Apoptosis最新文献

Mitochondrial transcription factor A (TFAM) is indispensable for mitochondrial DNA (mtDNA) maintenance and transcription, governing cellular bioenergetics. Despite its known physiological importance, TFAM plays a complex and often paradoxical role in cancer biology. This study integrates pan-cancer bioinformatics analyses with experimental evidence to comprehensively elucidate TFAM’s multifaceted impact on tumorigenesis. We systematically investigated the heterogeneity of TFAM across diverse cancer types, specifically focusing on its regulatory mechanisms in metabolic reprogramming, signal transduction, and immune microenvironment remodeling. Our analysis reveals that TFAM functions as a critical node connecting mitochondrial integrity to tumor progression, balancing tumor-promoting and tumor-suppressive roles depending on the context. Finally, we discuss the challenges of targeting TFAM, such as off-target toxicity, and highlight emerging precision oncology strategies, including mitochondria-targeted delivery systems, that aim to exploit these mitochondrial vulnerabilities.

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Protein lipidation and ubiquitination are two fundamental post-translational modifications that orchestrate protein localization, stability, and function. Beyond their independent roles, emerging evidence reveals a complex crosstalk between these modifications that profoundly shapes tumor biology. Lipidation promotes membrane anchorage and functional activation of key oncogenic drivers, whereas ubiquitination dynamically controls protein abundance through proteasomal degradation or signaling modulation. Their interplay regulates pivotal processes in cancer, including immune evasion, tumor microenvironment remodeling, metabolic reprogramming, invasion and metastasis, and uncontrolled proliferation. Mechanistically, lipidation can shield proteins from ubiquitin-mediated degradation or recruit deubiquitinases, while ubiquitination governs the turnover and activity of lipidation enzymes, together forming a dynamic antagonistic-synergistic network. Recent advances highlight the therapeutic promise of targeting this axis: inhibitors of NMTs, DHHC enzymes, and lipidation-dependent pathways, as well as ubiquitin-based technologies such as PROTACs, DUB inhibitors, and molecular glues, are being developed toward clinical translation. By integrating mechanistic insights with therapeutic innovation, this review underscores lipidation-ubiquitination crosstalk as a critical regulatory hub and potential dual-modification target for precision oncology.

Non-small cell lung cancer (NSCLC) metastasis, driven by tumor-associated macrophages (TAMs), remains a significant challenge due to poor prognosis and limited therapeutic options. This study developed DSPE-PEG-M2pep-modified liposomal nanoparticles (M2pep-LNP@siITGB4) delivering siRNA targeting integrin β4 (siITGB4) to reprogram M2 TAMs and induce apoptosis in NSCLC cells, thereby inhibiting metastasis. Cationic liposomes were prepared using thin-film hydration and ultrasonic emulsification, with M2pep peptides enhancing targeted delivery to M2 macrophages. In vitro, THP-1-derived M2 macrophages were co-cultured with A549 and NCI-H1299 cells, and the effects on macrophage polarization and tumor cell behavior were assessed via RT-qPCR, Western blot, and Transwell assays. In vivo, A549 xenograft and lung metastasis models were analyzed using IVIS, flow cytometry, and RNA sequencing. M2pep-LNP@siITGB4 downregulated M2 markers (CD206, Arg1, IL-10), upregulated M1 markers (CD86, iNOS), and increased CD8 + T cell infiltration. Silencing ITGB4 reduced GNB5 expression and FAK/Src/AKT phosphorylation, promoting apoptosis and inhibiting epithelial-mesenchymal transition (EMT). RNA-seq revealed 3494 differentially expressed genes, with suppressed ECM-receptor interactions. Tumor volumes and metastatic lesions were significantly reduced. This approach effectively reprograms TAMs, induces tumor cell apoptosis, and suppresses NSCLC metastasis, offering a novel nanomedicine-based strategy for enhancing anti-tumor immunity and improving therapeutic outcomes in NSCLC.

