International Journal of Biological Sciences最新文献

Macrophages play a central role in maintaining pulmonary immune homeostasis and responding to injury. In the lung, alveolar macrophages modulate their metabolic profiles to support essential functions such as microbial clearance, inflammation resolution, and tissue repair. Recent studies have shown that these metabolic adaptations are not merely byproducts of activation but represent key regulators of macrophage behavior. In chronic lung diseases including asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF), macrophage metabolism is pathologically reprogrammed, contributing to persistent inflammation in asthma and COPD, or to unrestrained fibrotic remodeling in IPF, and ultimately leading to ongoing tissue damage. Specifically, in asthma, type 2 cytokine signaling promotes alternative macrophage activation, accompanied by increased fatty acid oxidation and disrupted lipid mediator profiles. COPD-associated macrophages exhibit mitochondrial dysfunction, enhanced glycolysis, and iron overload, impairing bacterial phagocytosis and amplifying oxidative stress. In IPF, macrophages simultaneously engage glycolytic and oxidative pathways while losing regulatory metabolites such as itaconate, supporting persistent fibrogenic signaling. These disease-specific metabolic features sustain maladaptive macrophage phenotypes and constitute promising targets for therapeutic intervention. This review outlines current knowledge of macrophage immunometabolism in the lung and its contribution to chronic respiratory diseases. It also discusses strategies to restore metabolic balance, including the use of antioxidants, metabolic modulators, and targeted drug delivery. Understanding macrophage metabolism may open new avenues for treating chronic lung diseases at the level of cellular function.

Background: Hepatocellular carcinoma (HCC) exhibits limited therapeutic responses, partly due to undefined tumor suppressor networks. While TTC36 is downregulated in HCC and correlates with poor prognosis, its functional role, molecular mechanisms, and impact on targeted therapy remain unknown. Methods: By analyzing HCC tissues RNA-seq, and scRNA-seq data of HCC tissues, we investigated the expression pattern of TTC36. The clinical relevance was analyzed by using Kaplan-Meier Plotter. Cell proliferation, migration, invasion and apoptosis were detected to confirm the function of TTC36. Mechanistic insights into TTC36-mediated HCC suppression were obtained via RNA-seq analysis, mass spectrometry analysis, molecular docking, RNA pulldown, dual-luciferase reporter assays. In animal models, the tumor growth analysis, along with IHC staining and TUNNEL staining, was used to investigate the function of TTC36 and the response to sorafenib. Results: Bioinformatics and in vitro/vivo assays demonstrated TTC36 downregulation promotes HCC proliferation and correlates with poor survival. Mechanistically, TTC36 directly binds YBX3 and masks ubiquitination sites (K311/K350), inhibiting proteasomal degradation. Stabilized YBX3 enhances SPRED1 mRNA stability by binding the CACAUC motif in its 3'UTR, suppressing Ras/MAPK signaling. The TTC36/YBX3/SPRED1 axis inhibits tumor growth but induces sorafenib resistance via compensatory PI3K/Akt activation. Akt inhibition (MK-2206) reverses sorafenib resistance in TTC36-high HCC. Conclusion: TTC36 is a tumor suppressor that stabilizes YBX3 to upregulate SPRED1 and inhibit Ras/MAPK-driven proliferation. Paradoxically, TTC36-high HCC develops sorafenib resistance through PI3K/Akt hyperactivation, which is overcome by combined Akt inhibition. Thus, TTC36 may serves as a predictive biomarker to stratify HCC patients for personalized therapy: sorafenib monotherapy for TTC36-low tumors and sorafenib-Akt inhibitor combination for TTC36-high, sorafenib-resistant tumors.

