Biology Direct[JOURNAL]
Sun
200 papers
MYC promotes myocardial fibrosis via METTL1-mediated m7G modification of HILPDA.
Liu Y, Li K, Chen Y … +1 more , Xia H
Biol Direct · 2026 May · PMID 42116160 · Full text
BACKGROUND: Post-infarction myocardial fibrosis is a pivotal pathological process leading to heart failure; however, its epitranscriptional regulatory mechanisms remain poorly defined. The role of the MYC-METTL1-HILPDA a...
BACKGROUND: Post-infarction myocardial fibrosis is a pivotal pathological process leading to heart failure; however, its epitranscriptional regulatory mechanisms remain poorly defined. The role of the MYC-METTL1-HILPDA axis in this process remains unexplored. METHODS: Myocardial infarction (MI) models were established in mice, and hypoxia-induced mouse cardiac fibroblasts were used. A range of molecular techniques, including qRT-PCR, Western blot, immunohistochemistry, RNA immunoprecipitation, chromatin immunoprecipitation, and dual-luciferase reporter assays, were employed to investigate the MYC-METTL1-HILPDA axis. RESULTS: Following MI, METTL1 and HILPDA were significantly upregulated in cardiac tissue. METTL1 stabilized HILPDA mRNA via m7G modification, thereby enhancing its protein expression. Functional studies demonstrated that HILPDA overexpression induced mitochondrial dysfunction and fibroblast activation, whereas HILPDA knockdown attenuated these effects. Furthermore, the transcription factor MYC was identified as an upstream regulator that directly binds the METTL1 promoter to activate its transcription. Crucially, HILPDA knockdown improved cardiac function, attenuated fibrosis, and reduced infarct size in mice. CONCLUSION: This study identifies the MYC-METTL1-HILPDA axis as a novel driver of post-infarction myocardial fibrosis, which promotes mitochondrial dysfunction and fibroblast activation through m7G-mediated stabilization of HILPDA mRNA. These findings provide new mechanistic insights and reveal potential therapeutic targets for preventing heart failure.
Harnessing meta-analysis and artificial intelligence to reveal conserved regulatory biosignatures of abiotic stress in soybean.
Laskar P, Singh B
Biol Direct · 2026 May · PMID 42116101 · Full text
BACKGROUND: Soybeans are widely cultivated worldwide as an important source of edible vegetable oil and protein. Due to climate change, it is repeatedly exposed to various abiotic stressors in its natural habitat. Abioti...
BACKGROUND: Soybeans are widely cultivated worldwide as an important source of edible vegetable oil and protein. Due to climate change, it is repeatedly exposed to various abiotic stressors in its natural habitat. Abiotic stresses such as heat, drought, and salinity severely restrict soybean productivity, yet the conserved molecular mechanisms underlying multi-stress tolerance remain poorly understood. The integrated application of machine learning and co-expression network analysis for robust biosignature and hub gene discovery remains limited. Therefore, this study aimed to identify conserved stress-responsive biosignatures and explore their evolutionary and regulatory significance. RESULTS: Here, we explored the transcriptional regulation of soybean under multiple abiotic stress conditions, including heat, drought, and salt. A total of 14,503 genes are differentially expressed across three stress conditions, with 466 genes common to all three. Gene Ontology and KEGG pathway analyses indicated that the meta-DEGs primarily participate in oxidative stress, hormone signaling, and metabolic pathways. Segmental duplication is the key driving force of stress response gene expansion, and most of these expansions occurred through the recent whole-genome duplication (WGD) in soybean. The 12 abiotic stress-responsive biosignatures were identified using a wedge co-expression network and machine learning (ML)- based hub genes. A deep neural network (DNN) model was constructed to validate stress biosignatures, achieving 97.39% and 76.47% prediction accuracies on the test and external validation sets, respectively. CONCLUSIONS: Our findings revealed conserved stress-responsive genes, key regulatory hubs, and oxidative stress as a central molecular feature governing multi-stress adaptation. The integration of artificial intelligence enabled accurate validation of biosignatures, offering valuable insights into functional genomics and genomic-assisted breeding strategies. This study offers a strong foundation for AI applications in plant breeding and supplies valuable resources for soybean genetic improvement.
Cancer-associated fibroblasts-derived exosomal circ_0067557 promotes colorectal cancer epithelial-mesenchymal transition via BHLHE40-mediated transcriptional activation of OTUB2.
Zhang D, Zhang J, Yang C … +3 more , Wang Y, Wang M, Yu Z
Biol Direct · 2026 May · PMID 42115880 · Full text
OBJECTIVE: This study aimed to clarify how cancer-associated fibroblast-derived exosomal circ_0067557 (CAF-exo circ_0067557) promotes epithelial-mesenchymal transition (EMT) in colorectal cancer (CRC) through BHLHE40-med...
