BMB Reports最新文献

Both ethical imperatives and scientific limitations increasingly challenge the traditional reliance on animal models for toxicity testing and drug evaluation, particularly in the era of precision medicine. In response, a paradigm shift is underway, marked by the development of advanced in vitro and in silico technologies that can offer human-relevant and mechanistically informed alternatives. This review examines well-established alternatives, such as receptor binding assays, the monocyte activation test, and enzyme-linked immunosorbent assays, highlighting their applications, mechanisms, and limitations. We further explore emerging human-relevant technologies that include organoids, organ-on-a-chip systems, microphysiological systems, and artificial intelligence-powered modeling platforms. Special emphasis is placed on immune-integrated microphysiological systems as next-generation platforms to evaluate immunotherapy, vaccine responses, and immune toxicities. These models recapitulate dynamic human physiological processes, such as hematopoiesis and germinal center reactions, beyond the capabilities of traditional animal systems. Collectively, these technologies represent scientifically superior and ethically progressive trajectories for preclinical testing. Their integration into regulatory and industrial workflows requires continued refinement, cross-sector collaboration, and standardization.

To advance the development of novel therapies for lung cancer, we investigated tumor-associated molecules implicated in tumorigenesis. RNA-seq data were generated from paired tumors and adjacent normal tissues of four patients with lung squamous cell carcinoma (LUSC) and five patients with lung adenocarcinoma (LUAD). Additional analyses utilized RNA-seq data from The Cancer Genome Atlas (TCGA), including paired tumor and adjacent normal samples (51 LUSC, 57 LUAD) and tumor-only samples (450 LUSC, 461 LUAD). Adjacent normal tissues served as controls. Our RNA-seq results showed strong concordance with TCGA data. Ion channels Aqp1, Aqp4, and Clic5 were significantly downregulated in lung tumors, whereas enzymes involved in membrane lipid metabolism, including phosphatidylcholine (PC), sphingomyelin (SM), and cholesterol (Cho), were upregulated in lung tumors. Cardiolipin (CL), a mitochondrial inner membrane lipid, was downregulated in lung tumors. These changes might have impaired oxygen permeability and mitochondrial function, promoting hypoxia and reactive oxygen species (ROS) production. Hif1α expression was elevated in both LUSC and LUAD, along with a hypoxiaresponsive protein kinase Csnk2a1 and its downstream targets Hdac1 and Hdac2. ROS-responsive transcription factors Yy1, Foxm1, E2f1, and E2f8 were also significantly upregulated in both LUSC and LUAD. Notably, the master epigenetic regulator Uhrf1 activated by these transcription factors showed marked overexpression in tumors compared to that in normal tissues. TCGA data corroborated these findings. Our study identified tumor cell membrane-associated molecules, including ion channels (Aqp1, Aqp4, Clic5) and membrane lipid metabolism enzymes (PC, SM, Cho, and CL), as critical contributors to lung tumorigenesis. These molecules represent promising targets for developing innovative anti-cancer therapies.

Anaphase-promoting complex/cyclosome (APC/C) regulates the cell cycle by destruction of target proteins ubiquitination. However, understanding the control of APC/C has remained elusive. We identify APC2, the catalytic core subunit of APC/C, as a binding partner of active regulator of SIRT1 (AROS). Subsequent immunoprecipitation assays confirm the interaction in vivo. We reveal that AROS competes with APC11 for APC2 binding, thereby impeding the destruction of Cyclin B1. By contrast, the APC/C coactivator CDH1 ubiquitinates and degrades AROS in a D-box-dependent manner. Finally, we demonstrate that CDH1 suppresses the AROS-mediated protection of DNA damage-induced senescence. Overall, our findings provide evidence of the reciprocal role of AROS and APC/C-CDH1 in regulating APC/C activity and DNA damage-induced senescence, and highlight a potential role for AROS in the control of senescence.

B cell tolerance is critical for preventing autoimmunity, yet the mechanisms by which B cells discriminate self from non-self antigens remain incompletely understood. While early findings emphasize the role of classical antigen-mediated BCR signaling strength by varying antigen formats, emerging evidence highlights the importance of mechanical cues during antigen recognition. This review explores how mechanosensitive ion channels, particularly Piezo1, contribute to B cell activation and tolerance by integrating physical forces at the immune synapse. We discuss how membrane-bound and particulate antigens induce mechanotransduction through Piezo1, promoting enhanced B cell responses by extracellular calcium influx. Additionally, we consider the differential roles of Piezo1 in various physiological contexts, including shear stress, tissue migration, and substrate stiffness. Understanding mechanosensor-mediated signaling in coordination with other pathways such as antigen recognition, T cell help, or cytokine signaling expands our knowledge of B cell biology and introduces a new paradigm for modulating humoral immunity in health and disease.

The reverse β-oxidation (rBOX) pathway is emerging as a promising alternative to fossil fuel-based chemical production, providing a versatile platform for the synthesis of various valueadded biochemicals. Efficient application of rBOX depends on the selection of enzymes with high catalytic activity, suitable substrate specificity, and strong functional compatibility within the pathway. In this review, we focus on the structural and biochemical characteristics of four key enzymes-thiolase, 3-hydroxyacyl-CoA dehydrogenase, enoyl-CoA hydratase, and enoyl-CoA reductase-and explore how their individual features and combinations influence pathway performance. We then summarize previous studies that highlight the importance of enzyme cooperation in achieving optimal production outcomes. These insights provide valuable guidance for the rational design of rBOX-based biosynthetic pathways tailored to specific chemical targets.

