Biology Direct最新文献

{"title":"PCSK9 inhibitors do not increase cognitive risk.","authors":"Dongsheng Ni, Zeying Feng, Dehuan Liang, Zhaolai Qi, Yao Lu, Liyong Zhu, Guoping Li","doi":"10.1186/s13062-026-00865-6","DOIUrl":"10.1186/s13062-026-00865-6","url":null,"abstract":"<p><strong>Background: </strong>Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors are potent lipid-lowering therapies, however, concerns regarding their neurocognitive safety persist because of conflicting evidence.</p><p><strong>Methods: </strong>We applied an integrated approach combining real-world pharmacovigilance, genetic epidemiology, and preclinical models. Disproportionality analysis was performed using the FDA Adverse Event Reporting System (FAERS) data to assess cognitive adverse events. Two-sample Mendelian randomization (MR) was used to assess the causal effects of apolipoprotein B (ApoB) lowering and PCSK9 inhibition on Alzheimer's disease (AD) using UK Biobank and FinnGen data, with a factorial MR design to evaluate interactions stratified by ApoB and PCSK9 polygenic risk. Preclinically, hepatocyte-specific knockout and pharmacological inhibition of PCSK9 in AD-transgenic mice were assessed through cognitive testing and neuropathological assessment.</p><p><strong>Results: </strong>FAERS analysis showed no increased reporting signal for cognitive adverse events with PCSK9 inhibitors. For AD, the ROR was below unity (ROR = 0.62, 95% CI 0.45-0.87), whereas no statistically significant signal was observed for dementia (ROR = 0.92, 95% CI 0.79-1.08). In contrast, statins showed significant disproportionality signals for AD (ROR = 2.86, 95% CI 2.51-3.26) and dementia (ROR = 1.51, 95% CI 1.36-1.67). MR analysis revealed no causal association between genetically proxied PCSK9 inhibition and AD risk (OR = 1.00, 95% CI 0.93-1.07), or between ApoB and AD risk (OR = 0.79, 95% CI 0.56-1.11). In AD-transgenic mice, PCSK9 knockout reduced low-density lipoprotein-cholesterol by 54% without impairing cognition or neuronal integrity, or increasing amyloid-β plaques and astrocytes. Pharmacological inhibition of PCSK9 similarly showed no cognitive deficits.</p><p><strong>Conclusions: </strong>Integrated evidence from pharmacovigilance, genetic epidemiology, and preclinical models robustly supports the neurocognitive safety of PCSK9 inhibitors, including in individuals with high ApoB levels. These findings affirm their long-term neurocognitive safety profile in the management of atherosclerotic cardiovascular disease.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13543531/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148300931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deciphering mitotic catastrophe-associated transcriptomic patterns in renal cell carcinoma: prognostic significance and immunotherapy-related associations.","authors":"Zilin Wang, Xu Hu, Zhiyong Lin, Feng Che, Xinyuan Wei, Hao Zeng","doi":"10.1186/s13062-026-00863-8","DOIUrl":"10.1186/s13062-026-00863-8","url":null,"abstract":"<p><strong>Background: </strong>Renal cell carcinoma (RCC) is a highly heterogeneous malignancy with complex molecular features. Mitotic catastrophe (MC), a key regulator of cell fate during aberrant mitosis, contributes to tumor progression and therapeutic response; however, its prognostic relevance in RCC remains unclear.</p><p><strong>Methods: </strong>We integrated multi-omics, clinical, and imaging data from TCGA and multiple external cohorts. Prognostic mitotic catastrophe-related genes were identified to construct a mitotic catastrophe-related score (MCRS) using CoxBoost and random survival forest models. Associations with clinicopathologic features, immune contexture, and mutational profiles were analyzed. Single-cell RNA sequencing characterized Cyclin F (CCNF) expression and its association with immunotherapy-treated cohort outcomes, and these findings were further validated in vitro and in murine xenograft models.</p><p><strong>Results: </strong>The nine-gene MCRG signature stratified patients into high- and low-risk groups with strong prognostic performance (TCGA 1-, 3-, 5-year AUCs > 0.9). High MCRS correlated with advanced stage, adverse CT features, angiogenesis, inflammatory signaling, regulatory T-cell infiltration, and elevated LAG3/TIGIT expression. MTOR mutations were enriched in high-risk tumors. SurvSHAP(t) analysis identified CCNF as the top prognostic contributor. CCNF was upregulated in tumor tissues and enriched in proliferating cells and epithelial cells. High CCNF expression was associated with worse survival and inferior outcomes in immunotherapy-treated cohorts. Overexpression of CCNF promoted RCC cell proliferation, migration, invasion, and in vivo tumor growth, partly through mTOR pathway activation.