Glycolysis activation plays a critical role in sustaining the proinflammatory phenotype of macrophages, which is key to initiating and advancing liver fibrosis. However, the underlying mechanisms that trigger glycolytic activation and their contribution to inflammation remain poorly understood. In this study, we showed that inhibiting glycolysis markedly suppresses macrophage M1 polarization and alleviates liver inflammation and fibrosis, whereas enhancing glycolysis in hepatic macrophages produces the opposite effect. Additionally, our results demonstrated that glycolytic flux is necessary for activation of the STING/TBK1/IRF3 pathway. Moreover, STING activation was found to reciprocally stimulate glycolysis in macrophages. Mechanistically, we found that ATP generated through glycolysis promotes STING pathway activation and enhances the interferon-dependent immune response. Moreover, activation of IRF3, a downstream transcription factor of STING, upregulates HIF-1α transcription, further driving glycolysis. These findings uncover novel mechanistic links between STING signaling and glycolytic metabolism, emphasizing their coordinated role in promoting macrophage M1 polarization. Together, our data suggest that targeting the interaction between metabolic reprogramming and immune signaling offers an effective therapeutic approach for treating liver fibrosis and cirrhosis.

Background: Tumor-associated macrophages (TAMs) are pivotal mediators of the immunosuppressive tumor immune microenvironment (TIME) in colorectal cancer (CRC). However, genes of TAMs that potentiate immunotherapy remain to be explored. Methods: Single-cell RNA sequencing (scRNA-seq) data were analyzed to identify TAM molecular signatures, which were validated in patient cohorts from Huadong Hospital and TCGA to explore their clinical significance. Multidimensional characterization of CRC TIME and Dipeptidyl peptidase VII (DPP7)-positive TAMs functional state was achieved through cytometry by time-of-flight, multiplex immunofluorescence, in vitro and in vivo experiments. Mechanistic investigations integrating RNA-seq, Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS)-based proteomics, and targeted lipid metabolomics have revealed the reprogramming of key metabolic pathways. Finally, the therapeutic potential of DPP7, which targets the enhancement of anti-PD-1 immunotherapy efficacy, was demonstrated. Results: DPP7 was identified as the key gene in TAMs, and DPP7⁺TAMs correlated with metastasis and worse overall survival in multiple clinical cohorts. Functional characterization demonstrated that DPP7⁺TAMs drove the immunosuppressive TIME and promoted the exhaustion of CD8⁺T cells, thus exhibiting M2-polarized features. Mechanistically, DPP7 reduced ubiquitination-induced degradation of Carnitine Palmitoyltransferase 1A (CPT1A) by binding to CPT1A in a mutually exclusive manner with TRIM25, thus enhancing fatty acid oxidation (FAO) in TAMs. This metabolic reprogramming consumes lipids (including triglycerides and free fatty acids), elevates adenosine triphosphate (ATP) generation, and induces an immunosuppressive phenotype. In vivo, DPP7 knockdown in bone marrow-derived macrophages (BMDMs) synergized with anti-PD-1 therapy, achieving significant suppression of subcutaneous xenograft tumor growth and liver metastatic burden by reversing the immunosuppressive TIME. Conclusions: DPP7 is mainly expressed in TAMs and DPP7⁺TAMs are strongly associated with adverse prognosis in CRC. Mechanistically, DPP7 enhances FAO to promote the M2-polarized phenotype in TAMs, leading to an immunosuppressive TIME. Targeting DPP7⁺TAMs may potentiate the efficacy of immunotherapy for CRC.

Outer membrane vesicles (OMVs) are secreted by gram-negative bacteria and are genetically and environmentally regulated. The contents of OMVs are derived from the outer membrane and periplasm of bacteria, that can act as virulence factors to attack host cells. In periodontitis, the OMVs of Porphyromonas gingivalis and other important periodontal pathogens can destroy the host structure, induce host immune responses, and promote periodontitis progression. In oral squamous cell carcinoma (OSCC), OMVs accelerate cancer spread and metastasis by regulating the gene expression of tumour cells. In addition to their role in oral diseases, OMVs can spread from the oral cavity to the whole body, thereby participating in the development of many diseases, including circulatory diseases, endocrine diseases, autoimmune diseases, and neurologic diseases. In this review, we introduce the biogenesis, basic structure, and roles of OMVs and comprehensively summarize the biological characteristics of OMVs from various oral bacteria. In addition, we describe the impact of OMVs on oral diseases as well as systemic health and emphasize their therapeutic potential as drug targets, antigens, and immune adjuvants for application in periodontitis and OSCC. Finally, we discuss in depth the future research directions, application prospects, and challenges of OMVs.

