In this study, we report a novel function of protein phosphatase 1 regulatory subunit 3C (PPP1R3C)-which is known to promote glycogenesis by activating glycogen synthase and to inhibit glycogen breakdown by suppressing glycogen phosphorylase-as a tumor suppressor in endometrial cancer. First, the expression of PPP1R3C was strongly down-regulated in uterine corpus endometrial cancer (UCEC) tissues, and ectopic expression of PPP1R3C led to cell cycle arrest and apoptosis in HEC1A and HEC1B cells derived from UCEC. PPP1R3C also inhibited the growth of xenograft tumors in BALB/c nude mice. We found evidence indicating that the activation of glycogen synthesis was at least partly responsible for the tumor suppressor activity of PPP1R3C. Specifically, inhibition of glycogen synthase abrogated the effect of ectopic PPP1R3C expression on the growth inhibition of UCEC cells. Collectively, our data indicate that PPP1R3C is a tumor suppressor gene functioning through the induction of glycogen synthesis.

Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes are widely used to model cardiac development and disease, but directed differentiation produces heterogeneous cellular states whose regulatory mechanisms remain incompletely defined. Here, we used simultaneous high-throughput ATAC and RNA Expression with sequencing (SHARE-seq) to profile gene expression and chromatin accessibility during human iPSC-derived cardiomyocyte differentiation. Weighted nearest neighbor integration resolved sequential developmental cell states, including iPSCs, mesodermal cells, progenitor populations, cardiomyocytes, and off-target, mixed, or partially differentiated populations. Peak-to-gene linkage analysis nominated cell state-associated putative enhancer-gene relationships, including a cardiac-related regulatory linkage at the MYH6/MYH7 locus. Pseudotime analysis revealed progressive remodeling of transcriptional and chromatin-associated regulatory programs. In silico perturbation modeling further prioritized transcription factors (TFs) predicted to influence differentiation trajectory progression, and gene regulatory network inference identified candidate TF-centered modules associated with cardiac lineage progression. Comparative pseudotime analysis of these modules showed that motif-containing regulatory element accessibility appeared to emerge earlier than, or in parallel with, TF expression and downstream target module activation. Together, these findings provide a single-cell multimodal resource and analytical framework for linking cellular identity, chromatin accessibility, putative enhancer-gene relationships, and candidate transcription factor regulatory programs during human cardiomyocyte differentiation.

Spermatozoa are increasingly recognized as carriers of non-genetic paternal information, rather than passive vehicles for the haploid genome. During spermatogenesis and post-testicular epididymal maturation, the paternal germline establishes a compact but functionally organized epigenome composed of DNA methylation, retained histones and histone modifications, chromatin-associated factors, and diverse small RNAs. These layers are environmentally responsive. In animal models, paternal diet, stress, toxicant exposure, and inflammatory or microbiome-related challenges can alter sperm DNA methylation, chromatin states, and small RNA cargo, with many changes mapping to loci involved in development, metabolism, and stress-response pathways. After fertilization, the paternal genome undergoes extensive epigenetic reprogramming; nevertheless, a subset of DNA methylation and chromatin features can resist erasure or be functionally relayed, while sperm-derived RNAs can influence early embryonic gene expression. Recent work, including studies of diet-induced sperm mitochondrial tRNAs, further supports the concept that defined paternal exposures may be transmitted to the embryo through discrete RNA-mediated mechanisms. In humans, lifestyle and environmental exposures are associated with measurable sperm epigenomic variation and with offspring health outcomes, but most evidence remains observational and is vulnerable to confounding by genetics, maternal factors, and shared environments. A central challenge is therefore to connect specific sperm epigenetic alterations to molecular effects in the early embryo and to subsequent offspring phenotypes. Here, we review how paternal environmental information is encoded during spermatogenesis and epididymal maturation, reshaped by environmental exposures, and interpreted by the early embryo, emphasizing multilayer integration and the evidence required to move from association to mechanism.

Potassium channel tetramerization domain-containing protein 17 (KCTD17) is part of the BTB/POZ domain-containing KCTD protein family and serves as a multifunctional regulator of cellular homeostasis. As an adaptor protein associated with Cullin 3 (CUL3)-based E3 ubiquitin ligase complexes, KCTD17 plays a critical role in selective protein ubiquitination and proteasomal degradation, influencing the stability of various cellular proteins. This function links KCTD17 to numerous biological processes, including organelle dynamics, cell differentiation, intracellular signaling, metabolic regulation, stress responses, tissue remodeling, and disease progression. Notably, the effects of KCTD17 are highly context-dependent, varying with cell type, substrate availability, and pathological conditions. While recent studies have begun to uncover several pathways associated with KCTD17, its complete range of substrates, regulatory mechanisms, and physiological significance are still not fully understood. In this review, we summarize the current understanding of KCTD17's molecular functions and biological mechanisms, emphasizing its role as a proteostatic regulator. We also explore its potential relevance to human diseases and highlight key unresolved questions, such as substrate specificity, tissue-dependent functions, functional redundancy with related KCTD proteins, and therapeutic potential. Gaining a deeper understanding of KCTD17-dependent protein regulation may offer new insights into proteostasismediated cellular regulation and disease mechanisms. [BMB Reports 2026; 59(9): 418-424].

