Biology Direct[JOURNAL]
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200 papers
The role of alternative splicing in gastric cancer.
Huang Q, Ke J, Shen X … +3 more , Xu Y, Sun S, Huang C
Biol Direct · 2026 Apr · PMID 42045977 · Full text
Gastric cancer (GC) remains a major cause of cancer incidence and mortality worldwide. Alternative splicing (AS), a post-transcriptional mechanism that expands transcript diversity from a single pre-mRNA, plays critical...
Gastric cancer (GC) remains a major cause of cancer incidence and mortality worldwide. Alternative splicing (AS), a post-transcriptional mechanism that expands transcript diversity from a single pre-mRNA, plays critical regulatory roles in GC. This review summarizes the current knowledge of AS in GC. Accumulating evidence shows that aberrant AS contributes to the oncogenesis, progression, invasion, metastasis and drug resistance of GC. In addition, AS-related biomarkers like RBM4 and prognostic models for subtype prediction have been reported. However, most existing studies have focused on basic research, while patient-level validation remains limited and standardized detection and analytical workflows are still lacking. Future work should prioritize prospective cohorts and standardized pipelines.
A cyclin D1-CDK4/6-E2F dependency represents an acquired vulnerability in cisplatin-resistant bladder cancer.
Hsieh TH, Kuo HP, Pan CH … +4 more , Lin YC, Lin BJ, Chen MC, Chen CH
Biol Direct · 2026 Apr · PMID 42045965 · Full text
BACKGROUND: Cisplatin resistance remains a major obstacle in the treatment of bladder cancer (BC). This study aimed to define molecular drivers of cisplatin resistance and to assess potential therapeutic targets that may...
BACKGROUND: Cisplatin resistance remains a major obstacle in the treatment of bladder cancer (BC). This study aimed to define molecular drivers of cisplatin resistance and to assess potential therapeutic targets that may help restore treatment responsiveness. METHODS: Integrative transcriptomic analyses were performed using The Cancer Genome Atlas (TCGA) cohort to compare cisplatin non-responders with responders, alongside a cisplatin-resistant BC cell model to identify dysregulated pathways. Functional studies, including siRNA-mediated knockdown, SRB assay, flow cytometry, western blotting, and microarray-based transcriptomics, sphere formation assay, and clonogenic assay, were used to characterize the dysregulated pathways. RESULTS: Both cisplatin non-responders in TCGA dataset and resistant BC cells exhibited upregulation of CCND1 and enrichment of E2F target genes. Silencing Cyclin D1 restored cisplatin sensitivity in resistant BC cells. Abemaciclib, a CDK4/6 inhibitor, selectively inhibited proliferation of cisplatin-resistant BC cells, reduced RB phosphorylation, induced sub-G1 accumulation, and suppressed expression of key regulators of cell-cycle progression and homologous recombination repair. Combined treatment with abemaciclib and cisplatin synergistically suppressed the proliferation of cisplatin-resistant BC cells in vitro and produced significantly greater tumor growth inhibition in an RT112 xenograft model in vivo. Furthermore, Abemaciclib reduced sphere-forming capability and enhanced the anti-clonogenic effect of cisplatin in cisplatin-resistant BC cells. CONCLUSION: These findings identify a Cyclin D1/CDK4/6–E2F signaling dependency as a characteristic feature of the cisplatin-resistant state in BC. Targeting this acquired vulnerability provides a mechanistic rationale for combination strategies to enhance cisplatin responsiveness for refractory BC.
SH3BGRL3 promotes radioresistance and immune evasion in triple-negative breast cancer by regulating Rab27a.
Wang L, Lu F, Gao J … +4 more , Li Y, Li S, Li M, Dong R
Biol Direct · 2026 Apr · PMID 42045928 · Full text
OBJECTIVE: This study aims to elucidate the molecular mechanisms by which SH3BGRL3 regulates radiosensitivity and immune evasion in triple-negative breast cancer (TNBC). METHODS: An orthotopic TNBC model was established...
OBJECTIVE: This study aims to elucidate the molecular mechanisms by which SH3BGRL3 regulates radiosensitivity and immune evasion in triple-negative breast cancer (TNBC). METHODS: An orthotopic TNBC model was established by injecting 4T1 cells into the mice. In vitro, BT549 cells were co-cultured with CD8+ T cells isolated to mimic the immune microenvironment. Cell proliferation was assessed by CCK-8 and colony formation assays, while migration was evaluated using Transwell. Key protein expression was analyzed by Western blot, immunofluorescence, and immunohistochemistry. RESULTS: Our study revealed that SH3BGRL3 is upregulated in TNBC, where its knockdown suppresses the proliferation and migration of irradiated BT549 cells in vitro and inhibits tumor growth in vivo. Additionally, SH3BGRL3 depletion downregulated ferroptosis-related proteins GPX4 and SLC7A11, elevated Fe²⁺, MDA, and lipid ROS levels, and reduced GSH-effects that were rescued by the ferroptosis inhibitor Fer-1. Our study further demonstrates that SH3BGRL3 knockdown reduces the expression of exhaustion markers (PD-1, TIM-3, LAG-3, TIGIT) on CD8⁺ T cells while increasing the secretion of effector molecules (IFNg, granzyme B, perforin). Notably, we found that Rab27a expression is also upregulated in TNBC, and SH3BGRL3 can bind to Rab27a and stabilize its protein level. Mechanistic studies revealed that knocking down SH3BGRL3 attenuates its interaction with Rab27a and reduces Rab27a expression, thereby promoting ferroptosis and enhancing radiosensitivity, while also inhibiting the Rab27a-mediated exosome release pathway, which in turn enhances CD8⁺ T cell function and suppresses tumor immune escape. CONCLUSION: This study demonstrates that SH3BGRL3 promotes radioresistance and immune evasion in triple-negative breast cancer by regulating Rab27a.