</p><p><strong>Conclusions: </strong>We established a robust MC-based prognostic model for RCC and identified CCNF as a key regulator of tumor progression and the immune microenvironment, characterized by increased Treg abundance and checkpoint expression. CCNF may represent a candidate biomarker and therapeutic target in RCC, although its relevance to outcomes in immunotherapy-treated cohorts requires further validation.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13543521/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148301001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polystyrene nanoplastics induce size-associated oxidative-inflammatory stress, hepatic insulin-signaling impairment and metabolic disturbances in normal and diabetic mice.","authors":"Fang Xu, Yuyang Jin, Zhiqiang Sha, Yadi Yang, Shangwen Wang, Ying Chen, Jianzhong Yin","doi":"10.1186/s13062-026-00867-4","DOIUrl":"10.1186/s13062-026-00867-4","url":null,"abstract":"<p><strong>Background: </strong>Nanoplastics are emerging pollutants that can cross biological barriers and perturb metabolic homeostasis. Polystyrene nanoplastics (PS-NPs) are frequently detected in food and drinking water; however, their size-dependent metabolic effects and the modifying role of pre-existing diabetes remain incompletely understood. This study aimed to investigate whether subchronic oral exposure to PS-NPs of different particle sizes altered hepatic insulin signaling and glucose-lipid homeostasis in normal and diabetic mice, and whether oxidative-inflammatory imbalance was associated with these responses.</p><p><strong>Results: </strong>We found that PS-NP exposure induced size-dependent disturbances in metabolic and hepatic signaling endpoints. Among the tested particle sizes, 25 nm PS-NPs generally showed the largest apparent changes across several inflammatory, oxidative-stress, glycemic and insulin-signaling outcomes, although direct between-size differences were not uniformly established for all endpoints. PS-NP exposure increased serum levels of inflammatory cytokines (IL-6, CRP and TNF-α) and altered hepatic oxidative-stress markers, including the lipid peroxidation marker malondialdehyde (MDA) and antioxidant enzyme activities (CAT, SOD and GSH-Px), suggesting systemic inflammatory activation accompanied by hepatic oxidative-stress imbalance. These changes were associated with suppression of the hepatic IRS1-AKT-PPARγ axis and downregulation of GLUT4 expression, consistent with impaired insulin signaling and metabolic regulation. Compared with normal mice, diabetic mice exhibited exacerbated oxidative stress, inflammatory activation, and metabolic disturbance upon PS-NP exposure, suggesting higher susceptibility of metabolically compromised hosts to PS-NPs. Exploratory SEM provided supportive evidence for an association between oxidative-inflammatory imbalance and hepatic insulin-signaling impairment, while downstream links to systemic metabolic disturbance require further validation. Exploratory multivariate analyses, including principal component analysis (PCA), linear discriminant analysis (LDA), and random forest (RF), suggested response patterns associated with metabolic background and particle size, but these analyses should be interpreted as supportive pattern-recognition tools rather than validated predictive models.</p><p><strong>Conclusions: </strong>This study suggests that PS-NPs may act as metabolic stressors under the present experimental conditions, with their effects influenced by particle size and host metabolic background. By integrating classical toxicological methods with exploratory computational modeling, our findings provide mechanistic clues and preliminary data-driven evidence that PS-NP exposure may be associated with hepatic insulin-signaling impairment and metabolic disturbance, underscoring the need to assess nanomaterial safety in metabolically vulnerable populations.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13543472/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148276114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypoxia and lactate metabolism-related gene COL5A3 promotes triple negative breast cancer progression via DDR1/FAK/PI3K/AKT pathway.","authors":"Quan-Feng Shao, Zi-Ying Wang, Wei Liang, Yuan-Yuan Li, Bei Zhu, Wei-Xian Chen","doi":"10.1186/s13062-026-00872-7","DOIUrl":"10.1186/s13062-026-00872-7","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Triple-negative breast cancer (TNBC) is a highly aggressive subtype characterized by a lack of hormone receptors and specific molecular targets, leading to limited treatment options, high recurrence rates, and poor clinical prognosis. The Warburg effect in cancer cells generates a tumor microenvironment characterized by hypoxia, low glucose, and high lactate levels, which severely promotes chemoresistance, immune escape, and distant metastasis. Nevertheless, the prognostic significance of hypoxia and lactate metabolism-related genes in TNBC remains largely unclear, and more accurate prediction models are urgently needed.