OBJECTIVE: This study aimed to clarify how cancer-associated fibroblast-derived exosomal circ_0067557 (CAF-exo circ_0067557) promotes epithelial-mesenchymal transition (EMT) in colorectal cancer (CRC) through BHLHE40-mediated transcriptional activation of OTUB2. METHODS: CAF-derived exosomes were isolated and characterized from CRC tissues, while normal fibroblast-derived exosomes were obtained from adjacent normal tissues. The transfer of circ_0067557 was tracked using fluorescence labeling and endocytosis assays. Expression of circ_0067557, BHLHE40, OTUB2, and EMT-related markers was assessed by qRT-PCR, Western blotting, and immunofluorescence. Gain- and loss-of-function models were established to determine the biological role of circ_0067557. RNA sequencing identified OTUB2 as a key downstream target. ChIP-qPCR and dual-luciferase reporter assays were performed to verify BHLHE40 binding to the OTUB2 promoter. RIP and RNA pull-down assays confirmed the interaction between circ_0067557 and BHLHE40. Mouse xenograft and tail vein metastasis models were used to evaluate the oncogenic effects of circ_0067557 in vivo. RESULTS: CAF-exos successfully delivered circ_0067557 into CRC cells, significantly enhancing their proliferative, migratory, invasive, and EMT capabilities. Mechanistically, circ_0067557 interacted with and recruited BHLHE40, thereby increasing its binding to the OTUB2 promoter and promoting OTUB2 transcription. In vivo experiments further confirmed that circ_0067557 markedly enhanced tumor growth and distant metastasis through the BHLHE40/OTUB2 signaling axis. CONCLUSION: CAF-exo circ_0067557 promotes EMT, invasion, metastasis, and tumor progression in CRC by recruiting BHLHE40 and activating OTUB2 transcription. These findings reveal a novel mechanism by which the tumor microenvironment (TME) regulates cancer cell metastasis.
Integrative satellitomics reveals distinct patterns of organization, transcription and evolution of satellite DNAs in Tenebrio molitor.
Majcen P, Sermek A, Ugarković Đ … +3 more , Oppert B, Plohl M, Šatović-Vukšić E
Biol Direct · 2026 May · PMID 42104515 · Full text
Satellite DNAs (satDNAs) are repetitive sequences that play important roles in chromosomal architecture, genome evolution, and regulation. Here, we present a comprehensive characterization of Tenebrio molitor satellitome...
Satellite DNAs (satDNAs) are repetitive sequences that play important roles in chromosomal architecture, genome evolution, and regulation. Here, we present a comprehensive characterization of Tenebrio molitor satellitome, integrating cytogenetic mapping, in silico genome annotation, divergence profiling, screening of extrachromosomal circular DNA (eccDNA), transcription analysis across developmental stages, and phylogenetic and age analyses. SatDNAs exhibited diverse chromosomal organizations, ranging from widespread to chromosome-restricted distributions. Discrepancies between assembly-based and physical mapping highlight limitations of individual approaches and underscore the importance of their integration. Divergence landscape analyses revealed different homogenization efficiencies and turnover rates, reflecting distinct evolutionary trajectories among individual satDNAs. Phylogenetic reconstruction revealed distinct patterns which include clear species-specific clustering of monomers, mixed interspecific clustering, and dispersed topologies. Comparative analyses across insect orders enabled age estimation, identifying both ancient (≥380 MYA) and lineage-specific satDNAs, apparently restricted to T. molitor. We designed and applied an approach that enables the simultaneous detection of multiple satDNAs within the eccDNA fraction which confirmed the presence of six satDNAs in eccDNA. RNA-seq analyses revealed coordinated, stage-specific transcription of all satDNAs, with elevated expression in late male pupae and early male adults. Together, these results reveal a highly dynamic, heterogeneous, and functionally relevant satDNA landscape in T. molitor and demonstrate the importance of integrative approaches for understanding molecular mechanisms and trajectories of satDNA evolution.
ELOVL1 promotes the progression of intrahepatic cholangiocarcinoma by enhancing endoplasmic reticulum stress and the PI3K/AKT/mTOR signaling pathway.
Wu W, Zhan D, Gao Y … +10 more , Jiang Y, Pang Q, Pei Y, Wang J, Li Y, Wang Y, Huang S, Wang R, He M, Chen W
Biol Direct · 2026 May · PMID 42104482 · Full text
BACKGROUND: Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive liver malignancy characterized by an adverse outcome attributed to delayed detection, elevated recurrence rates, and resistance to chemotherapy. I...
BACKGROUND: Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive liver malignancy characterized by an adverse outcome attributed to delayed detection, elevated recurrence rates, and resistance to chemotherapy. Identifying innovative indicators and therapeutic targets is essential for enhancing iCCA treatment. METHODS: We used bioinformatics, machine learning, and experimental approaches to explore the role of ELOVL1 in iCCA. Functional enrichment analysis of DEGs was carried out utilizing GO, KEGG, GSEA, and GSVA. WGCNA and LASSO regression identified key genes linked to iCCA progression. In vitro and in vivo experiments assessed the impact of ELOVL1 on tumor growth, migration, invasion, and chemotherapy response. Western blotting and immunofluorescence were used to evaluate signaling pathways and ER stress markers. RESULTS: Bioinformatics analysis identified ELOVL1 as a key gene upregulated in iCCA tissues. High ELOVL1 expression correlated with poor prognosis. Functional assays showed that ELOVL1 overexpression enhanced iCCA cell proliferation, migration, invasion, and cisplatin resistance, while knockdown inhibited these effects. Mechanistically, ELOVL1 activated the PI3K/AKT/mTOR pathway and induced ER stress, promoting iCCA progression. Molecular docking studies identified ELOVL1's interaction with the PI3K inhibitor Pictilisib, suggesting a therapeutic target. CONCLUSION: ELOVL1 promotes iCCA progression by regulating the PI3K/AKT/mTOR pathway and enhancing ER stress. ELOVL1 is a potential biomarker for predicting iCCA prognosis and drug response, offering new therapeutic strategies for iCCA.
