Biology Direct[JOURNAL]
Sun
200 papers
Integrative analysis of myeloid cell signatures identifies a prognostic risk model and potential mechanisms in bladder cancer.
Wang Y, Gong S, Shen J … +2 more , Liu G, Chen M
Biol Direct · 2026 Apr · PMID 41992284 · Full text
BACKGROUND: Bladder cancer (BLC) is one of the most common malignancies of the urinary system and represents a major public health burden. Myeloid cells are key components of the tumor microenvironment and play critical...
BACKGROUND: Bladder cancer (BLC) is one of the most common malignancies of the urinary system and represents a major public health burden. Myeloid cells are key components of the tumor microenvironment and play critical roles in tumor progression and therapeutic response; however, their prognostic significance in BLC remains incompletely understood. METHODS: The prognostic value of individual myeloid cell markers was evaluated using immunohistochemistry and survival analyses. A myeloid-based prognostic model was constructed using least absolute shrinkage and selection operator (LASSO) regression. The model was validated across multiple independent cohorts. Multiplex immunofluorescence staining and RNA sequencing were performed to investigate immune landscape alterations and signaling pathways associated with different risk groups. RESULTS: High CD68 expression within tumor regions was associated with favorable prognosis, whereas elevated expression of CD14, CD74, CD163, and S100A12 correlated with poor survival outcomes in BLC patients. A myeloid risk score (MRS) was subsequently established and demonstrated robust prognostic performance across validation cohorts. Transcriptomic analysis revealed significant activation of the PI3K–AKT signaling pathway in the MRS-high group. Furthermore, MRS-high tumors exhibited increased expression of PD-L1, FOXP3, and CD11b, along with reduced CD8⁺ T-cell infiltration, indicating a highly immunosuppressive tumor microenvironment. Potential therapeutic targets and candidate agents for MRS-high patients were also identified. CONCLUSIONS: We developed a robust myeloid cell–based prognostic model that effectively stratifies BLC patients by risk and reveals distinct immunosuppressive mechanisms in high-risk tumors. This model may facilitate personalized prognostic assessment and guide precision therapeutic strategies for patients with bladder cancer.
High INHBB expression in colorectal cancer is associated with poor prognosis and drives malignant phenotypes in tumor cells.
Chen H, Wu Y, Huang Z … +5 more , Luo D, Wang Z, Wu J, Zhou T, Zhao H
Biol Direct · 2026 Apr · PMID 41992239 · Full text
BACKGROUND: Colorectal cancer (CRC) represents a prevalent global malignancy, with its progression intimately associated with biological processes such as oxidative stress and anoikis. This study aimed to evaluate a prog...
BACKGROUND: Colorectal cancer (CRC) represents a prevalent global malignancy, with its progression intimately associated with biological processes such as oxidative stress and anoikis. This study aimed to evaluate a prognostic model derived from oxidative stress and anoikis-related genes (OARGs) in CRC and to elucidate the underlying mechanisms of the core gene, INHBB. RESULTS: We constructed a 12-genes prognostic model that retained independent predictive power for overall survival. Among the identified genes, INHBB was significantly upregulated in CRC tissues and cell lines, correlating with poor overall survival. Functional characterization revealed that INHBB overexpression markedly promoted malignant phenotypes, including proliferation, migration, and invasion. INHBB accelerates cell cycle progression, confers resistance to anoikis, exacerbates oxidative stress, and activates the epithelial-mesenchymal transition (EMT) pathway. CONCLUSION: Beyond validating a novel OARGs-based prognostic model, this study highlights INHBB as a critical malignant regulator driving colorectal cancer aggressiveness, suggesting its potential as a prognostic biomarker and precision therapeutic target. CLINICAL TRIAL NUMBER: Not applicable.
An integrated microbiome-drug interaction and bioinformatics approach identifies active deglycosylated and glycosidic chain metabolites of Platycodin D targeting PTPN2/HIF1A in acute lung injury.
Zhong Y, Peng Y, Zhang S … +9 more , Wen L, Liu G, Xu B, Liang Y, Huang H, He J, Feng Y, Zeng J, Liang J
Biol Direct · 2026 Apr · PMID 41987241 · Full text
BACKGROUND: Platycodin D (PD) is a typical triterpenoid saponin with low oral bioavailability. Despite its potent anti-ALI effects, its active metabolites and underlying mechanisms remain unclear, thereby significantly i...
BACKGROUND: Platycodin D (PD) is a typical triterpenoid saponin with low oral bioavailability. Despite its potent anti-ALI effects, its active metabolites and underlying mechanisms remain unclear, thereby significantly impeding its further development. This study aimed to establish a new integrated method combining microbiome-drug interaction analysis, bioinformatics approaches, and experimental validation to elucidate the active metabolites and mechanisms by which PD exerts anti-ALI effects. METHODS: Microbiome-drug interaction analysis identified PD-derived metabolites, including deglycosylated metabolites (DGMs), glycosidic chain metabolites (GCMs), and short-chain fatty acids (SCFAs) derived from the glycosidic chains, while simultaneously assessing PD’s modulatory effects on the intestinal microbiota. Bioinformatics approaches predicted the potential anti-ALI targets of the metabolites in the blood. The bioactivities and mechanisms of these metabolites were subsequently validated using LPS-induced and pseudo-sterile ALI mouse models and molecular docking. RESULTS: PD and its 9 DGMs were identified in vitro, while only Deapio-platycodin D (DPD), 3-O-β-D-glucopyranosyl platycodigenin (GPN) and platycodigenin (PN) were detected in serum; 9 GCMs including 1 trisaccharide, 2 disaccharides and 5 monosaccharides derived from the glycosidic chain of PD were identified in vitro. Only 5 monosaccharides of Glucose (Glu), Arabinose (Ara), Rhamnose (Rha), Xylose (Xyl) and Apiose (Api) were detected in serum. Notably, saccharide-to-SCFA transformation was markedly inhibited both in vitro and in serum. PD also modulated intestinal microbiota by increasing probiotics and reducing pathogens. Bioinformatics analysis showed DGMs targeted PTPN2, whereas GCMs co-targeted both PTPN2 and HIF1A. In vivo models confirmed the activities and mechanisms of PD, while molecular docking further verified the active metabolites were 2 DGMs of GPN, PN and 5 GCMs of Glu, Ara, Rha, Xyl and Api. CONCLUSIONS: Novel active metabolites and mechanisms of PD against ALI were elucidated and validated by the proposed strategy. Bioactivity of PD extends beyond its metabolites with parent nucleus, as GCMs of PD also showed significant activities. SCFAs are not necessarily active metabolites of PD despite its saccharide-rich structures. In addition, this study establishes a new paradigm for elucidating active metabolites and mechanisms of glycosides, especially those with low oral bioavailability, advancing natural product-based ALI treatment strategies.