Graphical abstract

Schematic illustration of the mechanism by which M2pep-LNP@siITGB4 silences ITGB4 to modulate the integrin-FAK/Src-AKT signaling axis, reprogram macrophage polarization, and inhibit EMT (created with BioRender).

Rheumatoid arthritis (RA) is a chronic autoimmune disorder marked by synovial inflammation and joint damage, with fibroblast-like synoviocytes (FLS) acting as key drivers of RA pathogenesis. Pyroptosis, a form of inflammatory programmed cell death, contributes to RA synovial pathology. Although aquaporin-1 (AQP1) has been implicated in RA progression, its role in pyroptosis and the underlying mechanisms remain unclear. Through bioinformatics analyses of multiple transcriptomic datasets and experimental validation in adjuvant-induced arthritis (AIA) rats, we identified AQP1 as a pyroptosis-related gene elevated in RA synovium. Functional assays revealed that AQP1 promotes pyroptotic cell death and induces the release of IL-1β and IL-18 in RA-FLS. Pathway enrichment analyses and experimental evidence identified β-catenin as a crucial downstream mediator of AQP1 in regulating pyroptosis in RA-FLS. Mechanistically, AQP1 binds to β-catenin via its C-terminal domain, disrupting the interaction between β-catenin and GSK-3β, thereby preventing GSK-3β-mediated phosphorylation and degradation of β-catenin. As a result, cytoplasmic β-catenin is stabilized and accumulates, which then interacts with NLRP3 to facilitate NLRP3-ASC complex formation and NLRP3 inflammasome assembly, thereby activating caspase-1 and triggering pyroptosis in RA-FLS. In AIA rats, intra-articular injection of adeno-associated virus to knock down AQP1 relieved paw swelling, synovial lesions, cartilage damage, and systemic inflammation, accompanied by reduced expression of β-catenin and pyroptosis-related markers within the synovium. Collectively, this study demonstrates a novel AQP1/β-catenin/NLRP3 axis driving pyroptosis in RA-FLS and highlights targeting AQP1-induced pyroptosis as a potential strategy for RA treatment.

Apoptotic extracellular vesicles (ApoEVs), once dismissed as inert “cellular debris,” are now recognized as dynamic membrane-bound vesicles actively released during apoptosis, functioning as essential signaling platforms that coordinate tissue homeostasis and disease progression. Research reveals that through unique molecular signatures and surface properties, ApoEVs drive apoptotic corpse clearance, modulate immune responses, and mediate intercellular crosstalk, thereby exerting multifaceted influences on tissue repair and disease pathogenesis. This review systematically outlines the biogenesis, molecular regulators, and key characteristics of ApoEVs. We focus on their pivotal roles in both physiological homeostasis and disease states, highlighting their substantial translational potential for treating diverse conditions, including immune disorders, osteoporosis, skin injury, and cancer. Finally, we provide a forward-looking perspective on key challenges and translational opportunities, aiming to bridge fundamental insights into ApoEV biology with their clinical application in disease therapy.

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Biological functions and applications of ApoEVs.

Cerebral ischemia/reperfusion injury (CI/RI) is a common complication of cerebrovascular diseases such as stroke, characterized by mitochondrial dysfunction. This study investigates the function of proliferation-associated protein 2G4 (PA2G4) released by neural stem cells (NSCs)-derived exosomes (NSC-Exo) in treating middle cerebral artery occlusion/reperfusion (MCAO/R) by regulating mitophagy. NSC-Exo were extracted and identified. Treatment of NSC-Exo alleviated neurofunctional impairments in MCAO/R-induced mice, reduced oxidative stress and inflammatory responses in hippocampal tissues, and decreased neuronal apoptosis. We analyzed the alteration of molecular mechanisms under the effect of NSC-Exo treatment using bioinformatics analysis and RNA sequencing. PA2G4 was enriched in NSC-Exo, and the absence of PA2G4 in neurons impaired the mitigating effect of NSC-Exo on hippocampal neuronal injury and inhibited mitophagy. NSC-Exo delivered PA2G4 to recruit WW domain-containing protein 2 (WWP2), thereby mediating ubiquitination and degradation of Annexin A2 (ANXA2), and overexpression of PA2G4 or WWP2 reversed the accentuating effect of ANXA2 overexpression on MCAO injury. These findings indicate that PA2G4 delivered by NSC-Exo recruits WWP2 to mediate ubiquitination of ANXA2, thereby activating mitophagy to alleviate oxidative stress in hippocampal neurons in MCAO/R. This study offers a novel target for the treatment of CI/RI.

