JOURNAL OF CELLULAR AND MOLECULAR MEDICINE最新文献

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.

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.

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.

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.

RETRACTION: M. Balliu, L. Guandalini, M.N. Romanelli, M. D'Amico and F. Paoletti, “ HDAC-Inhibitor (S)-8 Disrupts HDAC6-PP1 Complex Prompting A375 Melanoma Cell Growth Arrest and Apoptosis,” Journal of Cellular and Molecular Medicine 19, no. 1 (2015): 143–154, https://doi.org/10.1111/jcmm.12345.

The above article, published online on 06 November 2014 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 & Sons Ltd. The retraction has been agreed upon following an investigation into concerns raised by a third party. The investigation identified duplication involving α-tubulin bands in Figure 3A and AKT bands in Figure 3D. Furthermore, the GAPDH bands presented in Figure 7C appear to be duplicated in another article published later by two of the same authors. The authors were invited to comment on the concerns and provide supporting data. While the authors cooperated with the investigation and provided some data, the data did not correspond to the published images. Given the nature of the concerns, the editors have lost confidence in the results and conclusions. The authors disagree with the retraction.

RETRACTION: Z. Sun, S. Gao, L. Xuan, and X. Liu, “ Long Non-Coding RNA FEZF1-AS1 Induced Progression of Ovarian Cancer via Regulating miR-130a-5p/SOX4 Axis,” Journal of Cellular and Molecular Medicine 24, no. 7 (2020): 4275–4285. https://doi.org/10.1111/jcmm.15088.

The above article, published online on 05 March 2020 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Stefan Constantinescu; and John Wiley & Sons Ltd. A third party reported multiple instances of image duplications between this article and previously published articles. All images in Figure 2C had previously been published in [Zhu et al. 2019 (https://doi.org/10.1038/s41467-023-41612-z)] and reported as different samples. All images in Figures 3A, 3B, 4C, and 4D had previously been published in Li et al. 2017 [(https://doi.org/10.1038/cddis.2017.119)] and reported as different samples. The GAPDH band in Figure 5D and all bands in Figure 5H had previously been published in [Liu et al. 2017 (https://doi.org/10.1186/s12943-017-0625-8)] and all those images were manipulated and rotated. Furthermore, multiple images in Figure 5E had previously been published in Liu et al. 2017, where further manipulation and rotation had been applied to these images.

An investigation by the publisher confirmed these concerns and discovered additional instances of image duplication from other articles. Data in Figure 2D had previously been published in [Liang et al. 2018 (https://doi.org/10.1038/s41419-018-0582-1)], [Wang et al. 2019 (https://doi.org/10.18632/aging.102081)] and [Liang et al. 2020 (https://doi.org/10.1186/s12943-020-01206-5)]. Images in Figure 2C had previously been published in [Zhu et al. 2019 (https://doi.org/10.1038/s41467-018-07998-x)] and these images had been rotated. Multiple images in Figure 5E that were also previously published in Liu et al. 2017, were also later published in [Li et al. 2021 (https://doi.org/10.2147/OTT.S302800)].

The retraction has been agreed to because the evidence of image re-use and manipulation with multiple previously published articles fundamentally compromises the editors’ confidence in the results presented. The authors did not respond to our notice regarding the retraction.