JOURNAL OF CELLULAR AND MOLECULAR MEDICINE最新文献

Kruppel-like factors (KLFs) constitute a crucial family of transcription factors that are engaged in a variety of biological processes, such as erythropoiesis as well as liver development. A growing body of research underscores the increasing importance of the KLF family in the context of hepatocellular carcinoma (HCC). Despite this, the exact function of KLF1 within HCC remains unclear. Our study demonstrates a significant upregulation of KLF1 expression in tumour samples from HCC patients compared to normal liver tissue, with higher expression levels strongly correlating with poorer survival outcomes. Notably, in vitro experiments have shown that KLF1 enhances liver cancer cell proliferation by inhibiting ferroptosis, and this inhibition is negatively correlated with the transcription levels of fatty acid synthase 4 (ACSL4). These findings suggest that KLF1 may exert its oncogenic potential by repressing ferroptosis through the inhibition of ACSL4 transcription. Further mechanistic investigations reveal that KLF1 inhibits ACSL4 expression via transcriptional repression and suppresses ferroptosis through the ACSL4/LPCAT3 axis, ultimately promoting HCC tumour growth as well as its advancement. In conclusion, KLF1 is essential for onset as well as development in HCC through inhibiting ACSL4 transcription along with ferroptosis, thereby presenting novel therapeutic targets for HCC treatment.

Lipid metabolism reprogramming is one of the most prominent characteristics of cancer, but it is still unclear which regulatory pathways underlie this process in cancer cells. Circular RNAs (circRNAs) represent a novel category of non-coding RNAs with multifaceted regulatory functions. While the biological roles of circRNAs in cancer have been elucidated, there remains a dearth of knowledge regarding their involvement and regulatory mechanisms in lipid metabolism within the context of cancer. This article provides an overview of the regulatory roles and specific mechanisms of circRNAs in cancer lipid metabolism reprogramming. By elucidating these mechanisms, it enhances our comprehension of the metabolic rewiring driving tumour development and uncovers new avenues for targeted therapy.

High mobility group box 1 (HMGB1), a prototypical alarmin and chromatin-binding protein, has emerged as a critical mediator of tumour-associated inflammation and immune regulation. Although its soluble form has been implicated in various malignancies, the functional contribution of HMGB1 encapsulated within exosomes remains incompletely understood, particularly in the context of non-small–cell lung cancer (NSCLC). We profiled exosomal HMGB1 levels in the peripheral blood of 80 clinically annotated NSCLC patients and correlated its abundance with metastatic burden and survival outcomes. Functional experiments using HMGB1-overexpressing NSCLC cell lines were conducted to assess proliferative, migratory and stemness-associated phenotypes in vitro, alongside tumorigenicity and drug responsiveness in vivo. Mechanistic interrogation of the TLR4/NF-κB/IL-6/STAT3 signalling axis was performed via western blotting, ELISA, immunofluorescence and targeted pharmacologic inhibition. The impact of exosomal HMGB1 on macrophage plasticity was evaluated using THP-1-derived macrophage models, and therapeutic relevance was validated in murine tumour models under immunotherapy and chemotherapy regimens. Circulating exosomal HMGB1 levels were significantly elevated in patients with metastatic NSCLC and strongly correlated with poor prognosis. Exosomal HMGB1 markedly enhanced tumour cell proliferation, motility and self-renewal capacity, while promoting chemoresistance and immune evasion. Mechanistically, HMGB1-enriched exosomes activated the TLR4/NF-κB axis, elevating IL-6 secretion and subsequent STAT3 phosphorylation. These effects were further linked to the polarisation of macrophages towards an immunosuppressive M2 phenotype. Therapeutically, cotargeting STAT3 signalling overcame exosomal HMGB1–mediated resistance to paclitaxel in vivo. Our findings delineate a previously unrecognised exosome-mediated mechanism by which HMGB1 drives NSCLC progression and modulates the tumour immune microenvironment. Exosomal HMGB1 not only serves as a potential prognostic biomarker but also represents a tractable target for enhancing the efficacy of immuno- and chemotherapeutic strategies in NSCLC.

