BMB Reports最新文献

Glioblastoma (GBM) frequently expresses cytomegalovirus (CMV) antigens, making CMV-specific CD8＋T cells attractive candidates for adoptive immunotherapy due to their longevity and inherent tumor reactivity. However, these T cells encounter significant immunosuppressive challenges within the GBM microenvironment, including cytokine scarcity and checkpointmediated inhibition, which limit their proliferation and function. Here, we assessed strategies to overcome these limitations by modulating immune checkpoint pathways. Antigen stimulation combined with IL-2 robustly expanded high-avidity (tetramer-high) CMV-specific T cells with significant enrichment of CD62L＋ central memory (TCM) cells. In contrast, antigen stimulation alone modestly expanded tetramer-high cells with limited TCM enrichment. PD-L1 blockade in the absence of IL-2 favored expansion of tetramer-high CMV-specific CD8＋T cells, preserved CD62L expression, and enhanced CD226 expression. Furthermore, combining anti-PD-L1 blockade with an anti-CD226 agonist markedly enhanced proliferation, IFN-γ production, and TCM enrichment in both tetramer-high and tetramer-low populations, reaching levels comparable to IL-2-supported conditions. Together, these findings highlight that simultaneous modulation of PD-L1 and CD226 pathways can restore CMV-specific T cell function, offering a promising strategy to boost TCR-T efficacy in cytokine-deprived environments. [BMB Reports 2025; 58(7): 307-312].

Base editors, including adenine base editors (ABEs) and cytosine base editors (CBEs), are widely used in numerous organisms to introduce site-specific sequence modifications in genomic DNA without causing double-strand breaks (DSBs). However, these editors exhibit low editing efficiencies, particularly in dicot plants, thereby limiting their application in dicot plant genome engineering. In this study, we assessed the editing efficiencies of various base editors to identify those optimal for base editing in dicot plants. We discovered that ABE8e, an ABE variant, demonstrated superior A-to-G base editing efficiency within A5-A8 windows, and A3A/Y130F-V04, a CBE variant, exhibited the highest C-to-T base editing efficiency within C4-C15 windows in both Arabidopsis and soybean protoplasts. Overall, we recommend these two base editors as prime choices for efficient genome engineering in a range of crop plants. [BMB Reports 2025; 58(7): 288-292].

Quiescent cancer cells (QCCs) are considered an origin of cancer recurrence and present an ongoing challenge in cancer treatment. Following anti-cancer therapy, non-proliferating, therapy-resistant QCCs have been detected as subsets of residual cancer cells within patients. Clinicians and researchers widely believe that these minimal residual QCCs can eventually regain proliferative activity, acting as "seeds" for cancer recurrence. Despite the significance of QCCs, tracing and analyzing these microscopic residual cells in vivo models and patients remains extremely challenging, limiting our understanding. Consequently, reliable biomarkers for QCCs and the mechanisms underlying their 'reversible' reactivation are still poorly understood. This knowledge gap has hindered the development of diagnostics and targeted therapies for QCCs. The absence of diagnostic tools for QCCs also complicates predicting cancer relapse and determining the optimal duration of anti-cancer treatment. Moreover, without strategies to eradicate QCCs, preventing cancer recurrence remains elusive. This review aims to provide an overview of the current understanding of QCCs and related diagnostic efforts in both basic and clinical research. Additionally, potential strategies for the targeted elimination of QCCs are explored. Focused research and clinical attention to diagnosing and eradicating residual QCCs are essential for preventing cancer recurrence and ultimately conquering this deadly disease. [BMB Reports 2025; 58(7): 277-287].

Accumulating data have shown that targeting breast cancer stem cells (CSCs) is an auspicious way for anticancer therapies. This study demonstrated that the antirheumatic drug auranofin is a potent CSC inhibitor with anti-CSC action on breast cancer. This research focused on investigating the effect of auranofin on breast cancer and CSCs and its cellular mechanism. Mammosphere formation, colony formation, levels of CD44high/CD24low, and aldehyde dehydrogenase 1 expression in the cells were evaluated after auranofin treatment. The anti-CSC properties of auranofin were further examined by gel shift assay and cytokine detection. Auranofin suppressed cell growth, colony formation, migration, and mammosphere formation and triggered apoptosis in breast cancer. Auranofin decreased the CD44high/CD24low- and aldehyde dehydrogenaseexpressed subpopulations, as well as the Stat3-DNA interaction and phosphorylated Stat3 level. Auranofin also decreased the extracellular levels of interleukin-8 (IL-8) in the mammosphere media. Auranofin suppressed the Stat3/IL-8 signal and killed CSCs; therefore, it may be a potential target for CSCs. [BMB Reports 2025; 58(7): 293-299].