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Clinical information and gene expression profiles of patients with TNBC were obtained from online databases. LASSO and multivariate Cox regression analyses were used to establish the hypoxia and lactate metabolism-related prediction model, and the prognostic value was further validated using Kaplan-Meier plotter, receiver operating characteristic curves, and nomogram. Gene set enrichment analysis was performed to evaluate the pathways and molecular functions. Tumor mutation, microsatellite instability, RNA expression-based stemness scores, immune infiltration, and drug susceptibility analyses were performed to identify potential therapeutic targets. Single-cell transcriptome data were processed and quality-controlled using Seurat. Monocle2, CellChat, and ssGSEA analyses were used to investigate the relationship between COL5A3, malignant phenotype, and tumor microenvironment. A series of in vitro experiments was performed to evaluate the biological functions of hub gene COL5A3.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Five genes, COL5A3, LRRC8D, IGFL1, SEPTIN3, and PEG10, were identified to establish the hypoxia and lactate metabolism-related risk score. TNBC patients divided into high-risk or low-risk groups according to the risk score exhibited substantial differences in survival outcome, tumor mutation, immune infiltration, and drug sensitivity. The constructed model showed strong predictive performance, with receiver operating characteristic curves showing area under the curve values of 0.82, 0.86, and 0.90 at 365, 1085, and 1825 days, respectively. Single-cell analysis showed that high COL5A3 expression was associated with greater proliferative capacity, drug resistance, and stemness. COL5A3 is also involved in regulating the interaction between TNBC cells and other cells in the tumor microenvironment. In vitro studies have indicated that COL5A3 could promote tumor proliferation, migration, invasion, and drug resistance via the DDR1/FAK/PI3K/AKT pathway in TNBC cells. OF-1 was initially identified as a candidate compound with potential therapeutic relevance for TNBC.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;A novel hypoxia and lactate metabolism-related gene signature could be used for prognosis prediction in TNBC patients, and the hub gene COL5A3 promotes TNBC progression via ","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13543591/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148270352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dissecting mitochondria-nucleus contact sites using SPLICS reveals a distributed and dynamic tethering network.","authors":"Adamantia Deligiannopoulou, Lucia Barazzuol, Caterina Peggion, Elena Poggio, Michelangelo Campanella, Marisa Brini, Tito Calì","doi":"10.1186/s13062-026-00870-9","DOIUrl":"10.1186/s13062-026-00870-9","url":null,"abstract":"<p><p>Mitochondria-nucleus contact sites (also known as nucleus-associated mitochondria, NAMs) are emerging as important platforms for inter-organelle communication; however, their molecular organisation and regulation remain poorly understood. Here, we use split-GFP-based contact site sensors (SPLICS_S-P2A^NU-MT) to quantitatively dissect the contribution of candidate tethering proteins to the formation of short-range mitochondria-nucleus contacts in HeLa cells. Through systematic overexpression and downregulation approaches, we identify TOM70, MFN2, AKAP95, and the catalytic subunit of PKA as positive modulators of contact formation when individually overexpressed. In contrast, loss-of-function experiments reveal a selective role for TOM70, whose downregulation significantly induces contact site abundance, whereas depletion of other candidates has limited effects. These results suggest that mitochondria-nucleus contacts are not maintained by single dominant tethers but instead rely on the coordinated contribution of multiple proteins. To further investigate cooperative mechanisms, we performed co-expression experiments. Among the combinations tested, TSPO in conjunction with either the regulatory or catalytic subunits of PKA significantly increased contact site formation, indicating that specific protein partnerships are required to establish functional tethering. Overall, our data support a model in which mitochondria-nucleus contact sites are heterogeneous and regulated by a network of interacting factors rather than a single structural component. These findings highlight the complexity of inter-organelle communication and underscore the importance of dissecting both individual and combinatorial roles of contact site components to understand their functional relevance.