Transcription factor IRF1 modulates HDAC1 and PANoptosis to regulate preeclampsia progression.
Wang Z, Cheng L, Li G … +2 more , Kong L, Cheng H
Biol Direct · 2026 Apr · PMID 42035194 · Full text
BACKGROUND: Preeclampsia (PE) is a pregnancy-specific disorder posing significant maternal-fetal risks, while interferon regulatory factor 1 (IRF1) is a transcriptional regulator associated with inflammatory responses. I...
BACKGROUND: Preeclampsia (PE) is a pregnancy-specific disorder posing significant maternal-fetal risks, while interferon regulatory factor 1 (IRF1) is a transcriptional regulator associated with inflammatory responses. In this study, we aim to explore the pivotal correlation between PANoptosis and PE pathogenesis, as well as the regulatory role of IRF1 in PE progression. METHODS: Bioinformatics analysis identified differential transcription factors (TFs) and their association with PANoptosis in PE. In vitro, hypoxic HTR-8/SVneo cells were used; dual-luciferase reporter assay verified TFs' binding to the HDAC1 promoter, and IRF1-knockdown HTR-8/SVneo cells were established. CCK-8, colony formation, flow cytometry, wound healing, and transwell assays assessed cell viability, proliferation, apoptosis, migration, and invasion; angiogenesis assay evaluated vascular remodeling, and western blot detected PANoptosis-related protein expression. In vivo, a PE rat model was established with L-NAME; placental tissues were collected, and histopathological changes were analyzed via HE staining and immunohistochemistry. RESULTS: IRF1 was identified as a key PANoptosis-related TF at the intersection of 203 differential TFs and 65 PANoptosis-related genes, regulating HDAC1 by binding to its upstream regulatory region. Based on this, knockdown of IRF1 in HTR-8/SVneo cells increased HDAC1 expression, repaired cell viability, proliferation, migration, invasion, angiogenesis, and decreased the expression of PANoptosis markers (GSDMD, Caspase1/3/8, p-MLKL, p-RIPK3). In PE rats, sh-IRF1 alleviated hypertension, proteinuria, and fetal growth restriction, while placental HDAC1 upregulation mitigated trophoblast dysfunction and inhibited PE progression. CONCLUSION: Transcription factor IRF1 modulates HDAC1 and PANoptosis-associated signaling to regulate PE progression, offering new insights for PE prevention and management. CLINICAL TRIAL NUMBER: Not applicable.
Impeding hypoxia-driven tumor progression in hepatocellular carcinoma: clinical and pre-clinical analyses using 2D and 3D in vitro models.
Payo-Serafín T, Méndez-Blanco C, Martínez-Geijo J … +6 more , Kopsida M, San-Miguel B, Ortiz-de-Urbina JJ, García-Palomo A, Heindryckx F, Mauriz JL
Biol Direct · 2026 Apr · PMID 42035177 · Full text
BACKGROUND: Hypoxia is a hallmark of the hepatocellular carcinoma (HCC) microenvironment, promoting tumor progression, therapy resistance, and poor prognosis. Central mediators of the hypoxic response are the hypoxia-ind...
BACKGROUND: Hypoxia is a hallmark of the hepatocellular carcinoma (HCC) microenvironment, promoting tumor progression, therapy resistance, and poor prognosis. Central mediators of the hypoxic response are the hypoxia-inducible factors (HIFs), particularly HIF-1α, whose functional relevance in clinically representative models remains incompletely understood. METHODS: In this study, we performed an in-depth characterization and functional analysis of HIF-1α by generating HIF1A knockout (KO) models in two-dimensional (2D) and three-dimensional (3D) HCC culture systems, including tumor spheroids and fibrotic-like collagen-fibrin hydrogels, to better recapitulate the complexity of the tumor microenvironment (TME). RESULTS: Analyses of publicly available transcriptomic datasets revealed that HIF1A was significantly upregulated in tumor tissues and associated with higher grade, stage, and poor survival. In contrast, EPAS1 was downregulated and correlated with improved outcomes. Functional silencing and KO experiments confirmed that HIF-1α promoted tumor cell survival, invasion, and adaptation to hypoxia, while HIF-2α played only a limited role. HIF1A deletion impaired the expression of downstream targets such as VEGF and BNIP3 and altered ABCB1 levels. Importantly, HIF-1α loss markedly reduced viability and structural integrity in 3D cultures, highlighting the added value of using physiologically relevant models to uncover microenvironment-driven phenotypes. CONCLUSIONS: Altogether, our results identify HIF-1α as a central regulator of hypoxia-mediated tumor behavior in HCC and provide a strong rationale for its therapeutic targeting to disrupt tumor adaptation and improve patient outcomes. Moreover, these findings underscore the relevance of integrating both advanced 3D and complex 2D culture systems to better capture the structural, biochemical, and mechanical features of the TME.
A hybrid ST-ViT-driven multimodal architecture combining spatiotemporal MRI patterns and radiomic features for enhanced prediction of pCR in neoadjuvant breast cancer therapy.
Pattanayak S, Singh T, Kumar R … +1 more , Naik GR
Biol Direct · 2026 Apr · PMID 42032765 · Full text
Breast cancer response prediction plays a critical role in treatment planning, especially for identifying patients likely to achieve pathologic complete response (pCR). Traditional approaches rely primarily on baseline c...
