International Journal of Biological Sciences最新文献

Chimeric antigen receptor (CAR)-T cell therapy represents a breakthrough in cancer immunotherapy, demonstrating impressive clinical outcomes, particularly for hematologic malignancies. However, its broader therapeutic application, especially against solid tumors, remains limited. Key challenges include T cell exhaustion, limited persistence, cytokine-mediated toxicities, and logistical hurdles associated with manufacturing autologous products. Emerging gene editing technologies, such as CRISPR/Cas systems, base editing, and prime editing, offer novel approaches to optimize CAR-T cells, aiming to enhance efficacy while managing toxicity and improving accessibility. This review comprehensively examines the current landscape of these gene editing tools in CAR-T cell therapy, highlighting the latest advancements, persisting challenges, and future directions. Leveraging gene editing holds the potential to transform CAR-T therapy into a more potent, safer, and broadly applicable modality for cancer and beyond.

This review underscores the dynamic role of the extracellular matrix (ECM) in regulating cellular behavior and maintaining tissue homeostasis, highlighting its pivotal involvement in aging, calcification, and cancer diseases. In healthy tissues, controlled ECM remodeling provides essential biochemical and mechanical cues, but dysregulation (driven by chronic inflammation, cellular senescence, and altered intercellular communication) leads to fibrosis, calcification, and the creation of a pro-tumorigenic microenvironment. Senescent cells contribute to these changes through senescence-associated secretory phenotype (SASP), which reinforces inflammation and matrix degradation, while extracellular vesicles (EVs) mediate intercellular signaling and further modulate ECM structure and function. In cancer, ECM remodeling not only facilitates tumor progression and metastasis by forming physical and biochemical barriers but also hinders the efficacy of conventional and immunotherapeutic interventions. Similarly, in cardiovascular diseases, aberrant ECM remodeling exacerbates tissue damage and impairs regenerative processes. Emerging therapeutic strategies aim to restore ECM homeostasis through targeted interventions, including ECM-normalizing agents, EV-based therapies, and stem cell approaches that modulate matrix composition to improve tissue repair. By elucidating the complex interplay between ECM dysfunction, cellular senescence, and chronic inflammation, this review highlights promising avenues for developing personalized treatments that address the underlying causes of age-related and tumorigenic pathologies, ultimately, the way to improved clinical outcomes.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of human malignancy, and there is an urgency to develop more effective therapy. We previously showed that Metavert, a dual inhibitor of glycogen synthase kinase 3-beta (GSK-3β) and histone deacetylases (HDACs) prevents pancreatic ductal adenocarcinoma (PDAC) metastasis. In this study, we investigated the mechanisms that mediate metastasis and the roles of GSK-3β, HDACs, and Yes-associated protein (YAP) in this process. We found that HDAC4 and YAP are highly expressed in PDAC from patients with rapid disease progression and metastasis compared to those with prolonged recurrence-free survival. Pan-HDAC inhibition decreases metastasis in the splenic PDAC metastatic mouse model. Inhibition of HDAC4 reduces migration of cancer cells and decreases the mRNA and protein levels of transcription factor MYB Proto-Oncogene Like 1 (MybL1) and YAP. Mechanistic studies show that HDAC4 regulates transcription of YAP through up-regulating MybL1 expression. Comparable results were observed in colon and prostate cancers. ATAC-seq studies show that inhibition of HDAC4 causes chromatin remodeling in the YAP promoter region and reduces accessibility to the binding sites of multiple transcription factors, including those of MybL1. Pharmacological or molecular inhibition of YAP significantly decreases PDAC metastasis in vivo. Imaging Mass Cytometry (IMC) reveals no significant changes in immune cells, but a notable shift in the distribution patterns of cancer-associated hepatic stellate cells in the metastatic niche, when YAP is ablated in the cancer cells. The results demonstrate a novel metastasis-driving cell signaling pathway mediated by the functional interaction between HDAC4 and MybL1, which regulates YAP expression and metastasis.

