Acta biochimica et biophysica Sinica最新文献

Serum deprivation is a well-established inducer of apoptosis, yet the molecular mechanisms governing this process remain incompletely understood. Here, we show that serum starvation selectively triggers intrinsic apoptosis in high-density murine embryonic fibroblasts (MEFs) through coordinated HIF-1α activation and JNK signaling suppression. Knockdown of HIF-1α abolishes caspase-3 activation and apoptosis induced by serum deprivation, whereas upregulation of HIF-1α in low-density cells recapitulates the apoptotic response observed in high-density cultures. Simultaneously, serum deprivation leads to the suppression of the JNK pathway, which contributes to apoptosis. Notably, combined HIF-1α activation and JNK inhibition in low-density cells fully mimics the apoptotic phenotype of high-density conditions, underscoring the interplay between these pathways. Together, these findings define a density-dependent apoptotic switch in which HIF-1α drives metabolic stress adaptation, whereas JNK suppression removes a critical survival signal, converging to promote mitochondrial-mediated cell death. This work provides a mechanistic framework for understanding nutrient stress-induced apoptosis and suggests potential therapeutic targets for diseases characterized by aberrant cell survival.

The iron regulatory protein IREB2 (Iron Responsive Element Binding Protein 2) plays a crucial role in maintaining cellular iron homeostasis through the posttranscriptional regulation of genes involved in iron metabolism. Mutations in the IREB2 gene have been linked to NDCAMA (OMIM#618451), a rare genetic neurological disorder characterized by early-onset neurodegeneration, choreoathetoid movements, and microcytic anemia. However, the absence of an IREB2-mutated animal model has left the underlying pathogenic mechanisms poorly understood. To investigate this, we establish a CRISPR-Cas9-mediated Ireb2 ^D826V/D826V mouse model, which carries the c.2477A>T (p.D826V) pathogenic variant in IREB2 identified in a Chinese pedigree with NDCAMA. Behavioral studies, including the Morris water maze (MWM), open field test (OFT), and Y-maze, reveal significant neurobehavioral deficits, such as impaired spatial learning and memory and reduced motor activity, in Ireb2 ^D826V/D826V mice. Furthermore, we observe increased microglial activation and decreased dendritic spine density in the hippocampus, along with impaired long-term potentiation (LTP) and elevated paired-pulse facilitation (PPF), indicating synaptic dysfunction. Mechanistically, Ireb2 ^D826V/D826V mice present reduced Ireb2 protein levels, dysregulated iron metabolism, and an altered expression profile associated with neurological function. This study elucidates the molecular mechanisms underlying NDCAMA and establishes Ireb2 ^D826V/D826V mice as a model for iron metabolism-driven neurodegeneration. This finding links the instability of IREB2 to synaptic failure and neuroinflammation, highlighting potential therapeutic implications for neurodegenerative diseases.

As a critical component of amino acid metabolic reprogramming, serine metabolism has been demonstrated to be enhanced in a variety of cancer types, thereby supporting tumor progression. This enhancement is primarily driven by increased expression levels and augmented enzymatic activity of serine metabolic enzymes (phosphoglycerate dehydrogenase, phosphoserine aminotransferase 1, phosphoserine phosphatase and serine hydroxymethyltransferase). However, there is still lack of comprehensive summary on the regulation of serine metabolism in cancer. In this review, we provide a systematic overview of the currently discovered and proven regulatory mechanisms of serine metabolic enzymes in cancer, focusing on three levels: transcriptional, post-transcriptional, and post-translational regulation. Specifically, transcriptional regulation encompasses three major mechanisms: (1) transcription factor-mediated gene expression control, (2) histone modifications, and (3) DNA methylation. At the post-transcriptional level, regulation is primarily achieved through (1) non-coding RNAs, (2) RNA-binding proteins, and (3) RNA modifications. Post-translational regulation is predominantly mediated through diverse protein post-translational modifications. The transcriptional and post-transcriptional mechanisms primarily modulate the expression levels of serine metabolic enzymes, while post-translational modifications exert more diverse effects by altering the activity, protein stability or cellular localization of these enzymes. These regulations collectively modulate serine metabolism to influence tumor progression, offering promising targets for tumor-specific therapeutic interventions.