Breast cancer response prediction plays a critical role in treatment planning, especially for identifying patients likely to achieve pathologic complete response (pCR). Traditional approaches rely primarily on baseline clinical variables or static imaging features, limiting their ability to capture the complex biological and temporal dynamics of tumor evolution during therapy. This study presents a spatiotemporal multimodal framework that integrates quantitative clinicopathological variables, radiomics, and longitudinal DCE-MRI to enhance the prediction of pCR. We employ a Spatiotemporal Vision Transformer (ST-ViT) to model tumor evolution across four imaging time points and fuse it with quantitative radiomic and clinical features. The proposed framework captures both spatial heterogeneity and treatment-induced temporal changes, offering a comprehensive representation of tumor biology. Texture-based radiomic analysis reveals meaningful differences between pCR and non-pCR tumors, while enhancement-curve dynamics further highlight early perfusion and washout patterns linked to treatment sensitivity. The integrated spatiotemporal multimodal model demonstrates strong discriminatory power, yielding an AUC of 0.98 during training and 0.96 on the held-out test set. These results highlight the model’s ability to leverage dynamic MRI signatures, radiomic texture descriptors, and clinical features distinguish responders from non-responders effectively. By capturing both spatial and temporal tumor evolution, the framework offers a robust and clinically meaningful tool for early identification of treatment-sensitive phenotypes and supports precision-driven neoadjuvant therapy planning.
Single-cell analysis highlights the role of CD4 IFN-I-related T cells in Behcet's uveitis during Interferonα-2a therapy.
Wang M, Zhang D, Huang X … +8 more , Zhong Z, Wang Q, Liu H, Su G, Jing S, Yang T, Li N, Yang P
Biol Direct · 2026 Apr · PMID 42021381 · Full text
BACKGROUND: Behcet's disease (BD) involves multiple immune cells, but the mechanism by which interferon α-2a (IFNα-2a) exerts therapeutic effects on BD through immune cell modulation remains unclear. This study aimed to...
BACKGROUND: Behcet's disease (BD) involves multiple immune cells, but the mechanism by which interferon α-2a (IFNα-2a) exerts therapeutic effects on BD through immune cell modulation remains unclear. This study aimed to investigate the role of CD4 + IFN-I-related T cells in BD with active uveitis during IFNα-2a therapy. METHODS: A single-cell atlas of peripheral blood mononuclear cells (PBMCs) was constructed from BD patients with active uveitis, post-4-month IFNα-2a therapy BD patients, active BD patients, and healthy controls (HCs) by integrating in-house and public scRNA-seq data. Bulk mRNA sequencing of CD4 + T cells from active BD patients and HCs was performed for validation. Cell-cell interaction, in vitro coculture, and inhibitor experiments were used to explore the underlying mechanisms. RESULTS: CD4 + IFN-I-related T cells (characterized by high interferon-related gene expression) were significantly decreased in active BD patients but restored after IFNα-2a therapy. The LLT1-CD161 interaction intensity between CD4 + IFN-I-related T cells and NK cells was reduced in active BD and recovered post-therapy. CD4 + IFN-I-related T cells inhibited NK cell activation and IFN-γ secretion via the CD161 receptor. CONCLUSIONS: IFNα-2a therapy reverses the decreased frequency of CD4 + IFN-I-related T cells in active BD, which in turn inhibits the inflammatory phenotype of NK cells through LLT1-CD161 interaction, providing new insights into the therapeutic mechanism of IFNα-2a in BD.
Toxicological effects of acrylamide on oocyte maturation and subsequent embryonic development in a porcine model.
Oh NG, Jeong PS, Kang HG … +6 more , Jeon SB, Yun JH, Eom SY, Kim SU, Cho SK, Sim BW
Biol Direct · 2026 Apr · PMID 42015274 · Full text
BACKGROUND: Acrylamide (ACR) is a highly water-soluble vinyl monomer that is widely used in industrial applications. It can be released into aquatic environments through industrial effluents and subsequently transported...
BACKGROUND: Acrylamide (ACR) is a highly water-soluble vinyl monomer that is widely used in industrial applications. It can be released into aquatic environments through industrial effluents and subsequently transported into soil and groundwater. In addition to environmental exposure, ACR is formed during high-temperature cooking processes. Although ACR is well documented to exert neurotoxic, genotoxic, and carcinogenic effects, its impact on the female reproductive system remains insufficiently characterized. RESULTS: This study investigated the effects of ACR exposure during in vitro maturation (IVM) on porcine oocyte meiotic maturation and subsequent embryonic development following parthenogenetic activation. ACR exposure significantly reduced the proportion of matured oocytes and downregulated the transcriptional levels of genes associated with oocyte maturation compared with controls. Furthermore, ACR treatment during IVM markedly compromised embryonic developmental parameters, as evidenced by decreased cleavage rates; reduced proportions of two-cell, four-cell, and morula-stage embryos; a lower blastocyst formation rate; and an increased fragmentation rate relative to controls. ACR exposure during IVM also impaired blastocyst quality, as indicated by reduced total cell numbers and an elevated apoptosis rate compared with controls. In addition, ACR exposure disrupted cell cycle progression and cytoskeletal integrity. Moreover, ACR treatment increased levels of reactive oxygen species while decreasing glutathione content and mitochondrial abundance compared with controls. ACR exposure also elevated DNA damage, autophagy, and early apoptosis in oocytes. CONCLUSIONS: ACR exposure during IVM exerts detrimental effects on porcine oocyte meiotic maturation and subsequent embryonic development by inducing cell cycle arrest, oxidative stress, DNA damage, excessive autophagy, and early apoptosis.