Colorectal cancer (CRC) is one of the most common malignant cancers worldwide and its poor prognosis is mainly caused by metastasis. Although extensive studies, the potential molecular mechanisms of CRC metastasis are not fully understood. In the present study, we found that ETV4 was remarkably upregulated in CRC and its overexpression correlated with lymph node metastasis. ETV4 could significantly promote the growth, epithelial-mesenchymal transition (EMT) and metastasis of CRC cells in vitro and in vivo. Mechanistic investigations found that LOXL2 was a novel transcriptional target and a direct interacting partner of ETV4 and was vital to ETV4-induced CRC malignant phenotypes. Further studies revealed that ETV4/LOXL2 complex could bind NID1 promoter to mediate its demethylation, induce NID1 expression and subsequent ERK signaling pathway activation, which is required for ETV4/LOXL2-mediated EMT and metastasis of CRC. Meanwhile, the expression of ETV4 and LOXL2 were significantly negatively correlated with the methylation of NID1 promoter in clinical samples. Besides, the combined ETV4, LOXL2 and NID1 as prognostic markers is more reliable than any one alone. Taken together, in this study, we demonstrated that ETV4 played a critical role in CRC metastasis, and unraveled the novel regulatory axis of ETV4/LOXL2/NID1, which contributed to the malignant progression of CRC.

Homocysteine (Hcy) is an age-related risk factor for erectile dysfunction (ED), with enhanced vascular toxicity in middle-aged and elderly individuals. However, folate-based Hcy-lowering therapies have shown limited efficacy, necessitating a reevaluation of its age-dependent pathogenic mechanism. Here, we demonstrate that senescent endothelial cells exhibit heightened responsiveness of methionyl-tRNA synthetase 1 (MARS1) to Hcy, promoting the production of homocysteine thiolactone (HTL) and widespread N-homocysteinylation (K-Hcy) of proteins. K-Hcy, rather than acetylation, drives cytoplasmic translocation and extracellular release of high mobility group box proteins 1 and 2 (HMGB1/2), amplifying the senescence-associated secretory phenotype (SASP). Competitive inhibition of MARS1 with N-acetylcysteine (NAC) attenuates endothelial senescence and improves erectile function in middle-aged individuals with hyperhomocysteinemia by reducing HTL, rather than Hcy itself, while synergizing with tadalafil. Collectively, our findings highlight the pivotal role of the age-dependent MARS1-HTL axis in the pathogenesis of homocysteine-induced ED, offering a promising therapeutic strategy for ED in the aging population.

Muscle-invasive (MI) urothelial carcinoma (UC) is a clinically challenging malignancy with a poor prognosis. Understanding the cellular dynamics that drive UC progression is critical for the development of optimized therapeutic strategies. Through integrative analysis of large-scale single-cell transcriptomic datasets from non-muscle-invasive (NMI) and MI tumours and validation with spatial transcriptomic datasets, we systematically characterized immune cell dynamics and cancer cell plasticity during UC progression. Our analysis revealed an immunosuppressive tumour microenvironment and a subset of cancer cells with upregulated major histocompatibility complex II (MHC-II) expression in MI tumours. Notably, MHC-II⁺ cancer cells were induced by interferon-γ signalling, as confirmed through in vitro experiments, and exhibited phenotypic alterations characterized by enhanced proliferative and migratory capacities. Furthermore, MHC-II⁺ cancer cells spatially colocalized with CD8⁺ T cells, regulatory T cells, and SPP1⁺ macrophages, where they engaged with inhibitory receptors on these immune cells, promoted CD8⁺ T cell exhaustion and facilitated immune evasion.

The lack of expandable human hepatocytes in vitro hampers the clinical application of the bioartificial liver. Previous studies have shown that chemical cocktails containing growth factors can support long-term expansion of hepatocytes through dedifferentiation. Here, it is revealed that chemokine (C-C motif) ligand 2 (CCL2) is a key factor in liver regeneration. CCL2 could promote the long-term expansion (over 30 passages) of human primary hepatocytes and enhancing their proliferative efficiency. Subsequently, CCL2-mediated proliferation of hepatocytes can effectively expand in vitro, and repopulate the liver of Fah^-/- mice following 2-(2-nitro-4-trifluoromethylbenzyol)-1,3- cyclohexanedione (NTBC) withdrawal. Further studies revealed that CCL2-mediated hepatocyte proliferation could yield a sufficient number of highly active and well-functioning hepatocytes, crucial for supporting Bioartificial liver (BAL) therapy in treating acute liver failure (ALF) in a porcine model. Mechanically, BAL therapy effectively suppresses inflammatory responses, promotes liver regeneration, and subsequently protects extrahepatic organs, leading to improved survival rates in ALF porcine models.