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13543456/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148270324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EYA1 regulates CIITA phosphorylation to promote EYA1-CIITA-Runx2 complex formation and extracellular matrix integrity in osteoarthritis.","authors":"Guanghua Nie, Yi Li, Hongmou Zhao, Dong Wang, Yan Zhang, Xinquan Yang, Xiaodong Wen","doi":"10.1186/s13062-026-00871-8","DOIUrl":"10.1186/s13062-026-00871-8","url":null,"abstract":"<p><strong>Background: </strong>Osteoarthritis (OA) involves progressive extracellular matrix (ECM) degradation in articular cartilage. We previously revealed that the m⁶A demethylase ALKBH5 stabilizes Runx2 mRNA in chondrocytes via YTHDF1, thereby increasing MMP and ADAMTS expression, causing ECM degradation. However, the transcriptional co-regulators of Runx2 remain unidentified.</p><p><strong>Methods: </strong>OA was induced in mice via injection of sodium monoiodoacetate (MIA). The histological architecture and proteoglycan content of the articular cartilage were evaluated using H&E and Safranin O-Fast Green staining, while subchondral bone microarchitecture was assessed by micro-computed tomography. Circulating proinflammatory cytokine levels were determined by ELISA.</p><p><strong>Results: </strong>Immunoprecipitation and mass spectrometry analyses of articular cartilage from MIA-induced OA mice identified the transcriptional coactivator EYA1 (Eyes Absent Homolog 1) and CIITA (Class II Major Histocompatibility Complex Transactivator) as novel Runx2-interacting proteins. In vitro and in vivo experiments demonstrated that EYA1, CIITA, and Runx2 form a functional EYA1-CIITA-Runx2 complex that binds to the promoters of MMP and ADAMTS genes and activates their expression. Silencing any member of the complex significantly reduced transcription of these matrix-degrading enzymes. Furthermore, we identified EYA1 as a phosphatase that dephosphorylates CIITA at serine 782, a phosphorylation site targeted by Pim3 (provirus integration site for Moloney murine leukemia virus 3) under inflammatory conditions.</p><p><strong>Conclusion: </strong>Our findings uncover a previously unrecognized transcriptional mechanism in OA pathogenesis, in which EYA1 promotes ECM degradation by regulating CIITA dephosphorylation and assembling a transcriptional complex with CIITA and Runx2. Targeting this pathway may provide a promising therapeutic strategy for OA.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13505096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148263341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell multi-omics dissection of RevitalAge Markers uncovers age-dependent immunotherapy resistance and druggable targets in melanoma.","authors":"Hanxiao Zhou, Benliang Wei, Wenlu Tan, Ji Shi, Changyuan Ren, Jinhao Zhang, Changlin Yang, Zheng Zhao, Shangwei Ning","doi":"10.1186/s13062-026-00860-x","DOIUrl":"10.1186/s13062-026-00860-x","url":null,"abstract":"<p><p>Aging-related molecular reprogramming profoundly influences melanoma progression and therapeutic sensitivity, yet underlying mechanisms remain poorly understood. We constructed a comprehensive multi-omics atlas integrating mutations, transcription, methylation, and copy number variations, utilizing the MOFA algorithm to uncover key age-driving factors. Among 20 factors, Factor6 exhibited significant negative age correlation and survival protection (HR = 0.95, P = 4.494e-05), defined as \"RevitalAge Marker (RAM)\". Integration of three single-cell RNA sequencing datasets revealed 4,796 RAM+ cells (predominantly endothelial cells and fibroblasts) exerting tumor-suppressive functions through VEGFA-VEGFR2 angiogenic pathways and mitochondrial ATP synthesis, while 7,229 RAM- cells (dominated by malignant cells) exhibited enhanced EMT, hypoxic adaptation, and MAPK signaling activation. RAM+ cells were governed by ZFP42 and IRF8 maintaining anti-tumor immunity, while RAM- cells controlled by ILF2 and ISL1 promoted metastasis and immune evasion, with RAM- malignant cells enriched in patients over 65 years and associated with immunotherapy resistance. Machine learning analysis of RAM-associated genes identified five core signatures (GPR143, ST3GAL4, RAB38, GMPR, FDFT1) demonstrating superior immunotherapy response prediction (AUC = 0.78-1.00). Drug sensitivity profiling revealed ST3GAL4 exhibited strong correlations with AZ628 (pan-RAF inhibitor) and RDEA119 (MEK inhibitor), which was further validated by molecular docking showing excellent binding affinities (binding energies: -8.7 and - 7.2 kcal/mol). This study provides structural evidence for targeted therapeutic strategies in ST3GAL4-overexpressing melanoma and establishes foundations for age-stratified immunotherapy.