Apoptosis最新文献

Non-Coding regions contains genomic remnants called as Pseudogenes. For a long time, pseudogenes have been regarded as non-functional. This study investigates the previously unstudied Pseudogene CDC27P9 role in cervical cancer. Whole RNA-transcriptome profiling was performed from blood samples of n = 10 cervical cancer patients and n = 10 age matched healthy controls. CDC27P9 expression was validated in patient samples using RT-PCR. The putative CDC27P9-encoded protein structure was predicted using ChimeraX 1.9, refined predicted protein using (GROMACS 2022.2) and evaluated by Ramachandran plot. Post docking using (HADDOCK2.4) with parent gene CDC27 and other interacting genes, a 100ns MD Simulation (GROMACS 2022.2) was done. Functional studies done by siRNA-mediated silencing of CDC27P9 in HeLa cells to study Anaphase Promoting Complex/Cyclosome Pathway using RT-PCR. Cell Cycle, Mitochondrial Membrane Potential Loss and Apoptosis, using Flow Cytometry. Cell death and Chromatin Condensation was visualised using Laser Scanning Confocal Microscopy and validated in multimode microplate reader. Transcriptome sequencing revealed CDC27P9 upregulated with log₂FC = 10.68. RT-PCR validated overexpression of CDC27P9 in cervical cancer patients. Putative CDC27P9-encoded protein had an 93.11% of the residues point to protein structure reliability. Molecular docking and MD simulation showed strongest interactions with CDC27 and CDC20. Silencing of CDC27P9, downregulated CDC27 and Anaphase Promoting Complex/Cyclosome genes UBE2L3, PTTG1, ESPL1. In parallel downregulation of anti-apoptotic gene BCL2 while upregulation of pro-apoptotic BAX was observed. Silencing of CDC27P9 induced cell cycle arrest at S-phase, induces apoptosis and mitochondrial membrane potential loss. Observation of Condensed chromatin structure post silencing was an indicative of apoptotic signalling. Further cell death, growth inhibition and morphology changes was observed. Interestingly, silencing of CDC27P9 in cervical cancer HeLa cells caused downregulation of HPV 18. This study is the first to identify pseudogene CDC27P9 as functional with active transcripts and putative protein‑coding potential. Our findings suggest that CDC27P9 may contribute to cervical cancer progression by modulating APC/C‑mediated cell‑cycle pathways, prevent apoptosis thereby sustains cell survival in cancer cells and could be involved in HPV18-associated cellular pathways.

Enzalutamide resistance (EnzR) is a major challenge in the current treatment of castration-resistant prostate cancer, as tumors frequently progress to drug resistance after an initially effective treatment. Therefore, there is an urgent need to characterize the genes alterations that accompany EnzR in prostate cancer and to identify new therapeutic targets. In this study, we analyzed a total of 1273 publicly available transcriptomics datasets from patients who underwent prostate cancer surgery. We investigated transcriptomic changes after enzalutamide (ENZ) treatment, identified key genes involved in the process of EnzR, and developed EnzR scores to predict tumor progression. We further investigated the role of IGFBP3 in the regulation of EnzR in prostate cancer. The effect of IGFBP3 expression level on the malignant degree of EnzR cells was explored in vitro. In addition, we explored the downstream mechanism of IGFBP3 involvement in EnzR. We found that epithelial-mesenchymal transition (EMT), cancer stem cell-like properties, and neuroendocrine transformation occurred in tumor cells after ENZ treatment. Subsequently, we developed and validated EnzR scores to predict prostate cancer tumor progression. Furthermore, we experimentally confirmed that IGFBP3 promotes the proliferation of drug-resistant cells and enhances ENZ resistance via EMT signaling. Overall, we established a new EnzR scoring model through multidimensional analysis of EnzR patterns. This model can accurately predict the clinical prognosis of prostate cancer patients after surgery. Moreover, IGFBP3 can be used as a potential therapeutic target for ENZ resistance in prostate cancer.