Cellular identity is maintained by precise epigenetic regulation, but chronic stress and aging can disrupt this control, leading to mesenchymal drift (MD). Unlike the coordinated process of epithelial-mesenchymal transition (EMT), MD is a stochastic, lineage-independent phenomenon marked by increased epigenetic noise and the widespread activation of profibrotic gene programs. As originally defined, MD requires two components to co-occur: a compromised original cellular identity together with the acquisition or intensification of mesenchymal traits. Applying the MD framework to Alzheimer's disease (AD) provides a new perspective on its pathogenesis. In AD, brain cells do not merely survive or die due to protein toxicity; instead, they lose their specialized identities in an uncoordinated fashion. This transcriptomic drift has been reported across major cell types in the central nervous system: neural progenitor cells differentiate prematurely, mature neurons undergo transcriptomic dedifferentiation, endothelial cells develop features of vascular fibrosis, and glial cells lose their homeostatic functions. Direct enrichment of the MD signature in the AD brain, however, has so far been demonstrated only in astrocytes, oligodendrocytes, and pericytes, and, in our own reanalysis, in human-induced pluripotent stem cell (hiPSC)-derived neural progenitor cells carrying an APP mutation; we distinguish this evidence from observations documenting identity loss or a reactive state alone. We further caution that the novel cell populations identified in recent single-cell transcriptomic studies should not be assumed to represent genuinely new cell types: such clusters may equally reflect a blurring of existing cell lineages, or technical artifacts that produce the same appearance. A drifting transcriptomic profile also does not always signify a corresponding physiological change. These possibilities warrant careful attention, and we therefore emphasize the critical need to integrate transcriptomic data with in vivo functional and morphological validation. This integration is essential to determine whether these identity shifts contribute to AD progression or merely reflect underlying epigenetic instability. [BMB Reports 2026; 59(9): 407-417].

MicroRNA-31 (miR-31) acts as a tumor suppressor and is downregulated in breast cancer, but the mechanism responsible for its reduced maturation remains unclear. To investigate this, we examined the expression patterns of pri- and mature miR-31 across multiple human tumor cell lines. Quantitative PCR revealed that while pri-miR-31 was abundantly expressed, mature miR-31 levels were selectively decreased in breast cancer cells, indicating a block at the post-transcriptional processing step. Treatment with the histone deacetylase inhibitor trichostatin A (TSA) restored miR-31 expression while concurrently suppressing Galectin-3, suggesting a potential regulatory link between the two molecules. RNA electrophoretic mobility shift assays (EMSA) demonstrated direct binding of recombinant Galectin-3 to in vitro-transcribed pre-miR-31. Protein-RNA docking analysis further supported this interaction, identifying the CUGGG motif (C35-G39) within pre-miR-31 as the key contact region interacting with the carbohydrate recognition domain (CRD) of Galectin-3. Functional analyses in MCF7 cells, which exhibit the highest endogenous Galectin-3 levels, showed that Galectin-3 knockdown markedly increased mature miR-31 expression without altering pri-miR-31 levels, confirming regulation at the processing stage. TaqMan™ microRNA profiling revealed that Galectin-3 depletion selectively altered a subset of miRNAs, including miR-31, suggesting partial remodeling of the cellular miRNA landscape. Collectively, our findings identify Galectin-3 as a negative regulator of miR-31 maturation in breast cancer cells and suggest a novel role for this lectin in post-transcriptional control of microRNA biogenesis.

Hepatocellular carcinoma (HCC) displays significant molecular heterogeneity that clinical staging alone does not fully account for when assessing the risk of recurrence following curative treatment. To address this, we developed a multi-cohort survival modeling framework that translates bulk RNA-seq profiles into biologically meaningful tumor lineage scores. These scores are then used to stratify disease-free survival (DFS). Our study included 1,059 patients from four independent cohorts, where tumor immunogenic and proliferative lineage scores satisfied the proportional hazards assumptions and were integrated into a cohort-stratified Cox model. Each patient received a linear predictor (LP), and predefined cutpoints were established to categorize them into actionable risk groups. These groups exhibited consistent DFS separation in both the training (70%) and independent test (30%) sets. In ROC analyses, the LP demonstrated moderate overall discrimination (AUC 0.629, 95% CI 0.595-0.662). It showed higher discrimination for early recurrence (＜ 1 year; AUC 0.653, 95% CI 0.591-0.715) and lower discrimination for later recurrence (3-5 years; AUC 0.576, 95% CI 0.473-0.678). This approach establishes a biologically informed framework for stratifying recurrence risk based on RNA-seq data, potentially enhancing riskadapted surveillance and postoperative management for HCC. [BMB Reports 2026; 59(9): 438-442].