Glabridin improves cardiac remodeling after myocardial infarction by activating PPARγ to regulate the ubiquitination and degradation of EGFR.
Li Z, Hu Y, Jiang Y … +7 more , Fu B, Long T, Huang H, Yang J, Gu M, Niu H, Hua W
Biol Direct · 2026 Apr · PMID 42015151 · Full text
BACKGROUND: Acute myocardial infarction leads to myocardial inflammation and necroptosis, and is a major cause of heart failure, cardiovascular dysfunction, and mortality. Adverse remodeling and myocardial fibrosis follo...
BACKGROUND: Acute myocardial infarction leads to myocardial inflammation and necroptosis, and is a major cause of heart failure, cardiovascular dysfunction, and mortality. Adverse remodeling and myocardial fibrosis following myocardial infarction are key pathophysiological processes contributing to poor prognosis. Licorice, a widely utilized herb and food, contains glabridin, a bioactive component that acts as a potent PPARγ agonist. Glabridin has demonstrated multiple beneficial biological effects, including antioxidative stress, anti-inflammation, anti-atherosclerosis, and tumor progression inhibition. However, its role in cardiovascular diseases remains understudied. METHODS: Using C57BL/6 mice, a myocardial infarction model was established via left coronary artery ligation. Mice were treated with glabridin by oral gavage daily for 4 consecutive weeks post-surgery. Cardiac function and various indicators were assessed to evaluate the therapeutic effects. Additionally, primary cardiac fibroblasts were isolated from the mice for in vitro experiments to verify the effects of glabridin and further explore its mechanism of action. RESULTS: Glabridin treatment significantly improved cardiac fibrosis and alleviated cardiac dysfunction in mice. Mechanistically, glabridin activates PPARγ, thereby promoting the ubiquitination and degradation of EGFR, inhibiting the activation of the downstream PI3K/Akt signaling pathway, and mitigating myocardial fibrosis progression. CONCLUSION: Glabridin links the PI3K/Akt pathway and promote EGFR ubiquitination, offering insights into myocardial fibrosis mechanisms and potential therapeutic targets.
Activation of the TGR5/cAMP/PKA/CREB axis in cholangiocytes mediates epithelial-mesenchymal transition and fibrosis in hepatolithiasis.
Tang D, Yang J, Shi X … +2 more , Gu X, Zhao L
Biol Direct · 2026 Apr · PMID 42010695 · Full text
BACKGROUND: The molecular mechanisms linking bile acid signaling to biliary fibrosis in hepatolithiasis are unclear. We investigated the role of the bile acid receptor TGR5 in driving fibrotic progression. METHODS: We em...
BACKGROUND: The molecular mechanisms linking bile acid signaling to biliary fibrosis in hepatolithiasis are unclear. We investigated the role of the bile acid receptor TGR5 in driving fibrotic progression. METHODS: We employed an integrated strategy. TGR5 expression was assessed in human hepatolithiasis tissues and bioinformatics databases. A hepatolithiasis mouse model was compared with TGR5-knockout (TGR5-/-) mice, analyzing lipid metabolism, cholesterol transport, and fibrosis markers via ELISA, qPCR, and immunohistochemistry. In vitro, human intrahepatic biliary epithelial cells (HIBECs) were treated with bile acids, TGR5 agonists/inhibitors, and cAMP modulators. We assessed the cAMP/PKA/CREB pathway, epithelial-mesenchymal transition (EMT), and fibrosis. RESULTS: TGR5 was significantly overexpressed in hepatolithiasis tissues. Genetic deletion of TGR5 in mice alleviated metabolic disturbances and markedly reduced fibrosis markers (TGF-β1, α-SMA, Collagen I). In cholangiocytes, TGR5 activation stimulated the cAMP/PKA/CREB signaling cascade, promoting EMT and fibrosis. These pro-fibrotic effects were reversed by inhibiting TGR5 or cAMP. Mechanistically, TGR5-driven cAMP signaling induced CREB phosphorylation, leading to upregulated TGF-β1 expression, which sustains the fibrotic phenotype. CONCLUSION: This study defines a critical pathogenic axis in hepatolithiasis, whereby TGR5 activation in cholangiocytes triggers cAMP/PKA/CREB signaling to promote EMT and biliary fibrosis via TGF-β1. Our findings directly implicate TGR5 as a central therapeutic target for mitigating fibrosis in this disease.
Exosomes from tumor-associated macrophages promote glycolysis and malignant NSCLC progression by delivery of hsa_circ_0000896.
Liu J, Cai Q, Huang G … +2 more , Jin M, Huang Q
Biol Direct · 2026 Apr · PMID 42010627 · Full text
Non-small-cell lung cancer (NSCLC) is amongst the most common tumors, which is responsible for most cancer-related mortality worldwide. Tumor-associated macrophages (TAMs) can regulate tumor microenvironment (TME) and ma...