A pyroptosis-related molecular signature stratifies prognosis and highlights GSDMB-mediated malignancy in intrahepatic cholangiocarcinoma.
Zhao B, Zhu Y, Jin Z … +5 more , Li X, Lin K, Wang Y, Lu Y, Hua W
Biol Direct · 2026 May · PMID 42098854 · Full text
BACKGROUND: Pyroptosis, a form of inflammatory programmed cell death, plays a dual role in tumor progression and anti-tumor immunity. Its comprehensive clinical and biological significance in intrahepatic cholangiocarcin...
BACKGROUND: Pyroptosis, a form of inflammatory programmed cell death, plays a dual role in tumor progression and anti-tumor immunity. Its comprehensive clinical and biological significance in intrahepatic cholangiocarcinoma (iCCA) remains to be elucidated. METHODS: Utilizing bulk transcriptome, single-cell transcriptome, proteome, phosphoproteome, spatial transcriptomic profiling and genomic mutation data, we first identified three distinct iCCA molecular subtypes based on the expression patterns of prognostic pyroptosis-related genes (PRGs). Subsequently, we developed and validated an eight-PRG (CASP3, TIRAP, GPX4, NOD2, GSDMB, GSDMC, CASP9, IL6) prognostic signature using regression analyses. The tumor immune microenvironment was characterized, and metabolic pathways were analyzed. Single-cell RNA sequencing (scRNA-seq) of 165,236 cells from iCCA tissues was performed to investigate cellular communication. Spatial transcriptomic profiling was used to visualize cell distribution. In vitro functional assays, including TGF-β treatment, GSDMB and CDH3 knockdown, were conducted to validate mechanistic insights. RESULTS: The eight-PRG signature effectively stratified iCCA patients into high- and low-risk groups with significant survival differences. The high-risk subtype correlated with aggressive clinicopathological features, an immunosuppressive microenvironment, and dysregulated metabolism. scRNA-seq analysis revealed malignant epithelial cells expressing GSDMB showed heightened responsiveness to TGF-β signaling. Functional studies demonstrated that GSDMB knockdown inhibited iCCA cell proliferation, migration, and invasion, potentially through downregulation of CDH3. Further mechanistic studies validated that TGF-β promotes CDH3 transcription in a GSDMB-dependent manner. GSDMB knockdown reduced basal CDH3 expression and abolished TGF-β-induced CDH3 upregulation at both mRNA and protein levels. CONCLUSIONS: We established a novel and clinically applicable pyroptosis-based classifier for iCCA prognosis. Our findings hint at a possible connection of the TGF-β-GSDMB-CDH3 axis with enhanced tumor aggressiveness, providing new insights for patient risk stratification and revealing potential therapeutic targets for iCCA.
CircPTP4A2 (hsa_circ_0007364) facilitates non-small cell lung cancer progression by regulating miR-127-5p/SMC3.
Feng Y, Hong J, Yang C … +7 more , Cheng C, Xue Y, Zhang J, Lu Y, Cao X, Jiang G, Chong X
Biol Direct · 2026 May · PMID 42098805 · Full text
Non-small cell lung cancer (NSCLC) is a major subtype of lung cancer and accounts for a large proportion of cancer-related deaths worldwide. Despite extensive research progress in recent years, the diagnosis and treatmen...
Non-small cell lung cancer (NSCLC) is a major subtype of lung cancer and accounts for a large proportion of cancer-related deaths worldwide. Despite extensive research progress in recent years, the diagnosis and treatment of lung cancer remain insufficient. There is an urgent need to deepen the mechanistic understanding of lung cancer, develop early diagnostic strategies, and explore novel therapeutic targets. In this study, qRT-PCR was used to detect the expression of circPTP4A2 (circular RNA PTP4A2) in tumor and adjacent normal tissues from 50 NSCLC patients. CircPTP4A2 was significantly upregulated in tumor tissues and was closely associated with patient survival and prognosis. In vitro silencing of circPTP4A2 in NSCLC cell lines SPCA1 and H1299 significantly inhibited cell proliferation and malignant metastatic potential. Moreover, modulating the expression of miR-127-5p and SMC3 effectively reversed the phenotypic changes induced by circPTP4A2 knockdown. In conclusion, circPTP4A2 is upregulated in NSCLC and promotes tumorigenesis and progression through the miR-127-5p/SMC3 signaling axis.
Multi-omics analysis of deep brain stimulation associated with brain-gut axis modulation and symptom amelioration in a Parkinson's disease mouse model.
Song Y, Yang C, Tu J … +2 more , Dong J, Zhang X
Biol Direct · 2026 May · PMID 42092952 · Full text
This study aimed to systematically elucidate the molecular mechanisms underlying PD-associated brain-gut dysfunction through multi-omics analyses and to evaluate the therapeutic potential of combined Deep Brain Stimulati...