Rationale: The transition of fibroblasts into activated myofibroblasts is a pivotal driver of collagen deposition and adverse cardiac remodeling. Insulin-like growth factor-binding protein 6 (IGFBP6), a critical modulator of cellular growth and metabolism via its regulation of IGF-II activity, has been implicated in immune and fibrotic responses. However, its specific role in fibroblast-mediated cardiac remodeling, particularly in the regulation of myofibroblast transition, remains incompletely understood. Methods: We analyzed IGFBP6 expression in ischemic cardiomyopathy-associated cardiac fibrosis using Gene Expression Omnibus (GEO) dataset. Serum IGFBP6 levels in patients with chronic myocardial infarction (MI) were quantified via ELISA. Cardiac fibroblast and myofibroblast-specific IGFBP6 knockout mice were generated by crossing IGFBP6 floxed (IGFBP6^f/f) mice with tamoxifen-inducible Col1a2-Cre and Postn-MerCreMer mice. Cardiac function, tissues morphology, and molecular alterations were analyzed following MI or isoproterenol (ISO) challenge. The mechanisms underlying the regulation of fibroblast-to-myofibroblast transition (FMT) by IGFBP6 were elucidated using LC-MS/MS and RNA sequencing. Results: IGFBP6 expression was significantly upregulated in cardiac fibroblasts isolated from murine fibrotic hearts and was responsive to TGF-β1 stimulation. The elevated serum IGFBP6 levels were correlated with the incidence of chronic MI. Conditional knockout of IGFBP6 in cardiac fibroblasts and myofibroblasts markedly attenuated post-MI fibrotic remodeling, ventricular dysfunction, and ISO-induced cardiac hypertrophy and fibrosis. IGFBP6 silencing abolished TGF-β1-triggered FMT. Mechanistically, TGF-β1 stimulation facilitated the translocation of IGFBP6 in cardiac fibroblasts, where its N-terminal domain directly interacted with early growth regulator 1 (EGR1). This interaction enhanced EGR1 binding to the promoter of microfibril-associated protein 4 (MFAP4), a pro-fibrotic mediator. Overexpression of MFAP4 significantly reversed the protective effects by IGFBP6 knockout in cardiac fibroblast transition and adverse remodeling post-MI. Conclusion: Our study identifies fibroblast-derived IGFBP6 as a novel regulator of cardiac fibrosis through the EGR1-MFAP4 signaling axis, driving myofibroblasts differentiation and adverse remodeling. Targeting this pathway may offer therapeutic potential for cardiac remodeling disorders.

N⁶-methyladenosine (m⁶A), a well-known adenosine modification with newly recognized epigenetic functions, reportedly participates in the development of diverse liver diseases. Methyltransferases and demethylases, commonly referred to as "writers" and "erasers", respectively, play crucial roles in maintaining the balance of m⁶A modification. In liver disease research specifically, the functioning of these enzymes has piqued significant interest, revealing new perspectives on molecular pathogenic mechanisms. Writer proteins collaborate with co-factors to install m⁶A modification on RNA, while eraser proteins, exemplified by Fto and Alkbh5, remove modifications via different mechanisms. In liver diseases, the two are not simply antagonistic, but rather act jointly to affect disease progression. By focusing this review on the mechanisms of methyltransferases and demethylases in various liver diseases, we seek to enhance comprehension of m⁶A modification's role and support the advancement of related research and treatment strategies.