Background As the primary active component in tobacco, nicotine is significantly associated with chemotherapy resistance in colon cancer. However, the molecular mechanisms through which nicotine contributes to chemotherapy resistance in colon cancer cells remain unclear. Methods The effects of nicotine on malignant phenotypes and chemosensitivity of colon cancer cells were investigated through CCK-8 assays, Transwell assays, apoptosis assays, wound healing assays, and colony formation assays. The role of ferroptosis in nicotine-mediated chemotherapy resistance was explored by measuring intracellular levels of reactive oxygen species, iron ions, and malondialdehyde. Through RNA sequencing, the key mechanism by which nicotine inhibits ferroptosis in colon cancer cells was identified and further validated through cell-based experiments. Additionally, a xenograft tumor model was used to assess the impact of nicotine on oxaliplatin efficacy and ferroptosis in transplanted tumors. Results In vitro experiments demonstrated that nicotine enhanced malignant phenotypes and reduced the sensitivity of colon cancer cells to oxaliplatin. Furthermore, nicotine attenuated the chemotherapeutic effects of oxaliplatin by inhibiting oxaliplatin-induced ferroptosis. Mechanistic studies revealed that nicotine reduces the sensitivity of colon cancer cells to oxaliplatin by inhibiting ferroptosis through modulation of the HMOX1/NF-κB signaling pathway. In vivo experiments confirmed that xenograft tumors in nicotine-treated mice exhibited a significantly diminished therapeutic response to oxaliplatin, along with downregulated expression of ferroptosis markers in tumor tissues. ConclusionsThis study elucidates that nicotine suppresses ferroptosis in colon cancer cells via the HMOX1/NF-κB pathway to reduce oxaliplatin sensitivity. Targeted intervention of this pathway may offer a promising strategy to overcome nicotine-induced chemotherapy resistance.

Osteoarthritis (OA) is a common degenerative joint disease marked by cartilage degradation, inflammation, and subchondral bone remodeling. Ferroptosis, an iron-dependent form of programmed cell death, has recently emerged as a key contributor to OA progression. However, its upstream regulatory mechanisms remain unclear. HERC2, a HECT-domain E3 ubiquitin ligase, is known to regulate iron metabolism, but its role in OA has not been investigated. ATDC5 chondrocytes were treated with IL-1β or Erastin. The effects of HERC2 knockdown or overexpression on ferroptosis, autophagy, oxidative stress, and cartilage matrix proteins were evaluated. Proteins identified from HERC2 immunoprecipitation-mass spectrometry were cross-referenced with UbiBrowser-predicted substrates, and PPI networks were constructed using STRING and Cytoscape. HERC2-FTL interaction was validated via co-immunoprecipitation and ubiquitination assays. To identify therapeutic compounds, molecular docking was performed between HERC2and ferroptosis-related compounds from PubChem using AutoDock Vina. Proanthocyanidins (PAC) emerged as a top candidate and was validated in vitro. In vivo, HERC2-deficient mice underwent DMM surgery to induce OA. HERC2 was upregulated in OA and promoted ferroptosis by ubiquitinating and degrading ferritin light chain (FTL), resulting in iron accumulation, autophagy activation, and cartilage matrix loss. In vitro, treatment with the ferroptosis inhibitor Liproxstatin-1 or the HERC2-targeting compound PAC restored redox homeostasis, reduced lipid peroxidation, and improved chondrocyte viability under inflammatory and ferroptosis stress. In vivo, HERC2 deficiency alleviated OA severity, preserved cartilage and subchondral bone integrity, and improved joint function. HERC2 promotes OA progression by activating autophagy-dependent ferroptosis via FTL degradation. Targeting this pathway using ferroptosis inhibitors or HERC2-binding compounds like PAC may offer a promising disease-modifying approach for OA treatment.

Gastric cancer is a multifactorial disease and remains one of the leading causes of cancer-related deaths worldwide. CircRNAs have emerged as critical regulators in various cancers, while exosomes play essential roles in shaping the tumor microenvironment. However, the function of circTIMP2 and its interaction with exosomes are largely unknown. In this study, we evaluated the expression of circTIMP2 and investigated its biological roles in gastric cancer through a series of in vitro and in vivo experiments. The sponge mechanism of circTIMP2 for miR-106a, together with the target TIMP2, was validated using bioinformatics, luciferase, RNA immunoprecipitation, and fluorescence in situ hybridization assays. The involvement of exosomes and the influence on circTIMP2 were further explored. We found that circTIMP2 was significantly downregulated in gastric cancer, whereas miR-106a was upregulated, accompanied by downregulation of TIMP2. Overexpression of circTIMP2 attenuated malignant behaviors of cancer cells and suppressed subcutaneous tumor growth by upregulating its host gene TIMP2, coinciding with reduced miR-106a and inhibition of Wnt/β-catenin signaling pathway. Mechanistically, circTIMP2 acts as a competitive endogenous RNA by sequestering miR-106a to release its target TIMP2, thereby forming a circTIMP2/miR-106a/TIMP2 feedback loop that suppresses gastric cancer through inhibition of Wnt/β-catenin signaling. Importantly, tumor-derived exosomes counteracted the suppressive effects of circTIMP2, promoting orthotopic tumor progression by inhibiting TIMP2 and reactivating Wnt/β-catenin signaling. Our findings unveil a novel circRNA-guided feedback loop in gastric cancer and highlight how exosome-mediated mechanisms counteract this axis, providing new insights into the molecular pathogenesis of gastric cancer and suggesting potential therapeutic targets.

