metabolic disease. Metabolic reprogramming is a hallmark of the TME, where various nutrients, including glucose, lipids, and amino acids, play key roles in regulating tumor development by acting on both tumor cells and immune cells. T cells are the core mediators of anti-tumor immunity. Especially CD8⁺ T cells are considered the primary immune cells involved in the anti-tumor immune response. Upon stimulation by tumor antigens and other immune cells, CD8⁺ T cells undergo metabolic reprogramming through signaling pathways. Metabolites or metabolic checkpoints induce epigenetic changes in key genes, altering the differentiation and effector function of CD8⁺ T cells. This review first elaborates on the anti-tumor functional characteristics and metabolic profiles of CD8⁺ T cells at different stages of differentiation in the TME. Then we focus on the roles of key metabolites and metabolic checkpoints in shaping CD8⁺ T cell differentiation, functionality, and immune responses, specifically through glucose, lipid, and amino acid metabolism. Finally, we discuss the reasons for heterogeneity in the effects of metabolic checkpoints on CD8⁺ T cells and explore potential clinical applications of metabolic checkpoints in treatment. Understanding the correlation between CD8⁺ T cell metabolism and anti-tumor immunotherapy may facilitate the development of new strategies to enhance the efficacy of CD8⁺ T cell-based cancer treatments.

Insufficient infiltration or dysfunction of lymphocytes in the tumor immune microenvironment is considered to be a contributing factor to poor immunotherapy outcomes in solid tumors. Necroptosis, a form of immunogenic cell death, has attracted increasing interest because of its unique role in regulating tumor immune responses. CL-387785, a third-generation EGFR inhibitor, has been reported to inhibit tumors by regulating the cell cycle and inducing apoptosis; however, the underlying mechanisms remain unclear. In this study, we demonstrated that CL-387785 effectively suppressed the malignant phenotype of melanoma and lung cancer and confirmed that cancer cells undergo necroptosis, as evidenced by morphological and protein-level analyses. Further in vivo and in vitro experiments revealed that CL-387785 enhances tumor cell killing by immune cells by inducing CD80 expression on the tumor cell surface, thereby increasing CD8⁺ T lymphocyte function. Detailed mechanistic studies indicated that CL-387785 targets TRADD, recruiting RIPK1 to induce necroptosis in tumor cells, with subsequent nuclear translocation of NF-κB, which regulates CD80 transcription. In conclusion, our findings indicate that CL-387785 induces necroptosis in tumor cells via the TRADD/RIPK1/NF-κB/CD80 signaling pathway, thereby sensitizing tumors to anti-PD-1 therapy. These results suggest that CL-387785 is a promising candidate for increasing tumor immunotherapy efficacy.

Liver fibrosis is defined as the excessive accumulation of extracellular matrix proteins in the liver due to chronic liver injury. Targeted ferroptosis of activated hepatic stellate cells (HSCs) is considered a promising therapeutic strategy for liver fibrosis. Rubimaillin (Rub), a naphthoquinone compound extracted from traditional Chinese medicine Rubia cordifolia L., exhibits various activities in multiple diseases. This study aimed to investigate the anti-hepatic fibrosis effect, the direct protein target, and molecular mechanism of Rub. Here, our results demonstrated that Rub effectively ameliorated liver fibrosis via triggering the ferroptosis of activated HSCs in mice models. Subsequently, we confirmed that Rub directly binds to carnitine palmitoyltransferase 1A (CPT1A) at SER592, THR594, and THR689, and inhibits its activity using PROTAC technology, computer molecular dynamics simulations, CETSA, DARTS, BLI, and site mutation assays. Further, the inhibition or deficiency of CPT1A in activated HSCs could trigger metabolic reprogramming-mediated ferroptosis. Moreover, CPT1A deficiency or overexpression could eliminate the effects of Rub-induced ferroptosis. Mechanistically, Rub-induced ferroptosis in activated HSCs was associated with metabolic reprogramming mediated by targeting CPT1A. Taken together, our results indicate the beneficial effects, the direct protein target and the molecular mechanism via which Rub induces ferroptosis in activated HSCs to ameliorate liver fibrosis.

Cancer immunotherapy has markedly improved clinical outcomes for cancer patients. However, its broad application is constrained by low response rates, which limit therapeutic benefits to only a subset of individuals. A deeper understanding of the tumor microenvironment (TME) and the interactions between tumor and immune cells is crucial for overcoming resistance. In this context, the reprogramming of erythroid progenitor cells (EPCs) within the TME has emerged as an important mechanism of immunotherapy resistance. EPCs, a key population in erythroid differentiation, undergo epigenetic reprogramming that underlies various physiological and pathological states. Through epigenetic modifications, EPCs may interact with immune cells and thereby promote tumor immune evasion. This review summarizes EPC reprogramming in the TME from an epigenetic perspective and explores their crosstalk with tumor and immune cells. It also evaluates the therapeutic potential of epigenetic drugs targeting EPCs and discusses future research directions focused on reversing pathological epigenetic reprogramming in EPCs to enhance immunotherapy efficacy. These advances hold significant potential for optimizing clinical cancer care paradigms and improving patient prognosis.