Papillary thyroid carcinoma (PTC) remains among the most prevalent endocrine malignancies globally, with its incidence steadily rising. Although clinical outcomes are generally favorable, a clinically significant subset of patients exhibits highly aggressive tumor phenotypes, characterized by larger tumor size and increased lymph node metastasis. Accumulating evidence implicates metabolic reprogramming and epigenetic dysregulation as pivotal drivers of tumor progression. Lactate, one of the byproducts of tumor metabolism, has recently garnered attention for its regulatory functions beyond metabolism. Histone lactylation, a recently identified epigenetic modification dynamically regulated by intracellular lactate accumulation, has emerged as an important regulator of tumor proliferation, metastasis, immune evasion, and therapeutic resistance. However, the functional implications and mechanistic underpinnings of histone lactylation in PTC remain largely unexplored. Here, we report significantly elevated pan-lysine lactylation and histone H3 lysine 18 lactylation (H3K18la) levels in clinical PTC specimens, with tumor tissues exhibiting markedly higher levels compared to adjacent normal thyroid tissues., correlating positively with aggressive clinicopathological features. Relevant cellular phenotypic assays further support this conclusion. Mechanistically, we demonstrate that H3K18la modification directly facilitates the transcriptional activation of Signal Transducer and Activator of Transcription 1 (STAT1). Activated STAT1 subsequently promotes transcriptional upregulation of Lactate Dehydrogenase A (LDHA), thereby enhancing lactate biosynthesis and establishing a self-perpetuating positive feedback loop. Consequently, tumor-derived lactate orchestrates and sustains malignant progression in PTC through this "H3K18la-STAT1-LDHA" regulatory axis. Collectively, our findings uncover a novel mechanistic linkage between tumor metabolism and epigenetic regulation in PTC, providing critical insights into thyroid cancer pathogenesis. Furthermore, therapeutic targeting of the H3K18la-STAT1-LDHA axis may represent an innovative and promising strategy to improve outcomes for patients with aggressive and refractory PTC.

Human pluripotent stem cell (hPSC)-derived alveolar organoids have emerged as valuable tools for studying lung development, modeling pulmonary diseases, and drug discovery, though their application has been hindered by laborious differentiation protocols and technical complexity. Here, we present an hPSC-derived alveolar organoid (hALO) system with exceptional long-term expandability (>30 passages), efficient cryopreservation resilience, and streamlined production achieved through earlier 3D culture initiation and elimination of cell sorting requirements. Transcriptomic analysis across passages confirmed hALOs contain alveolar progenitors and AT2 lineages, recapitulating pseudoglandular-to-canalicular development while partially maintaining adult AT2 immune-related functions. The system permits alveolar epithelial differentiation via pharmacological modulation of WNT/YAP signaling or through orthotopic transplantation, while multiplex genetic engineering enables programmable disease modeling and adenocarcinoma pathogenesis studies. These versatile capabilities establish hALOs as a robust dual-phase platform for mechanistic investigation of lung epithelial biology and disease modeling across in vitro and in vivo environments.

The development of physiologically relevant in vitro 3D models is crucial for studying lung biology and disease mechanisms. While airway organoids have significantly improved our ability to mimic lung tissue, they lack key nonepithelial components that are essential for tissue homeostasis. Here, we describe the generation of human airway assembloids, combining airway organoids, stromal fibroblasts, and endothelial cells to better replicate the native lung environment. The model was generated from healthy lung tissue donors by using a scaffold-free culture system to promote cell self-organization. Assembloids exhibited long-term viability, maintained typical airway epithelial markers, and demonstrated functional characteristics, such as mucus production and ciliary beating. This technology provides a powerful platform for studying airway physiology, disease mechanisms, and therapeutic approaches, with potential applications in regenerative and personalized medicine. Our study established a novel, reproducible 3D assembloid model of the human airways, bridging the gap between traditional organoid cultures and complex tissue engineering strategies.