Hepatocellular carcinoma (HCC), accounting for over 90% of primary liver cancers, remains a major global challenge for healthcare professionals. While immunotherapy has transformed the landscape of cancer treatment, its success is often limited by immune resistance, particularly through T cell exhaustion which remains a major barrier to effective immune responses in solid tumours, including HCC. As tumours progress, T cells undergo a gradual loss of functionality due to continuous antigen exposure and fail to exert effective anti-tumour responses. During this process, alterations in the epigenome, transcriptome, signalling pathways, and tumour metabolome, in addition to interactions with other cells in the tumour microenvironment, efficiently contribute to T cell exhaustion. Restoring T cell function brings hope for improving therapy outcomes and providing new treatment modalities for HCC patients. In this review, we explore the key cellular and molecular mechanisms driving T cell exhaustion, including the roles of immunosuppressive cells, metabolic stress, and epigenetic alterations focusing on HCC. We also discuss current and emerging strategies aimed at preventing or reversing T cell exhaustion, such as epigenetic modulation, immune checkpoint blockade, metabolic reprogramming, and combination therapies. Understanding these interconnected pathways is critical for designing more effective immunotherapy-based approaches for liver cancer.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, posing a global health challenge. It affects millions of people, causing cognitive decline and a heavy burden on healthcare systems. Neuroinflammation is a key pathological feature of AD, often associated with the dysregulation of microRNAs such as hsa-miR-146a-5p. WGX50 (N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-3-phenyl-acrylamide), a small molecule derived from Zanthoxylum bungeanum Maxim, has antioxidant and anti-inflammatory activities. While WGX50 demonstrates potent inhibition of neuroinflammation, its poor blood–brain barrier permeability may be improved using targeted delivery strategies. The current study aimed to design a novel nanoconjugate of WGX50 and curcumin with gold nanoparticles (AuNPs) to observe its therapeutic effects in a rat model. All nanoconjugates were synthesised as targeted (Cys-capped AuNPs with WGX50-insulin and curcumin-insulin) and non-targeted (without insulin). Immunohistochemical analysis revealed that both non-targeted (WGX50-NT) and targeted (WGX50-T) therapies have a significant effect in the rat model, with WGX50-T showing a more pronounced effect. The histopathology results of WGX50 and WGX50-T showed an approximate 80%–90% reduction in Aβ plaque deposition. The treatment with both curcumins targeted (C-T) and non-targeted (C-NT) formulations led to a significant reduction in Aβ levels in AD rats. Fluorescence microscopy confirmed that targeted delivery was more effective, potentially leading to better therapeutic outcomes. The expression levels of hsa-miR-146a-5p showed differential expression levels with targeted treatments correlating with lower expression levels, suggesting a role in modulating neuroinflammation and immune responses. Overall, these findings highlight the potential of targeted drug delivery systems in enhancing the efficacy of AD treatments.

Glucose metabolic reprogramming is a key hallmark of tumour cells, and the designed inhibitors targeting tumour glucose metabolism reprogramming may serve as an effective therapeutic strategy. The ETS Variant Transcription Factor 6 (ETV6) is a potent transcriptional repressor strongly associated with tumorgenesis. However, the precise role and underlying action mechanism of ETV6 in tumour glucose metabolism reprogramming remain unreported. In this study, we demonstrate that the ETV6-miR-429-CRKL regulatory axis contributes to metabolism reprogramming in HCC. Overexpression or knockdown of ETV6 and CRKL enhances or inhibits the Warburg effect and glycogen synthesis in HCC cells both in vitro and in vivo. In contrast, miR-429 overexpression and knockdown exert opposing effects on the Warburg effect compared to the overexpression and knockdown of ETV6 and CRKL. Moreover, miR-429 regulates the rate of glycogen production and degradation by enhancing the activities of GCS and GPa to promote glycogen synthesis, subsequently coupling with the aerobic glycolytic pathway by mediating glycogen shunting. Mechanistically, ETV6 binds to the miR-429 promoter, mediating glucose metabolic reprogramming in HCC cells by targeting CRKL via the PI3K/AKT pathway. Taken together, these findings reveal that the ETV6-miR-429-CRKL regulatory circuitry plays a crucial role in glucose metabolic reprogramming in HCC, offering novel insight and a potential target for cancer therapy.

RETRACTION: W.-L. Zhang, S.-S. Wang, Y.-P. Jiang, Y. Liu, X.-H. Yu, J.-B. Wu, K. Wang, X. Pang, P. Liao, X.-H. Liang, and Y.-L. Tang, “ Fatty Acid Synthase Contributes to Epithelial-Mesenchymal Transition and Invasion of Salivary Adenoid Cystic Carcinoma Through PRRX1/Wnt/β-Catenin Pathway,” Journal of Cellular and Molecular Medicine 24, no. 19 (2020): 11465–11476, https://doi.org/10.1111/jcmm.15760.