O-glycosylation is a key post-translational modification that profoundly shapes tumor biology by regulating cell proliferation, metastasis, and immune evasion. Aberrant O-glycosylation features truncated glycans such as Tn and sialyl-Tn antigens together with dysregulated glycosyltransferases and promotes oncogenesis in diverse malignancies. This review summarizes recent progress in elucidating the role of O-glycosylation in cancer with emphasis on its effects on cell-surface glycoproteins, intracellular signaling pathways, and emerging RNA modifications. Integration of multi-omics data and machine learning has transformed tumor classification and prognosis prediction through distinct glycosylation signatures and now supports personalized treatment strategies. Newly discovered O-glycosylation of RNA reveals additional regulatory layers and broadens the field of glycosylation research. Targeted interventions including glycosyltransferase inhibitors, gene editing, and combination with immunotherapy demonstrate promising therapeutic potential. Advanced high-throughput tools especially mass spectrometry and enzymatic release methods accelerate biomarker discovery and target validation. Collectively, this review underscores the multifaceted impact of O-glycosylation on cancer progression and treatment response while highlighting the urgent need for continued interdisciplinary collaboration to translate these findings into precision oncology and better patient outcomes.

Interferon regulatory factors irf3 and irf7 are pivotal for antiviral immunity, yet their cell-type-specific contributions, particularly within macrophage and dendritic cell (DC) lineages, have not been fully elucidated. Here, employing a multi-omics strategy encompassing in vitro assays, in vivo influenza A virus (IAV) infection models, NanoString, transcriptomic analyses, and scGPT-based computational modeling, we dissect the divergent and context-dependent roles of irf3 and irf7. We demonstrate macrophages exhibit heightened sensitivity to TLR3 stimulation, a response critically dependent on irf3. Conversely, DCs respond more robustly to TLR7 activation and very weakly to TLR3 activation. Unexpectedly, global Irf7 ^-/- mice displayed enhanced survival against IAV-induced lethality, whereas global Irf3 ^-/- mice exhibited similar mortality to WT mice but demonstrated accelerated physiological recovery during the resolution phase, indicative of reduced disease severity rather than improved survival. Deep transcriptomic profiling of lung alveolar macrophages (AM), DC1, and DC2 subsets revealed distinct irf3 and irf7 dependent gene programs, with irf7 prominently driving responses in AM and DC2 populations post-IAV infection. Furthermore, scGPT simulations predicted irf3-associated regulation of pathways like IL-17 signaling distinct from irf7-biased control over Th17 differentiation and JAK-STAT signaling, suggesting a model where irf3 mainly drives rapid pathogen sensing and defence, whereas irf7 regulates sustained inflammation and adaptive immune coordination. Cross-species analyses confirmed conserved and divergent irf3/irf7 activities in human myeloid cells. Our findings provide a detailed framework of irf3/irf7 cell-specific functions, illuminating their nuanced interplay in orchestrating antiviral defence and offering potential targets for immunomodulation. This knowledge may inform the development of targeted antiviral therapeutic strategies and contribute to a more nuanced understanding of innate immune regulation.

The transient receptor potential vanilloid 1 (TRPV1), the canonical capsaicin (CAP) receptor, has been implicated across diverse pathologies, yet its role in prostate cancer (PCa) remains elusive. Here, we uncover TRPV1 as a key regulator of PCa progression and a mediator of CAP's antiproliferative effects. Through a comprehensive strategy combining proteomic profiling, Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mouse modeling, and validation in human prostate biopsies, we assessed TRPV1 expression, its functional role, and its association with tumor markers. Both proteomic analysis and Western blotting of TRPV1-silenced cells revealed reduced expression of PCNA, Cyclin B1, and AURKA, along with elevated levels of the cell cycle inhibitor p21. Similarly, CAP treatment resulted in comparable changes in the proteomic profile. Functional assays demonstrated that both TRPV1 knockdown and CAP exposure significantly impaired cell cycle progression and mitosis. Moreover, sustained CAP treatment led to a reduction in TRPV1 expression, further supporting its oncogenic role. In TRAMP mice, a high-fat diet feeding elevated plasma PSA levels and TRPV1 expression in the prostate, whereas CAP supplementation reversed these effects. Importantly, TRPV1 expression correlated positively with cancer stem cell markers in both murine models and human samples. Collectively, our results reveal that TRPV1 is not only overexpressed in PCa but also contributes to proliferation regulation and stemness features, positioning it as a potential diagnostic and prognostic biomarker for prostate cancer.