BCL3 (B-cell CLL/lymphoma 3), initially identified in the t(14;19) chromosomal translocation in B-cell malignancies, is an atypical member of the inhibitor of NF-κB (IκB) protein family. Unlike classical IκB proteins, BCL3 predominantly localizes to the nucleus, where it exerts unique bidirectional transcriptional regulatory functions within the NF-κB signaling pathway. This complex functionality is finely modulated by post-translational modifications, particularly phosphorylation. Under pathological conditions, BCL3 functions as an oncogene, driving abnormal neoplastic cell proliferation, inhibiting apoptosis, and promoting metastasis and chemotherapy resistance in various hematological malignancies and solid neoplasms by activating multiple oncogenic signaling pathways. Conversely, BCL3 also serves as a critical regulatory factor of immune homeostasis, modulating the functions of macrophages, T cells, and dendritic cells (DCs), thereby influencing the pathogenesis of immune-related disorders. Beyond oncology and immunology, BCL3 plays pivotal roles in the nervous, cardiovascular, digestive, and musculoskeletal systems, highlighting its broad physiological and pathological significance. This article systematically reviews the molecular structure, post-translational regulatory mechanisms, and multifaceted roles of BCL3 in neoplastic and non-neoplastic diseases. By consolidating current research, this review aims to provide novel insights into the diagnostic and therapeutic potential of targeting BCL3 in related pathologies.

Piezo1 is a mechanically activated, non-selective cation channel characterized by its exquisite sensitivity to membrane tension and high permeability to calcium(Ca²⁺⁾, enabling the conversion of mechanical stimuli into intracellular signaling events. Activation of Piezo1 leads to Ca²⁺ influx, which initiates iron metabolism reprogramming-including transferrin receptor 1(TfR1)-dependent iron uptake, divalent metal transporter 1(DMT1)-mediated iron transport, and Nuclear Receptor Coactivator 4(NCOA4)-regulated ferritinophagy-thereby promoting the accumulation of reactive oxygen species (ROS) and lipid peroxidation. Ultimately, these events culminate in ferroptosis by suppressing glutathione peroxidase 4 (GPX4) activity. The "mechanical force-Piezo1-Ca²⁺-iron/lipid metabolism" axis establishes mechanical stress as a pivotal upstream regulator of ferroptosis. This axis facilitates the functional integration of mechanotransduction into inflammatory mediator production, vascular and extracellular matrix(ECM) remodeling, and metabolic reprogramming. Furthermore, this signaling pathway exerts context-dependent pathogenic or protective effects across diverse pathological conditions, including musculoskeletal degeneration, ischemia-reperfusion injury, inflammatory bowel disease, neurovascular disorders, and cancer. This review provides a comprehensive overview of the molecular mechanisms and clinical evidence governing Piezo1-mediated ferroptosis. We summarize current pharmacological and genetic interventions for its inhibition-along with associated limitations such as selectivity and pharmacokinetic challenges-and explores interventions targeting the channel itself, Ca²⁺signaling, and downstream ferroptotic processes, including iron chelation, lipid peroxidation suppression, and preservation of the GPX4/coenzyme Q10 (CoQ10) axis. Furthermore, the potential for integrating these interventions with established therapeutic modalities is also discussed. A profound understanding of the druggability and context-dependent dynamics of the Piezo1-ferroptosis axis is expected to facilitate the discovery of novel therapeutic targets and combinatorial regimens for the precision management of mechanosensitive diseases.

Background: Silver nanoparticles (AgNPs) are increasingly employed across diverse applications, raising concerns regarding their potential biosafety risks. The liver plays a pivotal role as a target organ upon exposure to AgNPs. The adverse outcome pathway (AOP) framework provides a structured, mechanism-based approach for assessing and managing toxicological risks.

Results: In this study, we applied the AOP framework to construct a mechanistic relationship map of AgNP-induced hepatotoxicity. Using in vitro (HepG2 cells) and in vivo (C57BL/6 mice) models, we identified mitochondrial dysfunction as a molecular initiating event (MIE), characterized by excessive dynamin-related protein 1 (DRP1)-mediated mitochondrial fission and increased mitochondrial reactive oxygen species (mtROS), which serve as key events (KEs). The cascade ultimately leads to programmed cell death and structural/functional liver injury, which constitute the AO. Further mechanistic investigations revealed that DRP1 phosphorylation at the Ser616 site activated sequestration 1 (p62)/PTEN-induced kinase 1 (PINK1)-dependent mitophagy, which partially mitigated the severity of the AO by preserving mitochondrial integrity and reducing oxidative damage.

Conclusion: These findings not only demonstrate the critical role of DRP1 activation in linking mitochondrial dynamics to hepatocellular ferroptosis, but also highlight the value of the AOP framework as a tool for predicting NPs risk assessment and regulatory decision-making.