Novel genetic insights into causal effects of potential metformin targets and immune mediation on sepsis.
Xiang L, Sun J, Yang L … +4 more , Luo Y, Wang Y, Chen K, Meng X
Biol Direct · 2026 Apr · PMID 41981622 · Full text
BACKGROUND: Sepsis remains a major global clinical challenge with limited therapies. Metformin shows promising therapeutic potential, likely through immune modulation, yet mechanistic evidence remains scarce. Hence, our...
BACKGROUND: Sepsis remains a major global clinical challenge with limited therapies. Metformin shows promising therapeutic potential, likely through immune modulation, yet mechanistic evidence remains scarce. Hence, our study aimed to investigate the causal effect of metformin on sepsis and explore the role of immune function in mediating this effect. METHODS: We first assessed metformin’s causal effect on sepsis using two-sample Mendelian randomization (MR), then employed two-step MR to evaluate immune mediation of this effect. MR-Egger regression was conducted to detect pleiotropy and heterogeneity. Database-based single-cell RNA-seq analysis and sepsis mouse model further validated the MR findings. RESULTS: Two-sample MR indicated that metformin use, via PRKAB1 activation, was associated with a reduced risk of sepsis (OR = 0.9743, 95% CI: 0.9538–0.9951, P = 0.0160). Mediation analysis showed that 10 specific immune cell subsets, including CD39 + CD4+%T cell, CD39 + CD4+AC, CD39 + secreting Treg AC, CD14 + CD16+ monocyte AC, CD86 on myeloid DC, CD14 + CD16+ monocyte% monocyte, CD127 on CD28 + CD4+, CD3-lymphocyte %leukocyte, CD127 on T cell and CD127 on CD45RA-CD4 not Treg mediated metformin’s protective effects. Single-cell RNA-seq analysis revealed reduced T cells and monocytes during sepsis, consistent with MR results that identified elevated T cells and monocytes as major protective factors. PRKAB1 and its homologous genes were highly expressed in the mediation-linked immune cells. In septic mice, metformin attenuated lung injury and inflammatory infiltration, concurrently upregulating PRKAB1 expression significantly. mIHC and IHC assays confirmed metformin pretreatment reversed sepsis-induced CD86 elevation and depletion of CD39, CD4 and CD14. CONCLUSION: Our findings implied that metformin might contribute to sepsis protection, potentially involving PRKAB1-mediated modulation of CD39, CD4, CD14 and CD86. These observations could provide clues for developing targeted therapeutic strategies combining metformin with immune modulation for sepsis.
The MST4-14-3-3ζ complex promotes pancreatic cancer by activating YAP.
Tian L, Zhao Z, Ding S … +9 more , Li M, Han Y, Zhu C, Pan Y, Wang X, Kang W, An L, Zhou Z, Tang Y
Biol Direct · 2026 Apr · PMID 41981454 · Full text
BACKGROUND: The mammalian STE20-like kinase 4 (MST4) has been implicated as a potential oncogene in various cancers, including pancreatic cancer (PC). However, the precise mechanisms through which MST4 promotes PC malign...
BACKGROUND: The mammalian STE20-like kinase 4 (MST4) has been implicated as a potential oncogene in various cancers, including pancreatic cancer (PC). However, the precise mechanisms through which MST4 promotes PC malignancy remain incompletely understood. METHODS: A Biotin identification (BioID)-based proximity labeling approach was employed to identify key MST4-interacting molecules in human PANC-1 pancreatic cancer (PC) cells, followed by cell migration assay to validate the synergistic promotional effect of the MST4-interacting complex on PC cell migration. Direct binding between MST4 and its interacting partners was confirmed via microscale thermophoresis (MST) and isothermal titration calorimetry (ITC), with further validation through X-ray crystallographic structural analysis. The efficacy of rationally designed peptides targeting this interaction was evaluated in both in vitro cell models and in vivo xenograft mouse models. RESULTS: In this study, we demonstrate that MST4 forms a phosphorylation-dependent complex with 14-3-3ζ, leading to Yes-associated protein (YAP) activation and synergistic enhancement of PC cell migration. We observed significant upregulation of both MST4 and 14-3-3ζ in PC patient samples, which correlated strongly with YAP activation and poor prognosis. Structural analysis revealed the detailed interface of the MST4–14-3-3ζ complex, facilitating the rational design of peptide inhibitors that disrupt this interaction. These peptides effectively suppressed YAP activation and exhibited potent anti-tumor effects both in vitro and in vivo. CONCLUSIONS: Our findings establish the MST4–14-3-3ζ complex as a critical regulator of YAP signaling that synergistically promotes PC cell migration. Furthermore, rationally designed peptides targeting this MST4–14-3-3ζ interaction represent a promising therapeutic strategy for pancreatic cancer and warrant further clinical exploration.
ZNF750 suppresses esophageal squamous cell carcinoma by maintaining epithelial barrier-driven mucosal immune homeostasis.