α-hederin is a natural compound that is used to treat colorectal cancer (CRC). However, the precise anti-CRC mechanism needs to be explored further, and its direct targets have not yet been reported. In the present study, for the first time, we revealed that α-hederin directly targeted ubiquitin specific peptidase 5 (USP5), decreased its expression, weakened its interaction with signal transducer and activator of transcription 3 (STAT3), and disrupted STAT3 deubiquitination, thereby inhibiting colorectal tumorigenesis. This is particularly significant because STAT3 is a key mediator of inflammation and tumorigenesis, and targeting STAT3 deubiquitination represents a promising pathway for combating CRC; however, its deubiquitination mechanism in CRC remains unclear. USP5, a deubiquitinating enzyme (DUB) involved in inflammatory responses that is highly expressed in primary CRC tissues and promotes tumorigenesis by stabilizing tumor proteins, was identified in our study as a novel DUB of STAT3. In addition, we showed that USP5 serves as an oncogene in CRC by deubiquitinating STAT3, which contributes to CRC progression. Overall, our study provided evidence that α-hederin exhibits significant potential in suppressing colorectal tumorigenesis by disrupting USP5-mediated STAT3 deubiquitination.

Radiotherapy is a primary treatment for glioblastoma (GBM), yet its effectiveness is limited by frequent recurrence due to radioresistance. Our previous studies have illustrated that GDF15 is highly expressed in radioresistant GBM cells and correlates strongly with recurrent GBM tissue. However, its role in radioresistance remained unclear. Here, we demonstrate that GDF15 promotes radioresistance by suppressing ferroptosis and altering the immune microenvironment. Mechanistically, GDF15 alleviates radiation-induced ferroptosis by stabilizing NRF2 protein through reduced ubiquitin-mediated degradation. Additionally, after radiation, GDF15 promotes M2 type macrophage infiltration, fostering an immunosuppressive microenvironment that further supports radioresistance. These findings emphasize GDF15 as a key mediator of GBM radioresistance and a potential therapeutic target to improve radiotherapy outcomes.

Background: Gastric cancer (GC), a prevalent and life-threatening malignancy, poses significant challenges in diagnosis and prognosis due to its complex molecular pathogenesis. Identifying novel biomarkers and therapeutic targets is crucial for advancing treatment strategies and improving patient outcomes. This study investigates the role of synaptotagmin-4 (SYT4), recently identified as an oncogene, in GC development. Methods: We integrated proteomic and clinical analyses to evaluate SYT4 expression levels and their correlations with clinical features. Bioinformatic and clinicopathological assessments further validated SYT4's clinical relevance. Through comprehensive in vitro and in vivo experiments-including immunoprecipitation-mass spectrometry (IP-MS), co-immunoprecipitation (Co-IP), GST pull-down assays, and TOP/FOP luciferase reporter assays-we delineated SYT4's biological functions and interaction mechanisms. Additionally, we investigated the therapeutic potential of borussertib, a specific SYT4 inhibitor, in suppressing GC tumorigenicity. Results: SYT4 expression was significantly upregulated in GC tissues and strongly correlated with poor prognosis. Functionally, SYT4 drove cell proliferation, promoted cell cycle progression, and suppressed apoptosis in both cellular and animal models. Mechanistic investigations revealed that SYT4 directly interacts with PSMC6 via its C2B domain (amino acids 288-423), and stabilizes PSMC6 protein, thereby activating the Wnt/β-catenin signaling pathway. Notably, borussertib, a targeted SYT4 inhibitor, markedly suppressed SYT4 activity, leading to attenuated GC progression. Conclusion: Our findings demonstrate that SYT4 is a critical driver of GC progression via activation of the Wnt/β-catenin pathway. Moreover, we uncovered a novel mechanism by which borussertib selectively inhibits SYT4's oncogenic activity, providing compelling evidence for its therapeutic potential in gastric cancer treatment.