Non-small-cell lung cancer (NSCLC) is amongst the most common tumors, which is responsible for most cancer-related mortality worldwide. Tumor-associated macrophages (TAMs) can regulate tumor microenvironment (TME) and malignant progression of NSCLC; however, the regulatory mechanisms of TAMs exosome (M2-Exo) in the context of NSCLC progression are still unclear. In this study, exosomes isolated from TAMs (M2-Exo) were subjected to FISH and RT-qPCR to explore hsa_circ_0000896 expressions in NSCLC specimens. Dual-luciferase reporter data were utilized to investigate hsa_circ_0000896 downstream targets. Transwell migration, 5-ethynyl-2′-deoxyuridine incorporation, cell counting, and wound hearing experiments were performed to assess NSCLC cell migration and proliferation. Hippocampus experiment was used to detect cellular metabolism. Mouse tumor xenograft model was constructed to assess the hsa_circ_0000896 roles in NSCLC metastasis and progressions. The data revealed that M2-Exo treatment promoted NSCLC cell proliferation and migrations. Hsa_circ_0000896 in M2-Exos mediated NSCLC malignant progression, which was ameliorated by downregulation of hsa_circ_0000896 expression. Both SLC2A3 and miR-503-5p were identified as hsa_circ_0000896 downstream targets. SLC2A3 overexpression or miR-503-5p suppression can reverse hsa_circ_0000896 silence inhibit effects to NSCLC malignant progression. The hippocampus experiment confirmed that downregulation of hsa_circ_0000896 inhibited aerobic glycolysis by regulating miR-503-5p/SLC2A3. A549-DDP were used to construct a subcutaneous tumor model, outcomes of which showed that downregulation of hsa_circ_0000896 increased NSCLC chemosensitivity. Together, our results revealed that exosomes from TAMs promoted glycolysis and malignant progression of NSCLC by delivering hsa_circ_0000896. And hsa_circ_0000896 can promote glycolysis by regulation miR-503-5p/SLC2A3.
CircAFF4 inhibits lung cancer progression via destabilizing GPX4 and triggering ferroptosis.
Wang J, Xin S, Zhang C … +3 more , Xie N, Kong P, Yu Y
Biol Direct · 2026 Apr · PMID 42010438 · Full text
BACKGROUND: Lung cancer has been the most common diagnosed cancer and the leading cause of cancer-related death. Growing evidence has demonstrated that circular RNAs (circRNAs) are closely associated with the occurrence...
BACKGROUND: Lung cancer has been the most common diagnosed cancer and the leading cause of cancer-related death. Growing evidence has demonstrated that circular RNAs (circRNAs) are closely associated with the occurrence and progression of tumors. Ferroptosis is an iron-dependent form of cell death triggered by the accumulation of lipid peroxides, and it has been considered as a potential target for cancer therapy. However, the specific mechanism by which circRNAs modulate ferroptosis in lung cancer remains largely unknown. METHODS: Through retrieval from The Cancer Genome Atlas (TCGA) database, the differential expression of AFF4 mRNA in lung cancer was identified. Further screening and validation revealed that circAFF4, a circular RNA derived from AFF4 host gene, also exhibited a similar trend in lung cancer. Subsequently, quantitative reverse transcription-PCR (qRT-PCR) and fluorescent in situ hybridization (FISH) were used to detect its expression pattern and distribution. Functional studies were conducted both in vitro and in vivo to determine the biological functions of circAFF4. Furthermore, the interaction between circAFF4 and ubiquitin-specific peptidase 10 (USP10) as well as the relationship between USP10 and Glutathione peroxidase 4 (GPX4), were investigated by biotin-labeled RNA pull-down, mass spectrometry, RNA immunoprecipitation (RIP), FISH and co-immunoprecipitation (Co-IP) assays. RESULTS: Here we demonstrated that circAFF4 was significantly downregulated in lung cancer tissues and lung cancer cells. In vitro and in vivo experiments suggested that circAFF4 inhibited the proliferation of lung cancer cells and promoted ferroptosis. Mechanistically, circAFF4 bound to the deubiquitinating enzyme USP10, which in turn suppressed USP10-mediated deubiquitination of GPX4, and enhanced the ubiquitin-dependent proteasome degradation of GPX4, thereby facilitating ferroptosis in lung cancer cells. CONCLUSIONS: Our findings reveal a novel mechanism by which circAFF4 interacts with USP10, impairing USP10-mediated stabilization of GPX4, promoting ferroptosis in lung cancer cells, and ultimately suppressing lung cancer progression. The circAFF4/USP10/GPX4 axis provides a new direction and may be a potential target for lung cancer treatment.
Inhibition of circZFX suppresses malignant phenotypes in cholangiocarcinoma via the miR-654-3p/HDGF and YAP1 signaling activation.
Liang T, Gong C, Yang X … +5 more , Shen J, Jiang G, Liu J, Yang G, Guo L
Biol Direct · 2026 Apr · PMID 42010436 · Full text
Cholangiocarcinoma (CCA) is a highly aggressive hepatobiliary malignancy by a poor prognosis. circular RNAs (circRNAs) have poorly characterized roles in CCA. This study identified that circZFX was significantly upregula...
Cholangiocarcinoma (CCA) is a highly aggressive hepatobiliary malignancy by a poor prognosis. circular RNAs (circRNAs) have poorly characterized roles in CCA. This study identified that circZFX was significantly upregulated in 4 CCA cell lines and 20 paired CCA/normal tissues. circZFX knockdown suppressed CCA proliferation, migration, and invasion in vitro and reduced xenograft tumor volume by 57% in vivo. Mechanistically, circZFX functions as a competing endogenous RNA for miR-654-3p, thus derepressing HDGF. miR-654-3p inhibitor could reverse the inhibitory effects on the proliferation activity, migration, and invasion capabilities of HuCCT1 and QBC939 cells caused by circZFX silencing. Importantly, co-immunoprecipitation revealed HDGF interaction with YAP1, and circZFX knockdown downregulated YAP1 expression. These findings indicate that inhibition of circZFX suppresses malignant phenotypes in cholangiocarcinoma via the miR-654-3p/HDGF and YAP1 signaling activation, highlighting this axis as a novel therapeutic target and providing mechanistic insights for molecular subtyping and the development of circRNA-based precision therapeutics.