Zhou T, Fan J, Wang M … +7 more , Cheng C, Yuan F, Li J, Wan H, Cui D, Miao Y, Bi Y
Biol Direct · 2026 Apr · PMID 41975543 · Full text
BACKGROUND: Recent studies have shown that zinc finger protein 750 (ZNF750), a key tumor suppressor in esophageal squamous cell carcinoma (ESCC), is associated with defective epithelial differentiation. At the same time,...
BACKGROUND: Recent studies have shown that zinc finger protein 750 (ZNF750), a key tumor suppressor in esophageal squamous cell carcinoma (ESCC), is associated with defective epithelial differentiation. At the same time, mucosal immune dysfunction is increasingly recognized as a key factor in the development of ESCC. Exploring the role of ZNF750 in regulating the mucosal immune microenvironment provides a new perspective on its tumor suppression mechanism. RESULTS: By integrating analyses across multiple platforms, including bulk transcriptomics (TCGA, GTEx, GEO), and single-cell RNA sequencing (scRNA-seq), we demonstrate that ZNF750 is significantly downregulated in ESCC, with high expression serving as an independent prognostic marker for longer survival. Mechanistically, ZNF750 suppresses ESCC progression by maintaining epithelial barrier–driven mucosal immune homeostasis. WGCNA analyses indicate that ZNF750-high tumors are enriched in mucosal immune response and antimicrobial defense pathways. Experimental validation reveals that ZNF750 positively regulates DEFB4A (human beta-defensin-2), a key antimicrobial peptide. In addition, ZNF750 fosters an anti-tumor immune environment by recruiting neutrophils and suppressing pro-tumor M2 macrophages, a finding corroborated by clinical validation showing that high ZNF750 expression correlates with elevated neutrophil infiltration. Clinical validation confirms that high ZNF750 expression correlates with elevated neutrophil infiltration. Additionally, ZNF750 expression is linked to a healthy mucosal microbiota and the exclusion of pro-carcinogenic bacteria. Single-cell analysis shows that ZNF750-expressing epithelial cells maintain barrier integrity and coordinate immune surveillance through MHC-I/II signaling. Loss of ZNF750 may drive mucosal immune dysregulation, where the immune network is replaced by a pre-fibrotic immunosuppressive niche dominated by cancer-associated fibroblasts (CAFs). CONCLUSIONS: Collectively, our findings identify ZNF750 as a key molecular link between epithelial barrier integrity and mucosal immune surveillance in ESCC, highlighting restoration of ZNF750-mediated barrier immunity as a potential therapeutic strategy for ESCC.
The miR-143/145 cluster in prostate cancer: molecular regulation, context-dependent functions, and medical implications.
Stope MB, Erb HHH
Biol Direct · 2026 Apr · PMID 41965814 · Full text
The microRNA (miR) cluster miR-143/145 represents a well-characterized tumor-suppressive regulatory system with a multifaceted role in prostate cancer. Both miRs are consistently downregulated during disease progression,...
The microRNA (miR) cluster miR-143/145 represents a well-characterized tumor-suppressive regulatory system with a multifaceted role in prostate cancer. Both miRs are consistently downregulated during disease progression, and their loss is associated with enhanced proliferation, invasion, epithelial–mesenchymal transition, and metastatic competence. Mechanistically, the cluster modulates Rat Sarcoma Viral Oncogene Homolog (RAS)-Mitogen Activated Protein Kinase (MAPK) signaling via Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) and Extracellular Signal-Regulated Kinase 5 (ERK5), Tumor Protein p53 (p53)-dependent growth control through MYC Proto-Oncogene, Basic Helix-Loop-Helix Transcription Factor (c-MYC) repression, apoptosis via B-Cell Lymphoma 2 Interacting Protein 3 (BNIP3), and cytoskeleton-associated motility factors including Fascin Actin-Bundling Protein 1 (FSCN1), Human Enhancer of Filamentation 1/ Neural Precursor Cell Expressed, Developmentally Down-Regulated Protein 9 (HEF1/NEDD9), Golgi Membrane Protein 1 (GOLM1), and Fibronectin Type III Domain Containing 3B (FNDC3B). Downregulation is mainly driven by p53 dysfunction, promoter methylation, and RAS-dependent transcriptional repression. A defining feature is pronounced cell-type specificity, with tumor-suppressive effects in epithelial cells and context-dependent pro-angiogenic functions in stromal compartments, with direct translational relevance. Clinically, miR-143/145 contribute to multimarker diagnostic signatures, while reduced miR-145 correlates with adverse pathology and biochemical recurrence. Preclinical replacement strategies reduce tumor growth and enhance docetaxel sensitivity, yet context-dependent effects necessitate cell type-specific delivery. Overall, the cluster represents a central regulator with diagnostic, prognostic, and therapeutic potential requiring prospective validation.
Paxillin mediates ARP2-dependent actin assembly for spindle migration in mammalian oocyte meiosis.
Wang Y, Wu ZJ, Pan WL … +6 more , Liu JC, Ju JQ, Pan ZN, Zhao X, Wang C, Sun SC
Biol Direct · 2026 Apr · PMID 41963992 · Full text
Paxillin is a multi-domain scaffold protein that is involved in several cellular functions, including focal adhesion, cell motility and cell aging. Previous studies have shown that Paxillin affects the resumption of meio...
Paxillin is a multi-domain scaffold protein that is involved in several cellular functions, including focal adhesion, cell motility and cell aging. Previous studies have shown that Paxillin affects the resumption of meiosis in Xenopus oocytes. In the present study, we report the distinct roles of Paxillin in mammalian oocytes including mice and pigs. Our results indicate that Paxillin is expressed in mouse oocytes and is primarily concentrated in the cortical area, which is closely associated with actin. Disruption of Paxillin expression or function did not influence the process of germinal vesicle breakdown in either mouse or porcine oocytes at GV stage, as confirmed by the expression levels of Mos and MPF. Furthermore, Paxillin disruption did not alter spindle morphology but did affect meiotic spindle migration and polar body extrusion, likely due to a decrease in actin filaments. Further analysis revealed that the actin nucleators Arp2/3 and N-WASP were reduced in Paxillin-knockdown oocytes at MI stage. Overexpression of Paxillin also did not impact GV breakdown, spindle formation, or polar body extrusion. However, the supplementation of exogenous Paxillin mRNA rescued the defects in spindle positioning and polar body extrusion caused by Paxillin knockdown. Taken together, our findings suggest that Paxillin plays a critical role in spindle migration during oocyte meiosis by mediating actin dynamics through the Arp2/3 complex, highlighting functional differences between species.