Diesel exhaust particles (DEPs), a major component of air pollution, are well-known to induce inflammation and vascular dysfunction. However, the molecular mechanisms linking DEP exposure to the disruption of the blood–retina barrier (BRB) remain poorly understood. Toll-like receptors (TLRs), particularly TLR2 and TLR4, play critical roles in inflammatory signaling and may contribute to DEP-induced retinal endothelial dysfunction. This study investigates the involvement of TLR2 and TLR4 in mediating DEP-induced disruption of the BRB and evaluates the protective effects of TLR inhibition using both in vitro and in vivo experiments. U937 human macrophages were exposed to DEPs of ultrafine size (＜0.2 μm), and the mRNA expression of TNF-α and IL-1β was quantified. Conditioned media from DEP-exposed U937 cultures were then used to treat human retinal endothelial cells (HRECs). DEP exposure significantly increased TNF-α and IL-1β mRNA expression in U937 macrophages. Conditioned media from DEP-exposed U937 macrophages reduced claudin-5 and ZO-1 expression in HRECs, resulting in increased BRB permeability. Inhibition of TLR2 and TLR4 using C29 and TAK242, respectively, significantly attenuated TNF-α and IL-1β mRNA expression in DEP-exposed U937 macrophages and preserved BRB integrity by maintaining claudin-5 and ZO-1 expression in HRECs. In the mouse model, DEP exposure caused a marked reduction in claudin-5 and ZO-1 levels in retinal vessels, whereas treatment with C29 and TAK242 mitigated the loss of these tight junction proteins. This study demonstrates that DEPs induce inflammation and BRB dysfunction through TLR2 and TLR4 activation, leading to increased vascular permeability and potential retinal damage. Furthermore, TLR2 and TLR4 inhibition may be a promising therapeutic strategy to protect retinal health from air pollution–induced damage. [BMB Reports 2025; 58(7): 300-306].

Skin aging is a complex biological process driven by intrinsic and extrinsic factors, leading to a progressive structural and functional decline. The balance between extracellular matrix (ECM) degradation and synthesis is critical for maintaining skin homeostasis, with collagen loss and reduced cell proliferation contributing to age-related deterioration. Serpin Family A Member 3 (SERPINA3), a serine protease inhibitor, has been implicated in inflammation and tissue remodeling. However, its role in skin aging remains largely unexplored. In this study, we examined the expression and function of SERPINA3 in human skin cells. RNA-seq analysis revealed that SERPINA3 expression is significantly downregulated in aged human dermal fibroblasts and was further diminished under oxidative stress. Functional assays demonstrated that SERPINA3 promotes cell proliferation, accelerates wound healing, and activates key signaling pathways such as ERK and AKT. These findings suggest that SERPINA3 may serve as a protective factor against skin aging by supporting ECM integrity and enhancing cellular regeneration. These results provide novel insights into the molecular functions of SERPINA3 and highlight its potential as a therapeutic target for age-related skin deterioration. [BMB Reports 2025; 58(6): 264-268].

Exercise is a key driver of metabolic enhancement, and the impact of exercise on methyltransferase-like14 protein (Mettl14)-mediated N⁶-methyladenosine (m⁶A) modification remains unexplored. This study investigates the role of Mettl14 in inguinal white adipose tissue (iWAT) concerning exercise-induced metabolic improvement and its underlying mechanisms. We examined voluntary wheel-running exercise in C57BL/6N mice and Mettl14 heterozygous knockout (HET) mice models. We assessed metabolic phenotyping and molecular responses through body composition analysis, blood profiles, indirect calorimetry, real-time PCR, immunoblotting, and immunohistology. m⁶A levels were significantly elevated in the iWAT of trained mice, a result of increased Mettl14 expression. Additionally, higher Mettl14 levels induced by exercise were positively associated with browning markers in iWAT. Mettl14 HET led to increased weight gain and fat accumulation in a mechanism dependent on m⁶A levels. Furthermore, HET mice demonstrated notable reductions in oxygen consumption and energy expenditure at baseline. m⁶A levels were notably reduced in the iWAT of exercise-induced HET mice, yet the associated metabolic impairment was significantly mitigated. Exercise substantially correlates with enhanced browning and metabolic improvements by modulating m⁶A levels through Mettl14 expression in iWAT. However, this pathway does not critically regulate exercise-induced browning and the enhancement of whole-body metabolism. [BMB Reports 2025; 58(6): 269-275].