Aberrant expression of acyl-CoA synthetase long-chain family member 1 (ACSL1) occurs in multiple cancer types and is closely linked to patient prognosis. Nevertheless, its precise mechanistic role in colorectal cancer (CRC) remains poorly understood. In this study, we assess ACSL1 expression in CRC and elucidate the molecular mechanisms through which ACSL1 regulates tumor proliferation and migration. Our results show that ACSL1 is significantly upregulated in CRC and is associated with poor patient survival. Knockdown of ACSL1 suppresses CRC cell proliferation both in vitro and in vivo. Furthermore, ACSL1 silencing downregulates the JAK2-STAT3 signaling axis. A strong correlation also exists between ACSL1 expression and epithelial-mesenchymal transition (EMT). Collectively, these findings indicate that ACSL1 is highly expressed in CRC tissues and is correlated with poor prognosis. Importantly, our study provides the first evidence that the ACSL1-JAK2-STAT3 pathway facilitates CRC cell proliferation and migration, highlighting its potential as a therapeutic target.

As the fifth most common cancer and the third leading cause of cancer death worldwide, gastric cancer (GC) has long been a serious global health challenge. The purpose of this study was to explore the expression of V-set and immunoglobulin domain containing 2 (VSIG2) in GC and to elucidate its role in GC progression and related mechanisms. Western blot analysis, qRT-PCR and immunohistochemical (IHC) staining are used to detect the expression of VSIG2 in GC cells and tissues. Kaplan-Meier survival curve analysis is performed. The effects of VSIG2 on biological effects related to GC progression in vitro are detected by CCK-8, EdU, Transwell and wound healing assays and in vivo by a nude mouse subcutaneous tumor model and a liver metastasis model. Mechanistically, co-immunoprecipitation, immunofluorescence and ubiquitination experiments are used to explore the regulatory effect of VSIG2 on ANXA2 and the regulatory effect between FBXW10 and ANXA2. VSIG2 is abnormally expressed at low levels in patients with GC and is associated with patient prognosis. Low VSIG2 expression is closely related to tumor size, lymph node metastasis, TNM stage and vascular invasion in GC patients. Functionally, in vitro and in vivo experiments reveal that VSIG2 could inhibit the growth, proliferation and metastasis of GC. Mechanistically, VSIG2 and ANXA2 interact directly in GCs and co-localize at the cell membrane. Further exploration reveals that highly expressed VSIG2 competes with FBXW10 for binding to ANXA2 and relies on FBXW10-mediated K63 polyubiquitination of ANXA2 to induce membrane localization of ANXA2 and further inactivate NF-κB, thereby suppressing GC progression. In summary, VSIG2 is expressed at abnormally low levels in patients with GC, and its low expression is associated with poor patient prognosis. VSIG2 can inhibit the proliferation and migration of GC via the ANXA2/NF-κB pathway. This study elucidates a new mechanism by which VSIG2 inhibits GC progression, which may provide a new perspective for the diagnosis and treatment of GC patients.

Acute myeloid leukemia (AML) is a clinically aggressive hematologic malignancy characterized by high relapse rates and treatment resistance, highlighting the need for novel biomarkers to improve clinical outcomes. In this study, we explore the roles of nuclear receptor-interacting protein 1 (NRIP1) in AML, focusing on its associations with tumor progression and immune infiltration. Analysis of public AML gene expression datasets reveals that NRIP1 expression is significantly increased in AML patients. Those with high NRIP1 expression have markedly shorter overall survival than those with low expression. Furthermore, NRIP1 expression is significantly associated with the infiltration of diverse immune cells, including B cells, dendritic cells, T cells, mast cells, eosinophils, and T helper cells, suggesting that NRIP1 may be a regulator of immune cell infiltration. Functional enrichment analysis indicates that NRIP1 and its interacting partners are involved in tumorigenesis, immune microenvironment remodeling, and metabolic reprogramming. Survival analysis confirms the prognostic value of NRIP1. Importantly, functional validation in AML cell lines confirms that NRIP1 knockdown suppresses proliferation and induces apoptosis. Our study identifies NRIP1 as a multifaceted regulator that promotes AML by driving tumor progression, regulating immune cell infiltration, and modulating ferroptosis, highlighting its role as a novel prognostic biomarker.

Dolutegravir (DTG) disrupts mouse embryonic development in a dose-dependent manner, culminating in neural-tube defects (NTDs). Using whole embryo culture (WEC), mouse embryos at embryonic day 8.5 (E8.5) are cultured for 24–48 h with 8, 10, or 12 μM DTG. The results reveal that higher DTG concentrations dose-dependently disrupt yolk sac development and markedly increase the frequency of NTDs. In vivo NTD models are generated by intraperitoneally injecting DTG at a dose of 7.5 mg/kg, and the resulting embryos exhibit disrupted yolk sac blood circulation, embryonic growth restriction, and malformations. Mechanistic studies suggest that DTG contributes to NTDs by inducing apoptosis: DTG exposure activates the Nrf2-SOD1/CAT antioxidant axis, yet it culminates in increased apoptosis and suppressed proliferation, ultimately impairing yolksac vasculogenesis and neuralepithelial closure, thereby producing NTDs. This study provides new evidence for assessing the potential risk of DTG in embryonic development and highlights the need to re-evaluate its clinical safety in future applications.