Single-cell RNA sequencing analysis reveals the evolution and regulatory features of specialized endothelial cell subsets in non-traumatic osteonecrosis of the femoral head.
Tang S, Lu H, Zheng X … +7 more , Dong Z, Liu J, Huang Q, Li B, Ding X, Zhao J, Liao S
Biol Direct · 2026 Apr · PMID 41957812 · Full text
Non-traumatic osteonecrosis of the femoral head (NONFH) is a disabling disease mainly caused by glucocorticoid use and alcohol abuse, characterized by local impairment of blood supply and limited bone repair; however, th...
Non-traumatic osteonecrosis of the femoral head (NONFH) is a disabling disease mainly caused by glucocorticoid use and alcohol abuse, characterized by local impairment of blood supply and limited bone repair; however, the composition and regulatory mechanisms of specialized endothelial cells (ECs) in its microenvironment remain unclear. In this study, we used single-cell RNA sequencing (scRNA-seq) to identify four EC subsets, including type L, type H, type R, and arterial ECs. Type H and type R ECs were primarily enriched in cell adhesion and angiogenesis pathways and represented key subsets that promote bone repair in NONFH. Their abundance increased during the mid-stage of NONFH but declined in the late stage. Stromal cells in the femoral head interacted with type H and type R ECs through multiple ligand–receptor axes, maintaining their function. Further screening identified PDK4 as a critical regulator of type H and type R EC abundance. PDK4 not only promotes endothelial fatty acid oxidation but also participates in iron homeostasis and angiogenesis. In vitro experiments showed that PDK4 knockdown significantly impaired the angiogenic phenotype of ECs, which was associated with suppressed fatty acid oxidation, highlighting PDK4’s role in sustaining the activity and function of type H and type R ECs under disease conditions. Peripheral blood transcriptome analysis revealed that the dynamic expression pattern of PDK4 across NONFH stages was consistent with the single-cell results, suggesting potential value for stage-specific diagnosis. By integrating single-cell and peripheral blood transcriptome analyses with in vitro experiments and metabolomic validation, this study elucidates the dynamic changes of specialized ECs and the PDK4-mediated metabolic regulatory mechanisms during NONFH progression. These findings provide new insights into vascular repair and potential therapeutic strategies for NONFH.
METTL16 promotes MASLD progression through the regulation of lipid synthesis and immune response.
Li G, Wang L, Zhang L … +2 more , Guo J, Sun Q
Biol Direct · 2026 Apr · PMID 41952207 · Full text
BACKGROUND: Methyltransferase-like 16 (METTL16) is a recently identified m6A RNA methyltransferase. Although its role in hepatocellular carcinoma has been explored, its function in metabolic dysfunction-associated steato...
BACKGROUND: Methyltransferase-like 16 (METTL16) is a recently identified m6A RNA methyltransferase. Although its role in hepatocellular carcinoma has been explored, its function in metabolic dysfunction-associated steatotic liver disease (MASLD) remains elusive. METHODS: Expression profiles of methylation-related genes were analyzed in a cohort comprising 206 MASLD patients and 10 healthy controls. Functional assays were conducted using MASLD cell models and diet-induced mouse models. Bioinformatic analyses were performed to evaluate immune cell infiltration and signaling pathway activation. Potential transcriptional regulators and small-molecule inhibitors of METTL16 were predicted through multiple databases. RESULTS: METTL16 expression was markedly upregulated in MASLD tissues and closely correlated with lipid metabolism-related pathways. Knockdown of METTL16 alleviated hepatic steatosis, insulin resistance, and fibrosis in high-fat diet-fed mice. Mechanistically, cell death-inducing DFF45-like effector family members A (CIDEA) was identified as a downstream mediator of METTL16-driven hepatic steatosis. Elevated hepatic METTL16 expression was associated with increased infiltration of innate immune cells, activation of immune-related signaling pathways, and upregulated expression of pro-fibrotic genes. Database mining further revealed that METTL16 may regulate immune-associated genes at both transcriptional and post-transcriptional levels. Additionally, EGR1 and MYC were identified as potential upstream transcriptional regulators of METTL16, and eleven small molecules were predicted to bind to and inhibit its biological activity. CONCLUSION: METTL16 promotes hepatic steatosis and immune-mediated fibrogenesis in MASLD. Targeting the METTL16-CIDEA axis or inhibiting METTL16 activity may serve as a promising therapeutic strategy for the treatment of MASLD.
NSDHL as a regulator of lipid peroxidation and ER stress-mediated apoptosis in ovarian cancer.
Shanshan X, Jinshi R, Wanlin C … +7 more , Yuwan L, Hanye J, Shizhou Y, Weidong F, Huimei Z, Yongmei X, Weiguo L
Biol Direct · 2026 Apr · PMID 41952197 · Full text
Elevated expression of NAD(P)-dependent steroid dehydrogenase-like (NSDHL), a key enzyme in cholesterol biosynthesis, is associated with ovarian cancer progression and poor prognosis. However, the mechanisms underlying i...