This study aimed to systematically elucidate the molecular mechanisms underlying PD-associated brain-gut dysfunction through multi-omics analyses and to evaluate the therapeutic potential of combined Deep Brain Stimulation (DBS) and Brain-Computer Interface (BCI) interventions. Transcriptomic and 16S rRNA datasets from Gene Expression Omnibus (GEO) and Sequence Read Archive (SRA) were integrated and analyzed using DESeq2, limma, Gene Set Enrichment Analysis (GSEA), and PICRUSt2 to identify disrupted pathways and microbial functional features. In the 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model, four groups (Normal, MPTP, MPTP + DBS, and MPTP + DBS+BCI) were assessed using behavioral testing, Local Field Potentials (LFP) recordings, molecular assays, and histological analysis. The findings revealed synaptic damage and metabolic pathway disruptions in PD brains, accompanied by reduced abundance of Short-Chain Fatty Acid (SCFA)-producing gut microbes. Combined DBS and BCI markedly improved motor deficits, suppressed aberrant β oscillations, restored gut barrier integrity and microbial homeostasis, and reduced pathological α-synuclein (αSyn) aggregation. Collectively, these results demonstrate that DBS + BCI is associated with improvements across neural, microbial and inflammatory readouts, supporting a correlative brain-gut-immune framework.
Protective effect of Caftaric Acid against hepatic cold ischemia/reperfusion injury in the liver.
Zhu Y, Li H, Li M … +5 more , Ruan W, Ding M, You G, Zhang L, Guo W
Biol Direct · 2026 May · PMID 42087237 · Full text
Hepatic cold ischemia/reperfusion (I/R) injury persists during the perioperative period of liver transplantation (LT), exerting a profound impact on graft survival and being closely associated with the occurrence of earl...
Hepatic cold ischemia/reperfusion (I/R) injury persists during the perioperative period of liver transplantation (LT), exerting a profound impact on graft survival and being closely associated with the occurrence of early allograft dysfunction (EAD). Currently, preventive strategies against cold I/R injury remain limited. This study aimed to investigate the protective effects and underlying molecular mechanisms of caftaric acid (CA), a metabolite specifically elevated in cold-adapted hibernating animals, against hepatic cold I/R injury. The results demonstrated that CA significantly reduced the area of hepatic necrosis, attenuated liver injury, inhibited hepatocyte apoptosis, and promoted the restoration of redox homeostasis. RNA-seq analysis suggested that the MAPK pathway, particularly the activation of JNK1, plays a pivotal role in the process of cold I/R injury. Through integrated experiments including drug-target screening, molecular docking, and surface plasmon resonance (SPR), this study confirmed that CA directly binds to and interacts with JNK1, thereby regulating its phosphorylation function. Further investigations revealed that CA modulates the MAPK cascade (JNK1/FOS) to alleviate oxidative stress, mitochondrial dysfunction, and cellular apoptosis during hepatic cold I/R injury. In summary, these findings suggest that CA holds promise as a potential therapeutic strategy for ameliorating hepatic cold I/R injury, with significant clinical implications.
BCL6B suppresses acute myeloid leukemia progression by transcriptionally repressing GGT5 and modulating MAPK signaling.
Pan Y, Wu K, Ma X … +5 more , Cheng S, Guo C, Li Y, Zhang Y, Du Y
Biol Direct · 2026 May · PMID 42083053 · Full text
BACKGROUND: BCL6B has been implicated as a tumor suppressor in several solid malignancies; however, its biological function and molecular mechanisms in acute myeloid leukemia (AML) remain insufficiently defined. METHODS:...
BACKGROUND: BCL6B has been implicated as a tumor suppressor in several solid malignancies; however, its biological function and molecular mechanisms in acute myeloid leukemia (AML) remain insufficiently defined. METHODS: Public datasets were analyzed to evaluate the expression pattern, diagnostic performance, and prognostic relevance of BCL6B in AML. Epigenetic regulation was explored using decitabine treatment. Gain- and loss-of-function experiments were conducted in AML cell lines to determine the effects of BCL6B on apoptosis, cell cycle progression, and proliferation. Transcriptome sequencing, dual-luciferase reporter assays, and electrophoretic mobility shift assays (EMSA) were performed to identify and validate downstream targets. MAPK pathway alterations were examined by Western blotting. Zebrafish and nude mouse xenograft models were used for in vivo validation. RESULTS: BCL6B expression was significantly reduced in AML compared with normal controls and demonstrated diagnostic value across molecular subgroups. Higher BCL6B expression was associated with prolonged overall survival, indicating that BCL6B may serve as a prognostically relevant biomarker. Decitabine treatment restored BCL6B expression, suggesting that BCL6B expression may be regulated by epigenetic mechanisms. Functionally, BCL6B overexpression promoted apoptosis, induced G0/G1 cell cycle arrest, and suppressed proliferation in AML cells, whereas BCL6B knockdown exerted opposite effects. Mechanistically, GGT5 was identified as a direct transcriptional target of BCL6B. BCL6B repressed GGT5 promoter activity and counteracted GGT5-mediated pro-proliferative and anti-apoptotic phenotypes. Pathway analyses revealed that BCL6B modulated MAPK signaling in a GGT5-dependent manner, characterized by decreased ERK phosphorylation and enhanced p38/JNK activation. In vivo, BCL6B overexpression suppressed tumor growth, migration, angiogenesis, and prolonged survival. CONCLUSIONS: BCL6B functions as a tumor suppressor in AML by transcriptionally repressing GGT5 and modulating MAPK signaling. These findings provide mechanistic insight into BCL6B-mediated leukemogenesis and support its potential as a diagnostic biomarker and therapeutic target.