Senescence is a cellular response closely associated with genotoxic stress and plays a critical role in determining cell fate following irradiation exposure. Primary cilia, which are sensory organelles on the cell surface, detect and transmit diverse signaling cues. However, the relationship between primary cilia and senescence in long-term cell fate decisions after ionizing radiation (IR) remains poorly understood. Here, we show that the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) colocalizes with centromeres during various stages of mitosis, whereas during interphase, phosphorylated DNA-PKcs (p-DNA-PKcs) is confined to the nucleus in tumor cells. Following irradiation exposure, primary cilia are formed and persistently maintained at high levels in senescent tumor cells. Inhibition of DNA-PKcs enhances primary cilia formation, whereas combined inhibition with siDNA-PKcs and irradiation reduces cilia generation. Moreover, chloral hydrate-induced primary cilia removal results in senescent cell death and decreases p-DNA-PKcs protein expression. Notably, treatment with the apoptosis inducer ABT263 also leads to increased cell death and decreased incidence of primary cilia. Inhibition of either primary cilia or DNA-PKcs further enhances the radiosensitivity of tumor cells. These findings suggest that DNA-PKcs contributes to primary cilia formation after irradiation and plays a critical role in both the induction and maintenance of cellular senescence.

Mitochondrial dysfunction is closely related to tumor development. Adenine nucleotide translocator 1 (ANT1), which promotes ADP/ATP translocation across the inner mitochondrial membrane, is an important protein involved in mitochondrial function and plays a role in a variety of diseases, including cancers. However, its role in colorectal cancer (CRC) progression remains poorly understood. This study aims to explore the potential role of ANT1 in CRC and its relationship with mitophagy. Through immunohistochemical analysis, we find that ANT1 expression is significantly higher in the tumor tissues of CRC patients than in adjacent normal tissues and that its overexpression is associated with poor prognosis. Further experiments demonstrate that ANT1 knockdown significantly inhibits CRC cell proliferation, migration, and invasion and leads to mitochondrial dysfunction, increased ROS production, and apoptosis by suppressing mitophagy. Mechanistically, ANT1 knockdown downregulates the PINK1/Parkin pathway, thereby inhibiting mitophagy activity. Notably, PINK1 overexpression partially rescues the cellular dysfunction induced by ANT1 knockdown, suggesting a potential role for PINK1 in reversing the suppression of mitophagy. In vivo xenograft models also show that ANT1 knockdown markedly inhibits tumor growth. In conclusion, ANT1 may play a critical role in CRC progression by regulating mitophagy, providing a basis for its potential as a therapeutic target.

Hepatocellular carcinoma (HCC) continues to pose a chief threat to the global healthcare landscape and is characterized by scarce therapeutic options and poor clinical outcomes, especially in advanced-stage disease. Although lymphocyte antigen 96 (LY96) is associated with immunogenic cell death, its specific role in HCC progression and therapeutic potential remains unclear. To identify prospective therapeutic targets in HCC, by combining the cancer-immunity cycle score with WGCNA and systems biology methods, we identify pivotal molecular interactions. By integrating the cancer-immunity cycle score with WGCNA and systems-level approaches, we systematically identify potential therapeutic targets in HCC. We evaluate LY96 expression at the transcriptomic and proteomic levels in HCC tissues and explore its prognostic relevance by drawing upon information from The Cancer Genome Atlas (TCGA) repository. The functional role of LY96 is delineated through a panel of cellular assays conducted in vitro, complemented by in vivo tumorigenesis models. To identify the downstream signaling cascades associated with LY96, gene set enrichment analysis (GSEA) is performed to elucidate the implicated pathways, which are then confirmed via experimental validation. Furthermore, we employ a lipid-polymer hybrid nanoparticle (NP) platform to facilitate the systemic delivery of an LY96 inhibitor and demonstrate its potential as a newly proposed intervention strategy for HCC. Clinically, marked LY96 overexpression occurs in HCC samples, where elevated LY96 expression is strongly associated with reduced overall survival (OS) among liver cancer patients. LY96 facilitates the progression of HCC via complementary in vitro and in vivo approaches. Mechanistically, LY96 induces the activation of the TGF-β1/Smad2/3 signaling axis in HCC. For therapeutic applications, we develop a liposome-based nanoparticle system that delivers the LY96 inhibitor L6H21 to tumor cells and effectively suppresses HCC progression through a combination of in vivo and in vitro studies. Taken together, the current observations identify LY96 as a promising diagnostic indicator and a viable intervention for therapeutic modulation to improve HCC treatment.