The B7 family subgroup reflects tumor cell heterogeneity and patient post-operative prognosis in gallbladder cancer.
Ma C, Hu H, Li Y … +8 more , Zhong C, Dong Y, Chang Z, Xu S, Zhang Y, Hu H, Lv C, Tian Y
Biol Direct · 2026 Apr · PMID 42001193 · Full text
PURPOSE: To elucidate the biological heterogeneity of gallbladder cancer (GBC) cells and refine post-operative risk stratification by investigating the expression and downstream signaling of the B7-family immune checkpoi...
PURPOSE: To elucidate the biological heterogeneity of gallbladder cancer (GBC) cells and refine post-operative risk stratification by investigating the expression and downstream signaling of the B7-family immune checkpoint molecules CD276 (B7-H3), VTCN1 (B7-H4), and HHLA2 (B7-H7) at single-cell resolution. METHODS: Single-cell RNA sequencing (scRNA-seq) data from seven primary tumors delineated five epithelial subgroups via non-negative matrix factorization (NMF). The functional association between HHLA2 and RAC1/CDC42-PAK1-Cofilin signaling was validated by lentiviral manipulation, pharmacologic inhibition, and subcutaneous xenografts. A total of 188 surgically treated GBC patients were enrolled for survival modeling. Seven machine-learning survival algorithms were trained on five variables (CD276, VTCN1, HHLA2 expression, tumor size, and differentiation) and compared by C-index, ROC-AUC, and calibration curves. RESULTS: CD276 + and VTCN1 + epithelial cells displayed pro-proliferative profiles, whereas HHLA2 + cells exhibited high EMT and migration signatures. HHLA2 overexpression led to increased RAC1/CDC42-PAK1-Cofilin signaling activity, enhanced proliferation, invasion, and EMT in vitro, and accelerated tumor growth in vivo. These effects were reversed by RAC1, CDC42, or PAK1 inhibitors, as well as by CFL1 knockdown. NMF classified tumor epithelial cells into five functionally distinct subgroups. A gradient-boosting machine (GBM) model integrating expression of the three B7 molecules with tumor size and differentiation achieved superior discrimination and accurate calibration on both the training and validation sets. CONCLUSION: B7-family expression delineates biologically distinct GBC subpopulations; HHLA2 promotes EMT via RAC1/CDC42-PAK1-Cofilin signaling. The GBM model incorporating CD276, VTCN1, and HHLA2 expression with tumor size and differentiation demonstrates potential for enhanced post-operative risk stratification, offering promising candidates for biomarker development and targeted therapeutic interventions.
mC RNA modification in gastrointestinal cancers: a comprehensive review from molecular mechanism to clinical implication.
Xu C, Ye Q, Wang H … +1 more , Yu Y
Biol Direct · 2026 Apr · PMID 41998787 · Full text
5-methylcytosine (m5C) modification has emerged as a novel epigenetic modification of ribonucleic acids (RNAs), encompassing messenger RNAs (mRNAs) and non- coding RNAs, in recent years. This reversible modification, whi...
5-methylcytosine (m5C) modification has emerged as a novel epigenetic modification of ribonucleic acids (RNAs), encompassing messenger RNAs (mRNAs) and non- coding RNAs, in recent years. This reversible modification, which is regulated by m5C regulators consisting of methyltransferases, demethyltransferases, and RNA-binding proteins, modulates all aspects of RNA metabolism and gene expression. Gastrointestinal (GI) cancers are prevalent malignancies with a high mortality rate globally. Accumulating evidence has indicated the significant role of m5C RNA modification in the tumorigenesis and progression of GI cancers. In this review, we provide a comprehensive overview of the functions and underlying molecular mechanisms of m5C RNA modification in RNA metabolism for the regulation of tumor biology, including cell proliferation, apoptosis, invasion/metastasis, chemoresistance, and other biological functions. Furthermore, we summarize the specific role of m5C modification in GI cancers and propose some insights regarding its application as a tumor biomarker and therapeutic target, aiming to offer a new perspective for m5C modification in GI cancer diagnosis and treatment in the future.
Prenatal bisphenol A exposure perturbs sex-dependent transcriptomic regionalization of autism-associated genes in the developing brain.
Sukjamnong S, Saeliw T, Panjabud P … +5 more , Thongkorn S, Kanlayaprasit S, Lertpeerapan P, Hu VW, Sarachana T
Biol Direct · 2026 Apr · PMID 41998730 · Full text
BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in communication, social interaction, and behavioral regulation. Its etiology arises from a combination of genetic vul...
BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in communication, social interaction, and behavioral regulation. Its etiology arises from a combination of genetic vulnerabilities and environmental influences. Bisphenol A (BPA) is an endocrine-disrupting chemical found in plastic-containing materials, including micro- and nanoplastic pollutants. Recent studies have shown that prenatal BPA exposure can alter behavior and the expression of genes related to autism and neurodevelopment. METHODS: This study integrated and reanalyzed published RNA sequencing datasets from the hippocampus and prefrontal cortex of rat offspring prenatally exposed to BPA through maternal intragastric administration during gestation to investigate the effects of prenatal BPA exposure on transcriptomic regionalization. Quantitative RT-PCR was performed to evaluate selected RNA-seq findings in individual, non-pooled biological samples. The associations between differentially expressed genes (DEGs) and ASD candidate genes were assessed via a hypergeometric distribution analysis. RESULTS: Prenatal BPA exposure was associated with altered transcriptomic profiles in the hippocampus and prefrontal cortex, together with sex-dependent changes in regional expression contrasts between these brain regions. Several ASD-relevant genes, including Msx2, Syncrip, Agtr2, and Myh9, showed altered regional expression patterns following prenatal BPA exposure. Genes showing altered regional expression contrasts after BPA exposure were annotated by IPA with functions, upstream regulators, and canonical pathways relevant to neurodevelopment and neurological disorders. Exploratory correlation analyses further identified region- and sex-dependent associations between disrupted regional gene-expression patterns and behavioral measures. CONCLUSIONS: This reanalysis suggests that prenatal BPA exposure is associated with altered regional transcriptomic patterning in the developing rat brain and identifies candidate genes and pathways for future mechanistic and replication studies.