ETV4 promotes colorectal cancer progression through SLC7A11-mediated ferroptosis inhibition.
Chao Z, Yin J, Huang F … +6 more , Xu J, Lv Y, Chen J, Xu A, Zhu W, Wang J
Biol Direct · 2026 May · PMID 42067922 · Full text
BACKGROUND: Colorectal cancer (CRC) remains a leading cause of cancer-related mortality globally. Ferroptosis, a regulated form of cell death, has emerged as a promising frontier in CRC treatment. The transcriptional reg...
BACKGROUND: Colorectal cancer (CRC) remains a leading cause of cancer-related mortality globally. Ferroptosis, a regulated form of cell death, has emerged as a promising frontier in CRC treatment. The transcriptional regulator ETV4 (ETS variant transcription factor 4) is implicated in CRC pathogenesis. However, its functional role has not been fully elucidated, and its potential to modulate ferroptosis in CRC is entirely unknown. This study aimed to investigate whether ETV4 modulates ferroptosis in CRC by regulating SLC7A11 and to explore the underlying mechanism involved. METHODS: Bioinformatic analysis was conducted to detect ETV4 expression and to identify pathways regulated by ETV4. Real‑time quantitative PCR (RT‑qPCR) and Western blot assays were used to measure gene expression at the mRNA and protein levels. The biological functions of ETV4 were assessed via CCK‑8, colony formation, wound‑healing, apoptosis analysis, transmission electron microscopy (TEM) and Transwell assays. Key ferroptosis markers-reactive oxygen species (ROS), malondialdehyde (MDA), mitochondrial membrane potential (JC‑1), and ferrous iron (FerroOrange) were examined to determine whether ETV4 knockdown promotes ferroptosis. RESULTS: ETV4 is highly expressed in CRC tissues and cell lines, and its expression level is positively correlated with advanced TNM stages. Silencing ETV4 suppressed CRC cell proliferation, clonogenicity, and migration. Bioinformatic analysis confirmed that ETV4 may suppress the ferroptosis pathway. Functional assays revealed that ETV4 knockdown enhanced ferroptosis in CRC cells. Mechanistically, ETV4 depletion downregulated SLC7A11, whereas SLC7A11 overexpression reversed the ferroptosis phenotype induced by ETV4 knockdown. CONCLUSION: ETV4 promotes CRC progression by inhibiting ferroptosis through the upregulation of SLC7A11. Therefore, the ETV4/SLC7A11 axis represents a potential therapeutic target for CRC treatment.
Discovering non-linear dynamics of miRNAs in Alzheimer's disease-related cognitive impairment: a cross-species approach with explainable machine learning.
Lee SH, Kim S, Lee SB
Biol Direct · 2026 Apr · PMID 42063169 · Full text
BACKGROUND: MicroRNA (miRNA) biomarker studies in Alzheimer's disease (AD) typically assume monotonic relationships between expression levels and disease status, overlooking the non-linear, context-dependent nature of mi...
BACKGROUND: MicroRNA (miRNA) biomarker studies in Alzheimer's disease (AD) typically assume monotonic relationships between expression levels and disease status, overlooking the non-linear, context-dependent nature of miRNA regulatory networks. This simplification limits mechanistic insight and clinical translation. We aimed to characterise non-linear contribution patterns of miRNAs across the AD continuum using explainable machine learning and to define stage-specific "operating windows" where individual miRNAs drive classification. METHODS: Candidate miRNAs were prioritised from APPtg/TAUtg mouse hippocampus (accession number GSE110743) using minimum-redundancy-maximum-relevance selection. A three-miRNA panel (miR-155-5p, miR-339-5p, and miR-455-5p) was validated in human serum (GSE120584; AD, MCI, and healthy controls). Linear and non-linear classifiers were compared, and SHAP dependence analysis was used to quantify sample-level contributions across expression ranges. RESULTS: Non-linear models (SVM-RBF and k-NN) consistently outperformed linear classifiers, with discrimination strongest for MCI vs. healthy controls (AUC: 0.844). SHAP analysis revealed that miR-155-5p functions as a stable primary driver across disease stages, whereas miR-339-5p and miR-455-5p act as context-dependent modulators contributing only within restricted expression ranges. Each miRNA exhibited distinct, stage-specific non-linear operating windows with threshold effects and inflection points rather than uniform dose-response patterns. CONCLUSIONS: This study reframes circulating miRNAs as dynamic, interaction-governed signals rather than static biomarkers. The operating window framework provides interpretable, threshold-aware guidance for clinical decision-making and supports stage-sensitive early screening strategies.
The role of autophagy in ocular health: mechanisms, pathologies, and therapeutic strategies.
Huang M, Lin Y, Zhang H … +11 more , Yuan R, Zeng L, Li S, Yang Q, Gong M, Xiao R, Jia P, Yuan L, Guo Q, Han Z, Xie L
Biol Direct · 2026 Apr · PMID 42063162 · Full text
Autophagy is a self-digestive process in which cellular components are degraded and recycled to maintain homeostasis and cope with stress. When cells are in a state of stress, autophagy will degrade proteins, lipids and...