Alternative splicing (AS) dysregulation is increasingly recognized as a critical factor in cancer progression and drug response. However, precisely detecting and characterizing complex splicing events, particularly those involving microexons, remains technically challenging. Ribosomal Protein 24 (RPS24), which contains three microexons (3, 18, and 22 bp), serves as an ideal model for studying complex AS regulation in cancer. We developed a high-resolution detection method for RPS24 microexon variations and investigate their relationship with KRAS proto-oncogene, GTPase (KRAS) inhibition in lung adenocarcinoma (LUAD) to identify potential biomarkers for KRAS-targeted inhibitors. We established an integrated methodological approach combining RNA-seq analysis with fragment analysis to detect RPS24 AS patterns. Using this method, we analyzed RPS24 AS across a panel of lung cancer cell lines and examined AS changes in KRAS-mutant cell lines following treatment with KRAS inhibitors. Our method successfully characterized distinct RPS24 AS isoform compositions across lung cancer cell lines, demonstrating high accuracy in detecting 3 bp variations. In KRASmutant cell lines, we observed a consistent upregulation of the 3 bp-containing isoform following KRAS inhibition, indicating a specific correlation with treatment response. This study provides a robust methodology for analyzing complex AS events and supports the RPS24 3 bp-containing isoform as a potential biomarker for KRAS inhibitor response in LUAD. These findings offer new insights into the molecular mechanisms of KRAS inhibitor therapy and strategies for monitoring treatment response. [BMB Reports 2025; 58(6): 244-249].

Ferroptosis, an iron-dependent form of programmed cell death, is primarily driven by the accumulation of lipid peroxides through radical generation, notably via the Fenton reaction. Emerging evidence highlights the intricate link between ferroptosis and cellular metabolism, with metabolic enzymes playing pivotal roles in its regulation. Sulfide quinone oxidoreductase (SQOR), traditionally recognized for its role in hydrogen sulfide (H2S) detoxification and electron transport chain (ETC) activation, has recently been identified as a promiscuous enzyme with a novel function in ferroptosis regulation. This review explores SQOR's canonical function in H2S metabolism and its emerging role in ferroptosis resistance through the production of ubiquinol and hydropersulfides, radical-trapping antioxidants. Additionally, we provide insights into potential future research directions, emphasizing SQOR's therapeutic relevance in ferroptosis-associated diseases. [BMB Reports 2025; 58(6): 233-237].

Leukocyte cell-derived chemotaxin 2 (LECT2), a secreted protein, is implicated in various physiological and pathological processes. As a hepatokine, LECT2 is predominantly synthesized and secreted by hepatocytes, with elevated levels being associated with multiple human inflammatory diseases. Although LECT2 plays a critical role in liver and systemic inflammation, the intracellular signaling mechanisms governing its expression under inflammatory conditions remain unclear. This study demonstrates that lipopolysaccharide (LPS) directly induces LECT2 expression in AML12 mouse hepatocytes. Use of a TLR4-specific inhibitor confirmed that LPS-induced LECT2 expression is mediated via its canonical receptor, TLR4. Furthermore, the p38 MAPK pathway was identified as a key mediator of this response, as evidenced by pharmacological modulation with a p38-specific inhibitor and agonist. Promoter analysis of the Lect2 gene revealed the presence of a putative AP-1-like binding site, suggesting transcriptional regulation by AP-1. Overexpression of c-Fos and c-Jun, along with ChIP-qPCR analysis, confirmed that AP-1 directly binds to Lect2 promoter, and regulates its transcription in response to LPS. Together, these findings reveal a novel TLR4/p38 MAPK/AP-1 signaling axis that, during inflammation, regulates LECT2 expression in hepatocytes, providing new insights into the molecular mechanisms underlying liver inflammation and LECT2-mediated pathophysiology. [BMB Reports 2025; 58(6): 250-256].