Elevated expression of NAD(P)-dependent steroid dehydrogenase-like (NSDHL), a key enzyme in cholesterol biosynthesis, is associated with ovarian cancer progression and poor prognosis. However, the mechanisms underlying its tumor-promoting effects remain unclear. Here, we show that high NSDHL expression correlates with adverse clinical outcomes, particularly in aggressive subtypes such as high-grade serous ovarian cancer. NSDHL knockdown in cultured ovarian cancer cells reduced viability, triggered lipid peroxidation, and disrupted cholesterol and redox homeostasis, accompanied by elevated reactive oxygen species (ROS). Quantitative proteomic profiling revealed broad alterations in lipid metabolism, including suppression of fatty acid oxidation and PPARγ signaling, with upregulation of ACSL4 and downregulation of ACSL3. This shift toward polyunsaturated fatty acid (PUFA) enrichment enhanced susceptibility to oxidative stress but did not induce ferroptosis, owing to reduced intracellular iron levels. Notably, this paradoxical increase in lipid peroxidation despite iron deficiency contrasts with the classical ferroptosis model, in which iron is required to initiate and propagate lipid peroxidation, suggesting that NSDHL depletion uncouples oxidative membrane damage from canonical ferroptotic execution. Instead, apoptosis was mediated by lipid peroxidation–induced endoplasmic reticulum (ER) stress, as confirmed by upregulation of ER stress markers and activation of ER-specific caspases. Importantly, NSDHL depletion suppressed tumor growth and promoted ER stress–mediated apoptosis in ovarian cancer xenografts. These findings identify NSDHL as a key regulator of lipid metabolism and oxidative stress in ovarian cancer and highlight its potential as a therapeutic target.
TYMP upregulation mediated by the hyperactivated IL-17/NF-κB1 axis promotes psoriasis through enhancing aberrant keratinization and neutrophil-mediated inflammation.
Wang J, Zhou Z, Chen Y … +5 more , Li Q, Zhai L, Li D, Qin S, He Y
Biol Direct · 2026 Apr · PMID 41952181 · Full text
Psoriasis is a common, chronic, and recurrent immune-mediated disorder with global prevalence, underscoring the need for novel biomarkers to improve diagnosis and treatment. In this study, differentially expressed genes...
Psoriasis is a common, chronic, and recurrent immune-mediated disorder with global prevalence, underscoring the need for novel biomarkers to improve diagnosis and treatment. In this study, differentially expressed genes (DEGs) in psoriatic tissues were comprehensively identified through integrated single-cell and bulk RNA-seq analyses. Thymidine phosphorylase (TYMP) emerged as one of the most significantly upregulated biomarkers in psoriasis. Multiplex immunohistochemistry (mIHC) and IHC assays jointly confirmed marked overexpression of TYMP in psoriatic keratinocytes. Mechanistically, we demonstrated that IL-17-mediated inflammatory signaling transcriptionally induces TYMP expression via NF-κB1. TYMP overexpression promotes keratinocyte proliferation and activates signaling pathways associated with keratinization and neutrophil degranulation in psoriasis. Immune infiltration analysis, blood routine tests, and ELISA verified that TYMP upregulation is closely correlated with neutrophil degranulation in psoriasis. In the imiquimod (IMQ)-induced psoriasis-like mouse model, pharmacological inhibition of TYMP by tipiracil partially reverses the pathological effects of TYMP overexpression, including accelerated keratinocyte proliferation, aberrant keratinization, and neutrophil-driven inflammation. In summary, TYMP is overexpressed in psoriasis due to hyperactivation of the IL-17/NF-κB1 signaling. Targeting TYMP by Tipiracil ameliorates psoriasis symptoms by suppressing abnormal keratinization and neutrophil degranulation, thereby highlighting its potential as a therapeutic target for psoriasis.
Identification and functional validation of mitochondria-related genes associated with tubular injury in kidney transplantation and ischemia-reperfusion injury.
Dong B, Bi H, Wang C … +9 more , Wang J, Wang Y, Chen Z, Wang J, Lu C, Ma R, Zheng J, Li Y, Ding X
Biol Direct · 2026 Apr · PMID 41947228 · Full text
BACKGROUND: Ischemia–reperfusion injury (IRI) limits graft function and long-term outcomes after kidney transplantation. Proximal tubular (PT) cells are highly mitochondria-rich and metabolically active, making them vuln...
BACKGROUND: Ischemia–reperfusion injury (IRI) limits graft function and long-term outcomes after kidney transplantation. Proximal tubular (PT) cells are highly mitochondria-rich and metabolically active, making them vulnerable to ischemic and oxidative stress. However, the molecular mechanisms linking mitochondrial dysfunction to graft function remain incompletely understood. METHODS: We integrated single-nucleus RNA sequencing, bioinformatics analyses, and experimental validation to identify mitochondria-associated genes in PT cells related to graft injury and vulnerability in the transplant setting. Mitochondria-related differentially expressed genes (Mito-DEGs) were used to construct machine learning models for delayed graft function (DGF) risk stratification. The candidate gene HAO2 was further evaluated by immunohistochemistry (IHC) in kidney transplant biopsies, a murine IRI model, and H₂O₂-treated HK-2 cells. Human biopsy samples were obtained at or prior to reperfusion and may not fully capture the extent of post-transplant IRI. Both overexpression and siRNA-mediated knockdown were performed to assess its function. Cell viability, apoptosis, and mitochondrial function were assessed using standard assays. RESULTS: PT cells from acute kidney injury samples exhibited mitochondrial dysfunction and metabolic impairment. Donor kidney clustering suggested heterogeneity in DGF risk associated with mitochondrial bioenergetic capacity. An eight-gene Mito-DEG signature demonstrated moderate performance in stratifying DGF risk. IHC analysis demonstrated that HAO2 expression was reduced in DGF recipient biopsies. Consistently, HAO2 was downregulated in murine IRI kidneys and injured HK-2 cells. Functionally, HAO2 overexpression alleviated oxidative stress, apoptosis, and mitochondrial dysfunction, whereas HAO2 knockdown exerted opposite effects and further aggravated H₂O₂-induced injury. Regulatory analysis identified 14 miRNAs and four TFs potentially controlling HAO2, while downstream pathways linked HAO2 to amino acid and fatty acid metabolism, extracellular matrix organization, and immune responses. CONCLUSIONS: These findings suggest that HAO2 may serve as a functional indicator of mitochondrial metabolic capacity associated with graft vulnerability rather than being specific to IRI alone. Given the observational nature of the clinical data, further studies are required to determine whether HAO2 provides added value beyond established histopathological assessment and to clarify its potential role in guiding mitochondrial-targeted conditioning strategies, such as oxygenated machine perfusion, aimed at preserving graft function during transplantation. CLINICAL TRIAL NUMBER: Not applicable.