Autophagy is a self-digestive process in which cellular components are degraded and recycled to maintain homeostasis and cope with stress. When cells are in a state of stress, autophagy will degrade proteins, lipids and damaged organelles, and convert them into key nutrients and building cornerstones needed to maintain cell homeosis. More and more evidence shows that there is a link between autophagy process damage and the development of a variety of ophthalmic diseases that seriously threaten vision, including age-related macular degeneration, glaucoma and the formation of cataracts. Through a systematic review, we integrate experimental data covering basic biological mechanisms, genetic models and clinical evidence to clarify these pathological associations. With a focus on the mechanisms and regulation of autophagy in various ocular tissues and diseases, we analyzed research on autophagy in the lens, retina, cornea, and trabecular meshwork. Key findings elucidate the specific mechanisms of autophagy in maintaining lens transparency, promoting retinal ganglion cell survival, and regulating ocular immunity, demonstrating its critical role in preserving cellular equilibrium in ocular tissues. Furthermore, we evaluated potential therapeutic strategies targeting autophagic pathways, including mammalian target of rapamycin (mTOR) inhibition, transcription factor EB(TFEB) activation, noncoding RNA regulation, gene editing, and artificial intelligence-assisted diagnostics, which show significant promise for modulating autophagy to treat ocular diseases. The results of this review underscore the importance of autophagy in ocular health and disease.
Tetrahydropalmatine may alleviate doxorubicin-induced renal injury by activating the Sirt3-mediated Nrf2/HO-1 pathway.
Wang W, Hu Y, Xu Y … +4 more , Ding N, Wei J, Li C, Chen Y
Biol Direct · 2026 Apr · PMID 42063146 · Full text
BACKGROUND: Doxorubicin (DOX) is a widely used broad-spectrum chemotherapy drug, but its severe organ toxic and side effects limit its clinical application. Tetrahydropalmatine (THP) protects against DOX-induced renal in...
BACKGROUND: Doxorubicin (DOX) is a widely used broad-spectrum chemotherapy drug, but its severe organ toxic and side effects limit its clinical application. Tetrahydropalmatine (THP) protects against DOX-induced renal injury, yet its underlying mechanism remains unclear. This study aimed to verify THP’s protective effect and explore if it acts via the SIRT3-mediated Nrf2/HO-1 signaling pathway. METHODS: This study adopted an integrated in vivo and in vitro research system to explore the relevant mechanisms. In vivo, a DOX-induced mouse renal injury model was established with THP intervention; renal function was evaluated by detecting serum creatinine (Scr) and blood urea nitrogen (BUN), while renal injury severity was assessed via urine microalbumin (mALB) and urine albumin/creatinine ratio (UACR). Renal histopathological changes including glomerular injury and tubulointerstitial fibrosis were observed, and subcellular structures such as podocyte integrity and mitochondrial morphology were analyzed by transmission electron microscopy (TEM); additionally, the expression of pathway-related proteins was detected. In vitro, a DOX-induced cell injury model was constructed using mouse podocytes (MPC-5), and Western blot and immunofluorescence techniques were employed to determine the expression of key molecules in the Sirt3-Nrf2/HO-1 pathway, combined with in vivo and in vitro experiments to clarify the underlying mechanism. RESULTS: THP significantly attenuated DOX-induced renal injury, improved renal function (reduced Scr/BUN), mitigated histopathological/mitochondrial abnormalities, and preserved podocyte integrity. Molecularly, THP upregulates podocyte markers Nephrin/Podocin, enhances antioxidant capacity (increased GSH, SOD, and CAT, decreased MDA), inhibits inflammation (downregulated IL-6, IL-1β, and TNF-α), and suppresses apoptosis (downregulated Bax/caspase-3, upregulated Bcl-2). Notably, both in vivo and in vitro data link THP’s protection to SIRT3-mediated Nrf2/HO-1 pathway activation. CONCLUSION: THP protects against DOX-induced renal injury in mice. Mechanistically, this may involve activating the SIRT3-mediated Nrf2/HO-1 pathway, improving podocyte function, and inhibiting oxidative stress, inflammation, and apoptosis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13062-026-00773-9.
PPBP orchestrates autophagy-apoptosis imbalance to drive cartilage degeneration in osteoarthritis.
Zhang H, Hou K, Ma X … +7 more , Sun G, Kuai L, Wang T, Zhang Y, Chen G, Huang X, Zhang Y
Biol Direct · 2026 Apr · PMID 42062881 · Full text
Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by progressive cartilage destruction, in which dysregulated chondrocyte apoptosis and impaired autophagy play critical roles, yet the upstream m...
Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by progressive cartilage destruction, in which dysregulated chondrocyte apoptosis and impaired autophagy play critical roles, yet the upstream molecular drivers remain incompletely understood. Here, we identify pro-platelet basic protein (PPBP/CXCL7) as a previously unrecognized mediator of cartilage degeneration in OA. PPBP expression was markedly elevated in human OA cartilage, in the destabilization of the medial meniscus (DMM) mouse model, and in IL-1β-stimulated primary chondrocytes. Functional analyses revealed that PPBP overexpression augmented inflammatory and catabolic responses, suppressed autophagy, and promoted chondrocyte apoptosis, whereas PPBP knockdown preserved extracellular matrix homeostasis, enhanced LC3-associated autophagy, and reduced apoptotic cell death. Mechanistically, PPBP activation was associated with increased phosphorylation of PI3K and AKT and concomitant autophagy suppression; conversely, PPBP inhibition reduced PI3K and AKT phosphorylation, restored autophagic activity, and these protective effects were abolished by pharmacological autophagy inhibition using 3-methyladenine. Importantly, intra-articular silencing of PPBP in DMM mice attenuated cartilage erosion, preserved collagen II, reduced MMP13 expression, increased LC3 levels, and decreased chondrocyte apoptosis in vivo. Collectively, these findings establish PPBP as a key regulator of autophagy-apoptosis imbalance in OA chondrocytes and highlight PPBP as a potential therapeutic target for disease-modifying intervention in OA.