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13383403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148263321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptomic analysis of differential expression and correlation of coding and non-coding RNAs in urine from patients with idiopathic membranous nephropathy.","authors":"Jingwen Li, Zhelun Zhou, Rong Wu, Qi Chen","doi":"10.1186/s13062-026-00864-7","DOIUrl":"10.1186/s13062-026-00864-7","url":null,"abstract":"<p><strong>Background: </strong>The incidence rate of idiopathic membranous nephropathy (IMN) has been increasing, and its pathogenesis is still unclear. Exploring new diagnostic molecular markers and the molecular mechanisms of IMN.</p><p><strong>Methods: </strong>Fifteen healthy controls and fifteen IMN patients were recruited. Clinical baseline data of all participants, including age, gender, and body mass index (BMI), along with histopathological staging (Ehrenreich-Churg classification) and immunohistochemical staining results for phospholipase A2 receptor (PLA2R), were collected and analyzed. Meanwhile, peripheral blood and urine samples were obtained to detect renal function-related biochemical indicators, including serum creatinine (Scr), estimated glomerular filtration rate (eGFR), serum albumin, 24-hour urinary protein (24 h UPT), serum total cholesterol (TC), anti-PLA2R antibody titer, and serum immunoglobulin G (IgG). Urine samples (n = 10) were also used for high-throughput sequencing analysis.</p><p><strong>Results: </strong>Serum albumin was significantly downregulated in the IMN group, while 24 h UPT, TC, anti-PLA2R Ab titer, and IgG were upregulated. MicroRNA (miRNA) transcriptomic analysis identified 34 differentially expressed (DE) miRNAs. Hsa-miR-576-3p, hsa-miR-766-5p, and NovelmiRNA-837 exhibited strong diagnostic potential via ROC curve analysis (AUC > 0.8). Sixty-four DE mRNAs were identified in IMN tissues, with enrichment in pathways such as Ribosome and MAPK signaling-fly. ENST00000481739 (RXRA) was upregulated in IMN, correlated with anti-PLA2R Ab titer, and exhibited diagnostic potential (AUC = 0.929). Thirty-five DE lncRNAs were identified in IMN, enriched in autophagy, mitophagy, and apoptosis pathways. TCONS_00180924, TCONS_00176280, TCONS_00208611 correlated significantly with TC, 24-h urinary protein, and anti-PLA2R Ab titer.</p><p><strong>Conclusions: </strong>This study provides a foundation for developing non-invasive diagnostic tools and targeted therapies for IMN.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13339474/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148263318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ALDH1L2 suppresses ferroptosis-associated responses and reduces sunitinib sensitivity in renal cell carcinoma organoids.","authors":"Xinming Hu, Jie Yang, Desheng Li, Meizhou Deng, Mei Xie, Jiangtao Zhan, Changmin Yang, Xianping Che, Kangli Deng","doi":"10.1186/s13062-026-00854-9","DOIUrl":"10.1186/s13062-026-00854-9","url":null,"abstract":"<p><strong>Background: </strong>Sunitinib is an important therapeutic option for renal cell carcinoma (RCC), but reduced response to sunitinib still limits its clinical benefit. This study explored the mechanism underlying reduced sunitinib sensitivity in RCC and aimed to identify potential strategies to improve sunitinib response.</p><p><strong>Methods: </strong>RCC organoids were established and characterized, and sunitinib-responsive genes were screened by transcriptomic analysis. Public datasets and clinical RCC samples were used to evaluate the clinical relevance of ALDH1L2. ALDH1L2 overexpression and knockdown were performed in RCC organoids to examine its effects on sunitinib sensitivity and ferroptosis-related changes. Organoid-derived xenograft models were used for in vivo validation. Molecular docking, cytotoxicity assays, CETSA, SPR, and functional experiments were used to screen and validate candidate compounds targeting ALDH1L2.