PLIN3 overexpression in lung adenocarcinoma promotes M2 macrophage-myofibroblast transition in the tumor microenvironment.
Tian K, Ma G, Guo D … +5 more , Jiang H, Zhao X, Wang G, Du J, Pang Z
Biol Direct · 2026 Apr · PMID 41943031 · Full text
BACKGROUND: Macrophage–myofibroblast transition (MMT) promotes tumor progression. Studies have primarily emphasized macrophage-intrinsic regulation; however, whether lung adenocarcinoma (LUAD) cells actively drive MMT in...
BACKGROUND: Macrophage–myofibroblast transition (MMT) promotes tumor progression. Studies have primarily emphasized macrophage-intrinsic regulation; however, whether lung adenocarcinoma (LUAD) cells actively drive MMT in tumor-associated macrophages (TAMs) remains unclear. METHODS: We integrated LUAD single-cell RNA sequencing (scRNA-seq) and bulk transcriptomic datasets, applying MMT-infiltration-stratified differential analysis to identify tumor cell-derived upstream regulators of MMT. Multiple machine learning algorithms were used to construct an MMT-related risk score. SHAP analysis prioritized key genes, and NicheNet inferred tumor–macrophage ligand–receptor–target axes. Tumor cell–conditioned medium (CM)–driven MMT induction in M2 macrophages was examined by dual immunofluorescence and in vitro experiments. RESULTS: Single-cell analysis showed that M2 macrophages in LUAD exhibit variable activation of an MMT-related transcriptional program. Tumor-level differential analysis across MMT infiltration strata identified tumor cell-derived candidate regulators of MMT. A 9-gene MMT prognostic risk model was established using univariate Cox regression and machine learning analyses. This model achieved a higher C-index than previously reported models, and high-risk tumors displayed an immunosuppressive infiltration pattern. SHAP analysis identified PLIN3 as a key driver. NicheNet analysis suggested that PLIN3-high tumor cells may induce MMT through TGF-β1-related signaling. Immunohistochemistry demonstrated PLIN3 upregulation in LUAD tissues, while immunofluorescence further revealed enrichment of CD68⁺α-SMA⁺ macrophages around tumor cells in PLIN3-high samples. LUAD cell-derived CM induced MMT in M2 macrophages. PLIN3 knockdown in LUAD cells attenuated CM-induced MMT, whereas PLIN3 overexpression enhanced it. PLIN3 knockdown also suppressed LUAD cell migration, invasion, and colony formation. CONCLUSION: High PLIN3 expression in LUAD promotes MMT through tumor–macrophage crosstalk in the tumor microenvironment.
Exploring the intersection between necromass reutilization and genome protection reveals novel proteins that contribute to both processes in Ustilago maydis.
Stanovcic S, Milisavljevic M, Kolarevic S … +1 more , Kojic M
Biol Direct · 2026 Apr · PMID 41933420 · Full text
BACKGROUND: Recovery of microbial populations following severe stress and extensive loss of viability-termed RUS (repopulation upon shattering)-represents a fundamental biological challenge. Successful RUS depends on the...
BACKGROUND: Recovery of microbial populations following severe stress and extensive loss of viability-termed RUS (repopulation upon shattering)-represents a fundamental biological challenge. Successful RUS depends on the ability of surviving cells to acquire and recycle material released from dead cells. However, depending on the nature and intensity of stress, the liberated substrates may contain energy-rich yet potentially hazardous or genotoxic compounds. Previous studies in the basidiomycete fungus Ustilago maydis indicated that effective RUS requires not only metabolic recycling but genome-protection mechanisms. The principal aim of this study was to further investigate the link between RUS and genome stability. RESULTS: Supernatants derived from peroxide-treated cells induced significant DNA damage in untreated wild-type cells, demonstrating that substrates released from dead cells possess intrinsic genotoxic potential. Analysis of mutants deficient in genome-protection pathways revealed that deletion of several homologous recombination and excision repair factors caused minor impairment of substrate reutilization. In contrast, loss of key regulatory components-including the small acidic protein Dss1, the recombination- and cell cycle-associated factor Rec1, and especially the apical checkpoint kinase Atr1-resulted in strong defects in growth under supernatant-induced stress. Transcriptome-guided analysis identified additional genes linking RUS to genome protection. Deletion of a Nudix hydrolase (designated Ndx1) and a Pirin-like protein (Pir1) significantly impaired growth on substrates, while disruption of UMAG_05976 caused a severe RUS phenotype and sensitivity to DNA-damaging agents. UMAG_05976 belongs to a set of supernatant-induced genes lacking detectable conserved domains but with homologs restricted to closely related smut fungi within Ustilaginales. UMAG_05976 was designated Rdf1 (RUS-deployed factor 1). A complementary genetic screen identified mutations in genes encoding a class V myosin (Myo2), a PX-domain-containing protein (Lec1), a ubiquitin-specific protease (Usp1), and a leucine biosynthetic enzyme (Leu4), which all impaired substrate re-utilization and increased genotoxic sensitivity. CONCLUSIONS: Together, these findings demonstrate that growth on nutrients derived from damaged cells inherently challenges genome integrity and requires coordinated activity of checkpoint signaling, stress-response regulators, ubiquitin-mediated regulation, and membrane-associated processes. This study strengthens the conceptual link between RUS and genome protection and provides a framework for future investigations of microbial survival after extreme stress.
MiR-142-3p promotes radioresistance by targeting FOXO4 in colorectal cancer.