Carbomol hydrogels integrating chlorogenic acid-loaded exosomes promote diabetic wound healing through antibacterial and immunomodulatory activities.
Wang H, Guan M, Chu G … +1 more , Wang Y
Biol Direct · 2026 Apr · PMID 42057179 · Full text
Diabetic wounds represent a significant global clinical challenge, exacerbated by persistent bacterial infection and a dysregulated inflammatory microenvironment. Effective strategies for diabetic wounds are absent. Here...
Diabetic wounds represent a significant global clinical challenge, exacerbated by persistent bacterial infection and a dysregulated inflammatory microenvironment. Effective strategies for diabetic wounds are absent. Here, we found that NOD-like receptor thermal protein domain associated protein 3 (NLRP3) is an important regulating molecule associated with inflammatory microenvironment. We engineered Carbomol hydrogels integrating chlorogenic acid-loaded exosomes (Exo-CA@CB) to address both infection and NLRP3-mediated inflammation. The Carbomol hydrogel (CB) matrix provides biocompatibility, adhesion, self-healing properties, and sustained release, while the encapsulated Exo-CA deliver bioactive cargo. In vitro studies demonstrated the potent antibacterial activity of Exo-CA@CB against common wound pathogens. Crucially, Exo-CA@CB effectively promoted macrophage polarization towards the regenerative M2 phenotype. In the infected diabetic wound model, topical application of Exo-CA@CB hydrogels significantly accelerated healing. This study validates a new approach, initiated by single-cell analysis, for developing Exo-CA@CB hydrogels as a promising platform to manage infected diabetic wounds by concurrently tackling infection and NLRP3-driven inflammation.
HucMSC-derived exosomes alleviate inflammatory bowel disease via upregulating FXR to suppress macrophage ferroptosis.
Xia Y, Sun T, Zhou M … +2 more , Wang B, Mao F
Biol Direct · 2026 Apr · PMID 42057067 · Full text
Inflammatory bowel disease (IBD) is a chronic intestinal disorder characterized by excessive inflammation and intestinal damage. Known for its chronic and relapsing nature, IBD currently lacks curative pharmacological th...
Inflammatory bowel disease (IBD) is a chronic intestinal disorder characterized by excessive inflammation and intestinal damage. Known for its chronic and relapsing nature, IBD currently lacks curative pharmacological therapies. Herein, we investigated the therapeutic potential of human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-Ex) in IBD and explored the underlying mechanisms. In vivo and in vitro experiments demonstrated that the administration of hucMSC-Ex significantly attenuated inflammatory levels and ameliorated associated disease symptoms in IBD models. Concurrently, hucMSC-Ex treatment effectively modulated bile acid dysregulation in the IBD condition, contributing to the restoration of intestinal metabolic homeostasis. Mechanistically, the protective effects of hucMSC-Ex were mediated through the upregulation of farnesoid X receptor (FXR) expression. FXR, a critical regulator of intestinal homeostasis, plays a pivotal role, particularly in bile acid metabolism. Elevated FXR expression further suppressed ferroptosis in macrophages, as evidenced by reduced lipid peroxidation, diminished oxidative stress, restored iron metabolism homeostasis, and normalized expression of ferroptosis-related markers (GPX4, ACSL4, MBOAT1). Collectively, our findings indicate that hucMSC-Ex alleviates IBD by activating FXR in macrophages, thereby inhibiting lipid peroxidation and reducing ferroptosis, ultimately mitigating inflammation and ameliorating intestinal damage. This offers the potential of a FXR-targeted therapeutic strategy based on exosomes for the treatment of IBD.
Integrative transcriptomic profiling reveals NK cell exhaustion-associated prognostic genes and identifies CSF1 as a key immunoregulatory target in hepatocellular carcinoma.
Wang Y, Xu X, Qi Y … +7 more , Zhang Y, Ding L, Li Z, Long S, Yang G, Sun R, Guo X
Biol Direct · 2026 Apr · PMID 42050573 · Full text
BACKGROUND: Hepatocellular carcinoma (HCC) features a complex tumor immune microenvironment (TIME) where natural killer cell exhaustion (NKEX) facilitates immune evasion. Its regulatory networks and prognostic value rema...