T cell-based immunotherapies have transformed the treatment of hematological malignancies, but their efficacy in solid tumors remains inconsistent. Unlike blood cancers, solid tumors present multiple barriers that impede T cell infiltration, metabolic fitness, antigen recognition, and long-term persistence. These barriers include structural exclusion by the stroma, tumor-driven metabolic competition, antigen plasticity, and the progressive epigenetic fixation of T cell exhaustion states. This review integrates our current understanding of T celldirected therapeutic approaches and examines the tumorintrinsic and microenvironmental mechanisms that limit their activity in solid malignancies. We discuss how chronic stress signaling, altered nutrient availability, glycan-mediated epitope masking, and transcriptional reprogramming collectively destabilize therapeutic T cell function. Finally, we evaluate emerging strategies designed to remodel the tumor niche, diversify antigen targeting, and enhance T cell metabolic and epigenetic resilience. Thus, developing a mechanistic framework that combines intrinsic T cell reprogramming with adaptation to the tumor context will be crucial for extending durable T cell-mediated immunity to solid cancers.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide and is associated with a poor prognosis, even when diagnosed in its early stages. Therefore, identifying novel HCC targets for therapeutic drug development is critically needed. Our proteomic analysis identified Glucose-regulated protein 78 (GRP78) as a potential new target, showing enrichment in HCC spheroids. We observed that post-surgery HCC patients with elevated GRP78 expression in non-tumor tissues had an unfavorable prognosis. Inhibition of GRP78 expression suppressed cell proliferation and reduced viability by controlling the DNA damage response in HCC cells. GRP78 expression peaked during the G2/M phase of mitosis and was predominantly localized to the cytoskeleton. However, its expression decreased as the cell cycle progressed from the G2/M to the G1 phase in HCCs. Overexpression of GRP78 in HCC cells increased the interaction between PLK1 and GRP78, leading to the stabilization of PLK1 in the midbody during cytokinesis. This stabilization resulted in the failure of cells to exit mitosis, producing multinucleated HCC cells. These findings reveal novel functional roles for GRP78 in disrupting mitotic activity through the stabilization of PLK1 at the midbody, thereby fostering polyploidy development in HCC. This suggests that inhibiting GRP78 is a promising approach for enhancing HCC therapy. [BMB Reports 2026; 59(8): 398-406].

Radial glia are the principal neural stem cells in the developing human cerebral cortex and have been classified as three molecularly distinct subtypes: ventricular radial glia (vRG), outer radial glia (oRG), and truncated radial glia (tRG). Human cortical organoids (hCOs) from human pluripotent stem cells that recapitulate the developmental program of the human cortex have shown this progenitor diversity. vRG and oRG are readily generated and identified in hCOs from most differentiation protocols with oRG emergence dependent on specific signaling pathways, such as LIF/STAT3 supplementation. However, tRGs that have only recently been defined at the molecular level have not been systematically examined in any organoid system. Here we review the biology, signaling, and lineage potential of each radial glial subtype and assess how faithfully they are represented in cortical organoids. We highlight and discuss the studies on the tRG from hCOs. We discuss data consistent with latent tRG competence in hCOs, including ependymal cell generation from radial glia within organoids, CRYAB-positive progenitors in three-dimensional culture systems, and tRG-associated transcriptomic shifts upon genetic perturbation, while noting that definitive tRG identification has not yet been achieved. However, definitive identification through combinatorial marker co-expression and morphological validation has not yet been achieved. Faithfully establishing molecular signatures and signaling frameworks for tRG and their existence in hCOs will provide the foundation for systemically investigating and function of this cell type in vitro, and we discuss future directions for resolving whether tRG are generated during the neurogenesis-to-gliogenesis transition. [BMB Reports 2026; 59(8): 373-383].

Epigallocatechin gallate (EGCG), a major polyphenol in green tea, exhibits anti-obesity effects, but its precise mechanism remains to be fully elucidated. In this study, we found that EGCG suppresses the adipocyte differentiation of 3T3-L1 cells, which was achieved with its treatment limited to the first two days post-differentiation induction. EGCG inhibited the tetranectin (TN)-mediated increase in ERK and AKT phosphorylation. EGCG efficiently removed TN in the differentiation medium, suggesting TN as a direct target. Furthermore, TN was found to undergo endocytosis during early differentiation, which was attenuated by EGCG, indicating a potential intracellular role for TN. Collectively, these findings demonstrate that EGCG suppresses adipogenesis by reducing TN availability in the medium and inhibiting its subsequent endocytosis, thereby modulating the ERK and AKT signaling pathways.