Wang X, Hua WX, Liu Y … +1 more , Li HD
Biol Direct · 2026 Apr · PMID 41933410 · Full text
Radiation therapy (RT) is one of the most important strategies for killing cancer cells and shrinking tumors. However, in colorectal cancer, the application of radiotherapy is restricted due to radioresistance. Therefore...
Radiation therapy (RT) is one of the most important strategies for killing cancer cells and shrinking tumors. However, in colorectal cancer, the application of radiotherapy is restricted due to radioresistance. Therefore, exploring the detailed mechanisms of radioresistance may improve patient responses to irradiation and enhance survival rates. Here, we selected SW480 and SW620 cells for X-ray radiotherapy. To determine the D10 (the dose that reduces cell survival to 10%) of colorectal cancer cells to X-ray, we used a colony formation assay, and 6 Gy was chosen for further experiments. Through TCGA, we found that miR-142-3p was upregulated in colorectal cancer cells. We then transfected miR-142-3p into colorectal cancer cells, constructing stable lines. We discovered that miR-142-3p promoted the radioresistance of colorectal cancer cells, and in vivo assays also demonstrated the same effect. Mechanistically, we identified FOXO4 as the direct target of miR-142-3p by Dual Luciferase Reporter Assay. RNA sequencing revealed that miR-142-3p enhanced DNA damage repair. Western blot analysis determined that the NHEJ pathway was involved in regulating this process, including DNA-PKcs, Ku80, Rad50, NBS1, MRE11, XRCC1, LIG3, et al. Together, our findings suggest that miR-142-3p plays a radioresistant role in colorectal cancer and reveals a potential therapeutic target to enhance the effectiveness of radiotherapy. CLINICAL TRIAL NUMBER: Not applicable.
Plasma metabolomic profiling identifies a metabolic signature for non-muscle-invasive bladder cancer independent of hematuria.
Speziale R, Iacovelli V, Leoni G … +7 more , Anzillotti L, Puca F, Cipriani C, Carilli M, Carugo A, Toniatti C, Bove P
Biol Direct · 2026 Apr · PMID 41933405 · Full text
BACKGROUND: Non-muscle-invasive bladder cancer (NMIBC) accounts for approximately 75% of bladder cancer cases and, despite a generally favorable prognosis, requires lifelong cystoscopic surveillance, resulting in substan...
BACKGROUND: Non-muscle-invasive bladder cancer (NMIBC) accounts for approximately 75% of bladder cancer cases and, despite a generally favorable prognosis, requires lifelong cystoscopic surveillance, resulting in substantial clinical burden. Non-invasive biomarkers with metabolic and translational relevance are needed to improve disease detection and patient stratification. Plasma represents a stable systemic matrix that captures tumor-associated metabolic alterations while minimizing pre-analytical variability. RESULTS: Targeted metabolomic profiling of 630 metabolites and 252 metabolic indicators was performed in plasma samples from 249 individuals, including 51 patients with NMIBC and 198 control individuals. Integrated univariate and multivariate analyses were used to identify discriminant metabolites, assess pathway-level perturbations, and develop diagnostic models. Model robustness was evaluated with respect to hematuria status. A total of 29 metabolites and 17 metabolic indicators were significantly altered in NMIBC. The dominant metabolic signature involved lipid and bile acid metabolism, characterized by reduced conjugated bile acids and increased lysophosphatidylcholines and polyunsaturated fatty acid species. Pathway enrichment analysis indicated perturbations in bile acid biosynthesis, PUFA turnover, glutathione metabolism, and glycolytic pathways. A diagnostic model based on 11 metabolites achieved high accuracy (AUC = 0.92 in the training set and 0.88 in the test set). Hematuria status did not affect clustering or model performance. CONCLUSIONS: Plasma metabolomic profiling identifies a systemic metabolic signature associated with lipid and bile acid dysregulation in NMIBC and supports the development of clinically applicable, non-invasive plasma-based approaches for bladder cancer detection and patient stratification. Further validation in independent and longitudinal cohorts is warranted.
DLAT inhibits ferroptosis to promote malignant progression of gastric cancer through Nrf2/HO-1/GPX4 signaling pathway.
Li L, Zhao H, Niu X … +1 more , Liu P
Biol Direct · 2026 Apr · PMID 41928317 · Full text
BACKGROUND: Ferroptosis is a novel regulatory mechanism of cell death caused by iron-dependent lipid peroxidation (lipid-ROS) accumulation. The aim of this study was to explore whether dihydrolipoic acid transacetylase (...
BACKGROUND: Ferroptosis is a novel regulatory mechanism of cell death caused by iron-dependent lipid peroxidation (lipid-ROS) accumulation. The aim of this study was to explore whether dihydrolipoic acid transacetylase (DLAT) influences ferroptosis to promote the progression of gastric cancer (GC). METHODS: The expression of DLAT in GC tissues and cell lines was examined by qRT-PCR, western blotting, and immunohistochemistry. Kaplan–Meier survival curve analysis was used to estimate overall survival, and the log-rank test was used to estimate recurrence-free survival. The functional role of DLAT in GC was evaluated using in vitro and in vivo experiments including MTT, scratch healing tests, transwell assays and a xenograft tumor mouse model. Ferroptosis was evaluated by using malondialdehyde (MDA), reduced glutathione (GSH), lactate dehydrogenase (LDH), and superoxide dismutase (SOD) detection kits, iron accumulation assays, lipid ROS quantification, and mitochondrial deep red fluorescence staining kits. Western blotting was used to detect the biomarkers of ferroptosis and the interactions between DLAT and Nrf2, HO-1 and GPX4. RESULTS: We found that DLAT was upregulated in GC cells and tissues, and high DLAT expression indicated poor prognosis. Knockdown of DLAT inhibited the proliferation, invasion and metastasis of GC cells by increasing the levels of MDA and LDH, promoting the accumulation of Fe2+ and lipid ROS, consuming GSH and SOD, reducing mitochondrial membrane potential, and suppressing the expression of GPX4. Overexpression of GPX4 can specifically salvage the growth inhibition of GC cells caused by DLAT knockdown, but did not affect the activity of the upstream DLAT, Nrf2 and HO-1. The inhibition of ferroptosis by DLAT was related to the regulation of the Nrf2/HO-1/GPX4 antioxidant axis. In vivo, DLAT inhibited the Nrf2/HO-1 axis, hindering the growth of transplanted tumors. CONCLUSION: These results indicated that DLAT deficiency increased accumulation of Fe2+ and lipid ROS, enhanced disruption of mitochondrial membrane potential, and induced ferroptosis through the Nrf2/HO-1/GPX4 axis, thereby inhibiting the malignant progression of GC cells. DLAT serves as a prognostic biomarker and potential therapeutic target for GC. TRIAL REGISTRATION: Registry and the Registration of the study/trial: N/A.