Gene-guided repurposing identifies dihydroergotamine as a candidate inhibitor of the BCL2-SIVA1 axis in advanced gastric cancer in vitro.
Huang YL, Lu ZX, Shi ZY … +11 more , Qiu ZD, Zhong XG, Li L, Xu S, Lei YR, Huang HB, Deng MR, Lu XM, Dong XD, Kong FB, Wang XT
Biol Direct · 2026 Apr · PMID 41998706 · Full text
BACKGROUND: Advanced gastric cancer is frequently refractory to therapy because of multidrug resistance and apoptotic escape. BCL2 and SIVA1 are core apoptosis regulators, and their direct interaction suggests a potentia...
BACKGROUND: Advanced gastric cancer is frequently refractory to therapy because of multidrug resistance and apoptotic escape. BCL2 and SIVA1 are core apoptosis regulators, and their direct interaction suggests a potentially druggable BCL2–SIVA1 signaling axis that remains insufficiently explored in advanced gastric cancer. METHODS: We integrated bulk transcriptomics, single-cell RNA sequencing, spatial transcriptomics, and immune infiltration analyses from GEO/TCGA to characterize the BCL2–SIVA1 axis and applied a bioinformatics-guided drug-repurposing workflow (2D-QSAR machine learning, molecular docking, molecular dynamics, and MM/GBSA) followed by in vitro validation and mechanistic rescue experiments in NCI-N87 and HGC-27 cells. RESULTS: Multiomic analyses identified BCL2 as a progression-associated factor and revealed a strong positive correlation between BCL2 and SIVA1. Single-cell analysis showed that BCL2 was enriched and heterogeneous in malignant cells; pseudotime analysis placed BCL2-high states toward terminal branches, and hallmark scoring indicated increased proliferative and metastatic potential. Spatial transcriptomics demonstrated localized enrichment of BCL2 and SIVA1 in advanced gastric cancer tissues, and coimmunoprecipitation confirmed a direct BCL2–SIVA1 interaction, supporting a functional signaling axis. In silico screening prioritized dihydroergotamine as a high-affinity BCL2 binder, and dihydroergotamine suppressed proliferation and promoted apoptosis in both cell lines, accompanied by downregulation of BCL2/SIVA1 and upregulation of BAX and cleaved caspase 3. Rescue experiments further revealed that BCL2 overexpression during dihydroergotamine exposure partially restored SIVA1 protein levels and attenuated apoptosis, whereas SIVA1 overexpression did not restore BCL2 expression, supporting BCL2-linked coupling within this axis. CONCLUSION: By combining multiomic analyses with structure-based screening and in vitro validation, we identified the BCL2–SIVA1 axis as a potential apoptosis-related vulnerability in advanced gastric cancer and highlighted dihydroergotamine as a candidate modulator. Dihydroergotamine showed in vitro antiproliferative and proapoptotic effects consistent with the involvement of BCL2-associated apoptotic signaling, providing a preclinical rationale for further target dependency and translational feasibility studies.
Dapagliflozin induces renal lipidomic remodeling and systemic metabolic improvement.
Li A, Ye Y, Tang J … +5 more , Hu J, Shi M, Wu Y, Ji C, Zhang H
Biol Direct · 2026 Apr · PMID 41998678 · Full text
BACKGROUND: Diabetic nephropathy (DN) is a leading cause of end-stage renal disease worldwide. Sodium-glucose cotransporter-2 inhibitors (SGLT2is), such as dapagliflozin, have demonstrated renoprotective effects in the t...
BACKGROUND: Diabetic nephropathy (DN) is a leading cause of end-stage renal disease worldwide. Sodium-glucose cotransporter-2 inhibitors (SGLT2is), such as dapagliflozin, have demonstrated renoprotective effects in the treatment of DN. In addition to kidney protection, SGLT2is confer significant cardiovascular and hepatic benefits; however, the mechanisms underlying these multi-organ protective effects have not yet been fully elucidated. METHODS: A total of 51 patients with newly diagnosed DN were enrolled and received dapagliflozin treatment (10 mg/day; AstraZeneca) for 12 weeks. Circulating lipid profiles were analyzed using untargeted lipidomics. To further characterize renal lipid alterations, spatial metabolomics was performed on kidney tissues obtained from dapagliflozin-treated db/db mice. RESULTS: Dapagliflozin treatment significantly reduced serum triglyceride levels while increasing high-density lipoprotein cholesterol in DN patients. Untargeted lipidomic analysis revealed extensive remodeling of the circulating lipidome, marked by reductions in pro-fibrotic and pro-inflammatory lipid species and concurrent increases in renoprotective lipids, including fatty acid esters of hydroxy fatty acids. Machine-learning analyses identified specific lipid ratio changes that were positively correlated with renal function parameters, notably ratios involving SM(d14:0/30:1) and PC(16:0e/18:2). Furthermore, spatial metabolomic profiling in db/db mice demonstrated that dapagliflozin alleviated renal lipotoxicity by reducing the accumulation of toxic lipid species and promoting lipid redistribution predominantly within the renal cortex. Mechanistically, dapagliflozin treatment was associated with enhanced renal fatty acid β-oxidation and sphingolipid degradation while suppressing key anabolic pathways, including de novo lipogenesis and glycerophospholipid and sphingolipid biosynthesis. These metabolic alterations were further evidenced by altered expression of key regulatory enzymes. CONCLUSION: Dapagliflozin is associated with remodeling of renal lipid metabolism in DN, accompanied by improvements in systemic lipid profile. The improvement in circulating dyslipidemia may partially explain the cardiovascular and hepatic protective effects associated with dapagliflozin therapy. Collectively, these findings provide mechanistic insight into the lipid-mediated, multi-organ benefits of dapagliflozin in DN.