The above article, published online on 20 August 2020 in Wiley Online Library (wileyonlinelibrary.com) has been retracted by agreement between the journal Editor-in-Chief, Stefan N. Constantinescu; The Foundation for Cellular and Molecular Medicine; and John Wiley and Sons Ltd. The retraction has been agreed due to concerns raised by third parties. Specifically, instances of image duplication have been identified within Figures 3A and S1. The authors have acknowledged the issues, explaining that they resulted from inaccuracies during figure assembly in manuscript preparation, and have provided the corrected data. However, further post-publication review revealed that the article lacks critical details necessary for reproducing and interpreting the findings, including the sequences for FASN-shRNA, FASN overexpression, PRRX1 overexpression, and their respective negative controls, as well as the absence of a legend for Figure S1. Finally, the article does not sufficiently reference relevant prior literature related to salivary adenoid cystic carcinoma in support of the study's rationale and to contextualize the study's findings, and some cited references have since been retracted, leaving related claims unsupported. Accordingly, the article has been retracted as the editors no longer consider the article's conclusions to be reliable. The authors disagree with the retraction decision.

Renal cell carcinoma (RCC) presents a significant global health challenge, with a substantial proportion of patients diagnosed with advanced or metastatic disease due to the limitations of current diagnostic imaging and the lack of validated non-invasive biomarkers. These conventional methods, including computed tomography and magnetic resonance imaging, often lack the sensitivity and specificity to differentiate benign from malignant small renal masses reliably or to detect minimal residual disease (MRD) post-treatment. This review explores the transformative potential of liquid biopsy, explicitly focusing on circulating tumour DNA (ctDNA) fragmentomics and epigenetic signatures, to overcome these clinical hurdles. This review also explores how the analysis of ctDNA fragmentation patterns—such as size distribution, end motifs, and nucleosome footprints—provides a mutation-independent method to enhance RCC detection, even in low-shedding tumours. Concurrently, RCC-specific epigenetic alterations, particularly DNA methylation profiles, offer particular biomarkers for early detection, tumour classification, and prognostication. This Review examines evidence that integrating these multi-analyte approaches—combining fragmentomic and epigenetic data—synergistically improves diagnostic accuracy, enables sensitive MRD assessment, and allows precision monitoring of treatment response and tumour evolution. Despite existing technical and biological challenges, the convergence of ctDNA fragmentomics and epigenetic profiling heralds a new era for the non-invasive, dynamic, and personalised management of RCC, promising to improve patient outcomes through earlier intervention and tailored therapeutic strategies.

Thymoquinone (TQ), the principal active constituent of Nigella stativa, has demonstrated numerous biological properties and therapeutic effects on various diseases. However, its therapeutic potential against cardiac hypertrophy remains uncertain. This study aims to investigate the protective effects of TQ on stress-induced cardiac hypertrophy and elucidate the underlying mechanisms. Our findings reveal that TQ mitigates stress-induced cardiac hypertrophy in mice and AngII-induced hypertrophy in H9c2 cells. Moreover, TQ inhibits cardiomyocyte ferroptosis and apoptosis by downregulating PTGS2, Bax, and upregulating GPX4, Bcl-2, thereby alleviating cardiac hypertrophy and dysfunction. Mechanistically, the protective effects of TQ against ferroptosis and apoptosis in cardiac hypertrophy were reversed by the PPAR-γ inhibitor (GW9662). In addition, TQ treatment led to increased protein expression levels of P-PI3K and P-AKt. Taken together, our findings suggest that TQ could attenuate cardiac hypertrophy through activation of the PPAR-γ/PI3K/Akt signalling pathway.

Bronchopulmonary dysplasia (BPD) remains a severe complication in premature infants requiring prolonged oxygen therapy, with vascular endothelial dysfunction recognised as a critical contributor to disease progression. Mixed lineage kinase domain-like protein (MLKL)-mediated necroptosis, an essential form of regulated cell death implicated in various pulmonary disorders, has not been fully investigated in the context of BPD. Here, we utilised a neonatal mouse model of hyperoxia exposure to elucidate the role and mechanisms of MLKL-mediated necroptosis in BPD pathogenesis. Our analysis demonstrated morphological characteristics of necroptosis in pulmonary vascular endothelial cells (ECs) under hyperoxic conditions, accompanied by significant elevation of MLKL protein levels and marked upregulation of MLKL gene expression specifically in vascular ECs. Administration of the MLKL inhibitor necrosulfonamide (NSA), either immediately postnatally or at postnatal day 7, effectively mitigated lung injury, preserved alveolar structure and partially restored pulmonary vascular growth. Moreover, MLKL conditional knockout in ECs significantly attenuated both structural and functional pulmonary abnormalities induced by hyperoxia. Collectively, our findings indicate that MLKL-mediated necroptosis in vascular ECs plays a pivotal role in hyperoxia-induced BPD. Therapeutically targeting MLKL to maintain endothelial integrity presents a promising approach to prevent or alleviate BPD in premature infants.