BACKGROUND: Hepatocellular carcinoma (HCC) features a complex tumor immune microenvironment (TIME) where natural killer cell exhaustion (NKEX) facilitates immune evasion. Its regulatory networks and prognostic value remain insufficiently understood. METHODS: We integrated single-cell (GSE149614) and bulk RNA-seq (TCGA-LIHC) data. Following Seurat-based clustering, we utilized CellChat and pySCENIC for communication and transcription factor analysis. NKEX-associated modules were identified via gene set variation analysis and weighted gene co-expression network analysis. A prognostic signature was developed using LASSO-Cox regression and validated in an external cohort (ICGC). CSF1 was prioritized for validation through clinical immunohistochemistry, siRNA knockdown, and Western Blotting. Candidate compounds identified via reverse network pharmacology were validated through CCK-8 assays, docking, western blotting and quantitative PCR. RESULTS: Single-cell analysis revealed pronounced NKEX and disrupted communication in HCC. A four-gene prognostic signature (AKR1B1, SMS, CSF1, CFL1) demonstrated robust predictive performance in both TCGA (1-year AUC: 0.759) and external validation cohorts. High-risk patients showed significantly poorer survival. CSF1 was markedly upregulated in HCC tissues; its silencing inhibited Huh7 cell migration and invasion while upregulating CXCL10 in Huh7 cells and CXCR3 in NK92 cells. Molecular docking and CCK-8 assays justified the dosage and identified punicalagin and evoden as potent inhibitors that significantly suppressed CSF1 expression at both mRNA and protein levels. CONCLUSION: Through integrated multi-omics and experimental validation, we characterized NKEX in HCC and established a robust prognostic signature. CSF1 emerged as a key immunomodulatory target. Punicalagin and evoden were identified as potential lead compounds to modulate the CSF1, offering a promising strategy to restore antitumor immunity in HCC.
JUNB transcriptional regulation of KRT20 via ITGB1 activates PI3K/AKT signaling pathway against fibrosis-induced by renal injury.
Mei H, Ni X, Zheng Q … +10 more , Tang H, Yan Z, Yang S, Xiong Y, Hui Y, Jian J, Wang J, Yang X, Liu X, Chen Z
Biol Direct · 2026 Apr · PMID 42046140 · Full text
Chronic kidney disease and its progression to end-stage renal disease represent a major global health burden, driven by renal interstitial fibrosis. The function of the intermediate filament protein Keratin 20 (KRT20) in...
Chronic kidney disease and its progression to end-stage renal disease represent a major global health burden, driven by renal interstitial fibrosis. The function of the intermediate filament protein Keratin 20 (KRT20) in this context remains largely unexplored. This study investigated the role and mechanism of KRT20 in renal fibrosis. Integrated transcriptomic analysis revealed significant upregulation of KRT20 in fibrotic kidneys. With unilateral ureteral obstruction (UUO) mouse models and TGF-β1-stimulated human renal tubular epithelial (HK-2) cells, we found that KRT20 expression increased progressively with fibrotic severity. Functional studies demonstrated that KRT20 knockdown exacerbated fibrosis and epithelial-mesenchymal transition while its overexpression attenuated. Mechanistically, the transcription factor JUNB, activated by TGF-β1, directly bound to the KRT20 promoter to drive its transcription. Upregulated KRT20 protein subsequently interacted with integrin ITGB1, leading to activation of the PI3K/AKT survival signaling pathway. Collectively, these findings delineated a novel protective “JUNB–KRT20–ITGB1–PI3K/AKT” axis in renal fibrosis, identifying KRT20 as a potential therapeutic target for enhancing endogenous anti-fibrotic response.
ALDH2 inhibits FASN stabilization via the E3 ligase CBL to suppress lipid accumulation and liver cancer development.
Wang Y, Li L, Qu F … +14 more , Hua T, Chen C, Yang L, Jiang R, Liu X, Cheng P, Min H, Wang Y, Pan X, Sun D, Tang R, Liu R, You H, Kong F
Biol Direct · 2026 Apr · PMID 42046078 · Full text
BACKGROUND: Aldehyde dehydrogenase 2 (ALDH2) is implicated in the pathogenesis of multiple diseases. Nevertheless, the biological functions and underlying mechanisms linked to ALDH2 in liver cancer (LC) are not well eluc...
BACKGROUND: Aldehyde dehydrogenase 2 (ALDH2) is implicated in the pathogenesis of multiple diseases. Nevertheless, the biological functions and underlying mechanisms linked to ALDH2 in liver cancer (LC) are not well elucidated. METHODS: The expression pattern of ALDH2 and its clinical significance in LC were analyzed across multiple cohorts. The interaction between fatty acid synthase (FASN) and ALDH2 was investigated using co-immunoprecipitation (Co-IP) and mass spectrometry (MS). The effects of ALDH2 and casitas B-lineage lymphoma (CBL) on FASN protein stabilization and ubiquitination were evaluated via Co-IP and western blotting. Additionally, the biological roles of ALDH2 in LC cells through FASN inhibition were assessed in both in vitro and in vivo models. RESULTS: Our results showed that ALDH2 expression was downregulated in LC tissues, and this reduction was significantly related to adverse clinical parameters and shorter overall survival in LC patients. FASN, a key enzyme in lipid metabolism, was identified as an interacting partner of ALDH2 in LC cells. Mechanistic studies further revealed that ALDH2 inhibits FASN protein stabilization by enhancing its ubiquitination, thereby reducing FASN protein levels. Bioinformatics analyses and functional experiments confirmed that CBL acts as the E3 ubiquitin ligase for FASN. Importantly, ALDH2 promotes the interaction between CBL and FASN, accelerating FASN degradation. Consequently, ALDH2 suppresses lipid accumulation in LC cells and attenuates LC cell proliferation and migration through FASN inhibition, as validated in vitro and in vivo. CONCLUSION: Our findings discover a novel mechanism whereby ALDH2 exerts anti-LC effects by inducing FASN ubiquitination and degradation, to decrease lipid accumulation and biological functions in LC cells. Enhancing ALDH2 expression may thus represent a promising therapeutic strategy for LC.
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