Alzheimer's disease (AD) is marked by progressive cognitive decline and retinal abnormalities, including degeneration of the retinal pigment epithelium (RPE). In models of AD, the accumulation of amyloid-β (Aβ) peptides triggers chronic inflammation and activates the immunoproteasome (iP), primarily driven by tumor necrosis factor-alpha (TNFα) from glial cells. Although pharmacological inhibition of iP has demonstrated protective effects against retinal damage, the precise molecular mechanisms involved remain unclear. In this study, we reveal that Aβ stimulation initiates a signaling cascade from glia to RPE, mediated by TNFα, which in turn promotes iP activation and upregulation of the NLRP3 inflammasome in RPE cells. Aβ exposure significantly increased TNFα secretion in Müller glia, whereas RPE cells exhibited only a minimal intrinsic response to TNFα secretion in response to Aβ. Inhibition of iP reduced TNFα release from glial cells. Additionally, neutralizing gliaderived TNFα decreased iP activity and mitigated epithelialmesenchymal transition (EMT) in RPE cells, highlighting TNFα's crucial role in glial-induced retinal inflammation. These findings position glia-derived TNFα as a central factor in Aβ-induced RPE degeneration through the TNFα-iP-NLRP3 pathway, supporting the use of iP inhibition as a potential therapeutic approach to maintain retinal integrity in AD.

Hair loss is a psychologically debilitating condition affecting social interactions. Despite extensive research, current interventions are transient and provide limited efficacy. Emerging evidence highlights that oxidative stress, resulting from mitochondrial dysfunction, impairs hair growth and disrupts hair cycle regulation. Urolithin A (UA), known to enhance mitochondrial function via mitophagy activation, has not yet been studied for its protective effects against hair loss. Here, we investigate whether UA protects against oxidative stress and promotes hair growth by restoring mitochondrial function in human dermal papilla cells (hDPCs) and clinical cases. hDPCs were subjected to H2O2 to induce oxidative stress and treated with various UA concentrations. Protective effects were assessed via mitochondrial function, morphology, apoptosis assays and Wnt/β-catenin signaling activity. Clinical evaluation involved measuring hair root volume and shedding rates following topical UA application. UA treatment improved mitochondrial function, reduced cell death under oxidative stress conditions, and activated Wnt/β-catenin signaling by increasing Wnt and β-catenin expression in hDPCs. Clinically, UA application led to increased hair root volume and decreased hair shedding. These dual effects on mitochondrial function and Wnt/β-catenin signaling highlight the potential of UA as a novel intervention for hair loss management.

The specific roles of single-nucleotide polymorphisms and structural variants (SVs) in Korean patients with inflammatory bowel disease (IBD) susceptibility remain unclear; hence this study aimed to evaluate polygenic risk scores (PRS) for IBD and identify IBD-associated SVs in a Korean IBD cohort. Whole genome sequencing data from 75 Korean patients with IBD were analyzed, and compared with individuals from the general Korean population cohort. The PRS models significantly distinguished patients with IBD from the general Korean population, confirming the predictive power of PRS in Korean patients with IBD. SV analysis revealed IBD-associated deletions, with candidate loci including PLA2R1, PTPN2, LINC00484, CCND3, COMMD7, and ERAP2. Of these, DEL5948 in ERAP2 overlapped multiple IBD-associated SNP loci and disrupted key regulatory and coding regions, potentially influencing immune regulation. This study provides a comprehensive genome-wide analysis of PRS and SVs in Korean patients with IBD, highlighting novel genetic factors in IBD pathogenesis.

Targeting the behavior of myeloid-derived suppressor cells (MDSCs), either by decreasing their population or inhibiting their immunosuppressive activity, has become a promising approach in breast cancer therapy. As pivotal mediators within the tumor microenvironment (TME), MDSCs facilitate tumor progression via diverse mechanisms, including T-cell suppression, epithelial-mesenchymal transition (EMT), and the preservation of cancer cell stemness. EK-16005, a novel 2-anilinopyrimidine derivative, has shown robust inhibitory activity against breast cancer cells. In this investigation, we examined the impact of EK-16005 on the reciprocal interactions between MDSCs and cancer cells that modulate cytokine production and signaling pathway activation. EK-16005 downregulated the secretion of critical cytokines such as G-CSF, VEGF, and CXCL1/2, leading to blockade of STAT3 and Notch signaling cascades in vitro and in vivo. As a result, EK-16005 decreased MDSC expansion, tumor growth, and cancer stemness properties. Collectively, these results establish EK-16005 as a potential therapeutic candidate for interrupting MDSC-mediated tumor progression and improving outcomes in breast cancer treatment.