Patients with multiple myeloma develop resistance to thalidomide during therapy, and the mechanisms to counteract thalidomide resistance remain elusive. Here, we explored the interaction between cereblon and mitochondrial function to mitigate thalidomide resistance in multiple myeloma. Measurements of cell viability, ATP production, mitochondrial membrane potential, mitochondrial ROS, and protein expression via western blotting were conducted in vitro using KSM20 and KMS26 cells to assess the impact of thalidomide on multiple myeloma. An in vivo analysis using xenografted multiple myeloma cells in BALB/c nude mice revealed that KMS20 cells were resistant to thalidomide, whereas KMS26 cells were sensitive. Overexpression of CRBN in a KMS20 xenograft model reversed its resistance to thalidomide, reduced tumor growth, and significantly extended the survival rate of the mice. Overexpression of CRBN in thalidomide-resistant KMS20 cells during thalidomide treatment led to effective cell death through the modulation of mitochondrial function and protein expression, mediated by AMPKα1 signaling. Conversely, both genetic and pharmacological knockdowns of CRBN rendered KMS26 cells resistant to thalidomide, indicating that CRBN level modulation directly influences mitochondrial functions. These findings propose that targeting cereblon offers a promising strategy in overcoming thalidomide resistance in multiple myeloma through mitochondrial reprogramming.

RNA modifications are key epigenetic alterations that play regulatory functions in RNA biology, including RNA stability and translation. Emerging evidence indicates that RNA modification is crucial for various physiological and pathological processes, including aging. This review describes functions of key RNA modifications, including N⁶-methyladenosine (m⁶A), 5-methylcytosine (m⁵C), N⁷-methylguanosine (m⁷G), 2'-O-methylation (Nm), N¹-methyladenosine (m¹A), adenosine-to-inosine (A-to-I) RNA editing, pseudouridylation (ψ), and N4-acetylcytidine (ac4C), highlighting their roles in aging and age-associated diseases. We also discuss dynamics of RNA modifications and associated protein factors during aging. This review provides important information on molecular mechanisms underlying aging regulation, focusing on effects of RNA modifications, which can help us understand healthy longevity in humans. [BMB Reports 2025; 58(9): 389-396].

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a complex metabolic disorder that encompasses a spectrum of conditions, from simple hepatic steatosis to metabolicassociated steatohepatitis (MASH). MASH is characterized by inflammation and accelerated fibrosis progression, which can ultimately lead to cirrhosis and hepatocellular carcinoma. Given its steadily increasing prevalence, MASLD has emerged as a global health epidemic. Significantly, MASLD represents a stage where liver function can still be partially restored through dietary interventions and physical exercise. However, the longterm sustainability of these lifestyle changes poses a significant challenge. Furthermore, the complex and heterogeneous nature of MASH complicates the development of pharmacotherapeutic strategies and the identification of reliable biomarkers for effective treatment. Therefore, it is essential to gain a comprehensive understanding of the molecular mechanisms driving MASLD and to develop targeted therapeutic interventions. Recent studies have underscored the critical role of posttranslational modifications (PTMs) of proteins in regulating MASLD. PTMs, such as ubiquitination, SUMOylation, Neddylation, and UFMylation, are known to modulate protein function and diverse cellular processes. Among these, ubiquitination is particularly noteworthy for its dual role in mediating protein degradation through the ubiquitin-proteasome system and in regulating cellular signaling pathways in a non-proteolytic manner, depending on the specific linkages formed at the seven distinct lysine residues (K6, K11, K27, K29, K33, K48, and K63) and the Met1-linked (M1) linear ubiquitin chain. Despite significant progress in this area, studies focusing on linkage-specific ubiquitination events that regulate MASLD remain relatively limited. Thus, this review aims to provide a comprehensive summary of the role of linkage-specific ubiquitination in regulating MASLD, as well as exploring other ubiquitinlike modifications that may contribute to its pathophysiology. [BMB Reports 2025; 58(9): 371-388].

Repeat sequences account for approximately 45% of the human genome, and can produce noncanonical DNA secondary structures that include G-quadruplexes (G4s). Among these, G4s are unique, in that their formation and stability are largely influenced by metal cations, such as Na^＋, K^＋, Ca^2＋, and Mg^2＋. These cations stabilize G4 structures, while also influencing their folding and biological activities. Interactions between G4s and metal ions affect key cellular processes that include transcription, replication, and genome stability. This review highlights the structural diversity and functional roles of G4s, and further explores how their ion-dependent properties have been harnessed for applications in biosensing and therapeutic development. Future research directions to advance G4-targeted technologies for both diagnostic and clinical use are also discussed. [BMB Reports 2025; 58(9): 397-405].

[Erratum to: BMB Reports 2025; 58(8): 325-339, PMID: 40635200, PMCID: PMC12402691] BMB Reports recently published the article "Decoding tau acetylation in Alzheimer's disease and tauopathies: from site-specific mechanisms to therapeutic horizons" (BMB Rep. 2025; Vol. 58, No.8, pp.325-339) by Yoonah R. Oh et al. The original publication inadvertently omitted the ACKNOWLEDGEMENTS section. This section has now been added to the online version. ACKNOWLEDGEMENTS This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (RS-2023-00209597). All figures were created using BioRender. The authors and editorial office apologize for any inconvenience or confusion this omission may have caused to the authors and readers.