</p><p><strong>Results: </strong>Sunitinib inhibited RCC organoid growth, with IC50 values of approximately 8 μM. Transcriptomic analysis showed that ALDH1L2 was upregulated after sunitinib treatment. Clinical analyses indicated that ALDH1L2 was highly expressed in RCC tissues and was associated with poorer survival and advanced stage. In RCC organoids, ALDH1L2 overexpression attenuated sunitinib-induced ROS accumulation and ferroptosis-related changes, as reflected by changes in GPX4, SLC7A11, GSH/GSSG, NADP⁺ /NADPH, Fe^{2 +}, and MDA. In contrast, ALDH1L2 knockdown enhanced these changes and increased the sensitivity of RCC organoids to sunitinib. In organoid-derived xenograft models, ALDH1L2 overexpression reduced the antitumor effect of sunitinib and decreased tumor ROS accumulation. Erastin counteracted the protective effect of ALDH1L2 overexpression. Hederacolchiside A1 (HA-1) was identified as a candidate compound targeting ALDH1L2. HA-1 reduced ALDH1L2 protein abundance, altered its thermal stability, enhanced the inhibitory effect of sunitinib, and counteracted ALDH1L2-mediated sunitinib tolerance in RCC organoids.</p><p><strong>Conclusions: </strong>These findings suggest that ALDH1L2 contributes to reduced sunitinib sensitivity in RCC organoids by attenuating ferroptosis-related responses. HA-1 may improve the response of RCC organoids to sunitinib by targeting ALDH1L2, supporting further evaluation of this combination strategy.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13543589/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148263386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis and validation of abnormal signaling pathways and immune cell infiltration characteristics in digestive system cancers based on peroxisome-related genes.","authors":"Jie Wen, Zhihui Wang, Shuyang Luo, Abudureyimujiang Aili, Hongliang Zou, Shaoqing Niu, Haikuan Liu, Wenzhe Fan, Jiaping Li","doi":"10.1186/s13062-026-00861-w","DOIUrl":"10.1186/s13062-026-00861-w","url":null,"abstract":"<p><strong>Background: </strong>Although emerging evidence suggests a role for peroxisomes in tumorigenesis, their functions in digestive cancers remain unclear. This study aims to investigate the association between peroxisomes and digestive tract tumors.</p><p><strong>Methods: </strong>To systematically investigate peroxisomal functions in digestive cancers, we first constructed and validated tumor-specific prognostic signatures based on peroxisome-related genes (PRGs) through univariate Cox, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analyses. We then characterized the tumor immune microenvironment (TIME) with CIBERSORT, X-CELL, and EPIC algorithms, and identified tumor-specific and common signalings via Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA). Focusing on hepatocellular carcinoma (HCC), we experimentally validated peroxisome-related therapeutic responses by profiling signature genes in radioresistant cells and an orthotopic transarterial chemoembolization (TACE) rat model. PEX13 knockdown further assessed peroxisomal role in radiosensitivity and targeted therapy response. Clinical relevance of PEX13 was evaluated in HCC cohort. Single-cell RNA sequencing dataset and lipidomics further revealed peroxisomal mechanisms in HCC progression. Finally, peroxisomal function in colorectal cancer (CRC) was validated in vitro.</p><p><strong>Results: </strong>Novel peroxisome-related prognostic signatures demonstrated strong predictive power in HCC, colon adenocarcinoma, rectal adenocarcinoma, pancreatic adenocarcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, esophageal squamous cell carcinoma, and cholangiocarcinoma. High-risk patients displayed an immunosuppressive microenvironment, characterized by increased infiltration of regulatory T cells, M2 macrophages, Th2 cells, or cancer-associated fibroblasts, or Th1 cells' reduction. Peroxisomes engaged in several distinct yet convergent pathways, most notably \"positive regulation of response to stimuli\". HCC prognostic genes were dynamically regulated in response to therapeutic stimuli, including radiotherapy, targeted therapy, and TACE. Clinically, the expression of PEX13 was markedly upregulated in tumor tissues from therapy-resistant HCC patients. Mechanistically, peroxisomal dysfunction induced by silencing PEX13 in HCC or UBE2D2 in CRC may overcome therapeutic resistance (radiotherapy/ lenvatinib resistance in HCC, radioresistance in CRC) through reprogramming lipid metabolism.</p><p><strong>Conclusions: </strong>Peroxisomes act as pivotal regulators of digestive cancer progression by modulating signaling pathways, the TIME, therapeutic resistance, and lipid metabolism. Targeting peroxisomal function, particularly in high-risk subgroups of HCC and CRC, warrants further exploration as a promising therapeutic strategy.</p>","PeriodicalId":9164,"journal":{"name":"Biology Direct","volume":" ","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13536876/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148257271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}