A nanobody against CD63 for non-destructive exosome labeling.
Chen S, Wang F, Chen C … +4 more , Cheng Y, Chen M, Li Z, Tang X
Biol Direct · 2026 Apr · PMID 41992356 · Full text
Exosomes, also known as small extracellular vesicles, play crucial roles in cancer progression, inflammation, and tissue regeneration, serving as emerging platforms for diagnostics and therapeutic delivery. However, spec...
Exosomes, also known as small extracellular vesicles, play crucial roles in cancer progression, inflammation, and tissue regeneration, serving as emerging platforms for diagnostics and therapeutic delivery. However, specific and high-affinity binders for non-destructive exosome labeling remain essential due to their complex and heterogeneous nature. Here, we report a nanobody (2E-Nb) identified by phage display that enables precise targeting of CD63, a tetraspanin highly enriched on exosomal membranes, allowing rapid and stable exosome surface modification. Six unique nanobody sequences were isolated, among which 2E-Nb exhibited superior solubility and binding activity. Structural modeling revealed that aromatic and basic residues in the 2E-Nb CDR3 loop form complementary electrostatic and π-π interactions with the CD63 extracellular domain (CD63-ECD). Bio-layer interferometry (BLI) confirmed high-affinity binding with a dissociation constant (KD) of 4.81 × 10− 8 M, characterized by fast association and moderate dissociation kinetics. Confocal microscopy verified the co-localization of 2E-Nb with CD63 in wild-type but not CD63-knockout H293T cells, confirming target specificity. Furthermore, NanoFCM analysis demonstrated that 2E-Nb effectively recognized native exosomal CD63 isolated from H293T cells and mediated efficient fluorescent labeling. Collectively, our findings establish 2E-Nb as a high-affinity, non-destructive tool for exosome labeling and engineering. This nanobody-based strategy provides a convenient and scalable platform for targeted exosome modification, advancing both fundamental exosome research and translational applications.
Exploring and experimental validation of SLC7A11 and ferroptosis related prognostic genes in non-small cell lung cancer using bulk RNA sequencing and single-cell RNA sequencing.
Diao X, Pan S, Duan Y … +1 more , Di L
Biol Direct · 2026 Apr · PMID 41992345 · Full text
BACKGROUND: Non-small cell lung cancer (NSCLC) patients face challenges such as recurrence or resistance to treatment. Multiple studies have demonstrated the importance of SLC7A11 and ferroptosis in NSCLC, but the specif...
BACKGROUND: Non-small cell lung cancer (NSCLC) patients face challenges such as recurrence or resistance to treatment. Multiple studies have demonstrated the importance of SLC7A11 and ferroptosis in NSCLC, but the specific mechanisms still require further investigation. Thus this study aimed to explore SLC7A11 and ferroptosis related prognostic genes and their mechanisms in NSCLC. METHODS: Differentially expressed genes1 (DEGs1) between NSCLC and control groups, and DEGs2 based on high and low SLC7A11 expression groups were intersected with ferroptosis related genes (FRGs) to produce candidate genes. Prognostic genes were then finalized through multiple regression analyses. Subsequently, the prognostic model and nomogram model were constructed and evaluated, followed by functional enrichment, immune microenvironment and molecular regulatory network analyses. The relationships between key cells, prognostic genes, SLC7A11, and NSCLC were then analyzed at the single-cell level. Ultimately, prognostic genes’ expression was determined using reverse transcription quantitative PCR (RT-qPCR). RESULTS: Through regression analyses, 5 prognostic genes (SLC2A1, TRIB3, HNF4A, NOS2, and FLT3) were identified. The prognostic model was subsequently validated in the validation set: survival differences were observed to be significant between risk groups (p < 0.01), and ROC evaluation indicated good diagnostic performance of the model (AUC > 0.6). The nomogram model was also evaluated and showed good disease prediction performance. mTORC1 signaling and glycolysis were found to be associated with NSCLC, and there were 14 different immune cells between 2 risk groups (p < 0.05). Additionally, macrophages were determined as key cells. The expression of SLC2A1, FLT3, and SLC7A11 was found to vary during macrophage differentiation. The RT-qPCR results confirmed that HNF4A and FLT3 was significantly downregulated in the NSCLC group, while SLC2A1 and TRIB3 were significantly upregulated, but there was no significant difference in NOS2. CONCLUSION: This study identified 5 prognostic genes (SLC2A1, TRIB3, HNF4A, NOS2, and FLT3) that might play significant roles in NSCLC, providing valuable insights for prognostic evaluation and mechanism exploration.
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