Medulloblastoma response to mevalonate pathway inhibition is independent of p53 status.
Comer C, Edwards C, Caporali S … +6 more , Lu Y, Butera A, Michod D, Gruber AJ, Amelio I, Niklison-Chirou MV
Biol Direct · 2026 Apr · PMID 41923098 · Full text
Medulloblastoma (MB) is the most common primary solid paediatric brain tumour. It arises in the cerebellum, the part of the brain responsible for equilibrium and coordination. Molecular profiling has identified four MB s...
Medulloblastoma (MB) is the most common primary solid paediatric brain tumour. It arises in the cerebellum, the part of the brain responsible for equilibrium and coordination. Molecular profiling has identified four MB subgroups named Wingless (WNT), Sonic hedgehog (SHH), Group 3 (G3), and Group 4 (G4), each of which possesses distinct genetic backgrounds and clinical outcomes. The treatment of MB requires intensive multimodal therapy that is associated with significant long-term side effects. Despite this necessary aggressive approach, MB remains fatal in approximately 30% of patients due to tumour recurrence and/or metastatic spread to the spinal cord. Thus, there is an urgent need for novel, less toxic and effective therapies for MB. The tumour-suppressor p53 is mutated in up to 30% of SHH-MB tumours and is associated with significantly poorer patient outcomes. Mutations in p53 have been acknowledged to confer oncogenic "gain-of-function" properties, including activation of the mevalonate pathway (MVP), which drives cholesterol and isoprenoid biosynthesis. MB is sensitive to inhibition of the MVP by treatment with simvastatin, leading us to hypothesise that targeting the mutant p53 (mutp53)-MVP axis could further sensitise mutp53 SHH-MB to statins. In this study, we show that silencing p53 does not alter simvastatin sensitivity in either mutp53 SHH-MB or wild-type p53 G3-MB cells. Moreover, p53 silencing had no effect in the mRNA expression of the key MVP enzymes 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), mevalonate kinase (MVK), mevalonate decarboxylase (MVD), and farnesyl diphosphate synthase (FDPS). Silencing p53 also failed to affect simvastatin-induced cell cycle arrest or impact the sensitivity of MB cells treated with simvastatin in combination with hypoxia, X-ray or azacitidine, an epigenetic therapy with DNA methyltransferase inhibition. Collectively, our findings indicate that MVP function is independent of p53 in MB.
Isolation and characterization of novel bacteriophages with broad-spectrum lytic activity against carbapenem-resistant Klebsiella pneumoniae capsular pathotypes K1, K2, K3, K5, and K20.
Ssekatawa K, Michniewski S, Ntulume I … +5 more , Byarugaba DK, Kansiime E, Jameson E, Wampande EM, Drago CK
Biol Direct · 2026 Mar · PMID 41888854 · Full text
BACKGROUND: Carbapenem-resistant Klebsiella pneumoniae (CRKP), particularly strains associated with virulent capsular pathotypes K1, K2, K3, K5, and K20, represent a major global health burden due to limited therapeutic...
BACKGROUND: Carbapenem-resistant Klebsiella pneumoniae (CRKP), particularly strains associated with virulent capsular pathotypes K1, K2, K3, K5, and K20, represent a major global health burden due to limited therapeutic options and poor clinical outcomes. This study aimed to isolate and characterize lytic bacteriophages targeting clinically relevant CRKP capsular types. METHODS: Bacteriophages were isolated from hospital sewage and purified by successive plaque assays. Biological characterization included adsorption kinetics, one-step growth analysis, and host range determination. TEM was used for morphological classification. Molecular characterization of the phages was achieved using whole-genome sequencing (WGS). RESULTS: Three phages, designated UGKSKpnP1, UGKSKpnP2, and UGKSKpnP3, were isolated. The phages exhibited a high and rapid adsorption rate of ~ 95% within 9–10.5 min, short latent periods (~ 25 min), and large burst sizes exceeding 300 PFU/infected cell. All phages efficiently lysed CRKP capsular types K1, K2, K3, K5, and K20. TEM analysis revealed that the phages exhibited siphovirus-like morphology, characterized by similar capsid–tail architecture with polyhedral heads and long non-contractile tails. Based on the current ICTV taxonomy, they were classified within the class Caudoviricetes and the family Drexlerviridae. WGS showed that UGKSKpnP1, UGKSKpnP2, and UGKSKpnP3 possess nearly identical genome sizes of 51,620 bp, 51,622 bp, and 51,622 bp, respectively, with high intra-group average nucleotide similarity (> 99% ANI) and were devoid of tRNA genes, lysogenic markers, virulence factors, and antibiotic-resistance determinants. Phylogenomic and VIRIDIC analyses placed the phages within the family Drexlerviridae and genus Webervirus, and revealed that the phages represent novel species within the Webervirus genus. CONCLUSION: Therefore, UGKSKpnP1, UGKSKpnP2, and UGKSKpnP3 demonstrated strong lytic activity, favorable replication dynamics, and genomic safety, underscoring their potential as candidates for phage therapy against CRKP.
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