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PA2G4 delivered by NSC-Exo recruits WWP2 and mediates ubiquitination modification of ANXA2 to activate mitophagy and mitigate oxidative stress in hippocampal neurons in mice challenged by MCAO/R.

The landscape of regulated cell death (RCD) has expanded substantially over the past decade, extending beyond the classic apoptosis–necrosis dichotomy to encompass a diverse array of lytic modalities, including pyroptosis, necroptosis, and ferroptosis. These pathways are generally defined by distinct biochemical executioners, such as caspases, gasdermins, or MLKL, which coordinate the loss of plasma membrane integrity. Despite these advances, how cells integrate metabolic stress with innate immune signaling to commit to lytic death has remained an unresolved question. In a recent issue of Cell, Wang et al. report a previously unrecognized lytic cell death modality termed mitoxyperilysis, in which plasma membrane rupture is driven not by canonical enzymatic effectors but by a physical, mitochondria-mediated oxidative attack.

Breast cancer is the most frequently diagnosed cancer globally, annually affecting around 2 million women. Situation is getting worse with rising incidence linked to improved detection, risk factors, and enhanced registration systems. Conventional treatments like surgery, chemotherapy, radiotherapy, and hormonal therapy with several limitations are replaced by approaches like immunotherapy, HER2-targeted therapies, and nanotechnology offering improved outcomes, in metastatic cases. Risk factors range from lifestyle (alcohol, obesity, inactivity, smoking), to hormonal imbalance (early menarche, late menopause, nulliparity), to genetic aspects (BRCA1/2, TP53), to environmental determinants as well. Prognostic biomarkers now lead precision medicine: PR, ER, and HER2 stands strong as established pillars, while circulating tumor DNA, and immune-related markers such as PD-L1 offer profound perceptions into treatment response and disease progression. State-of-the-art treatment integrates traditional modalities like surgery, radiotherapy, and chemotherapy with targeted and immune-based therapies. Endocrine agents, PARP inhibitors, HER2-directed monoclonal antibodies, and checkpoint inhibitors exemplify the architype swing toward personalized, mechanism-based interventions. The insight underscores the need for twin tactics, leveraging molecular detections for precision oncology while guaranteeing impartial global access to modern therapies. Future progress depends on translational research, and biomarker validation that bridge the gap between innovation and accessibility.

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Neurodegenerative diseases, specifically Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and Amyotrophic Lateral Sclerosis (ALS) are defined by progressively increased neuronal loss that lacks curative therapies. Increasing evidence supports that non-canonical regulated cell death pathways including ferroptosis, necroptosis, pyroptosis, and parthanatos, are implicated in pathological mechanisms of neuroinflammation, and oxidative stress, and mitochondrial dysfunction, likely impacting neurodegenerative pathologies. In this review, we summarize the existing literature on the molecular pathways and potential pathogenic implications of these cell death pathways in neurodegenerative diseases, highlighting their upstream triggers, regulatory proteins, and downstream effectors. We also briefly describe representative pharmacological agents, including ferrostatin-1, necrostatin-1, MCC950 and PARP-inhibitors, that have shown neuroprotective effects in experimental studies. Experimental studies provide valuable information, but translation to clinical treatments presents barriers including overlapping regulated cell death mechanisms, constraints of bloodbrain barrier penetrance and concern for safety. Future development may come through concepts such as biomarker-based patient stratification strategies, multivalent interventions, and improved translational models. Identifying these new regulated cell death pathways may eventually provide new avenues to slow the progression of neurodegeneration and develop more targeted therapies.

Diabetic kidney disease (DKD) is a microvascular complication of diabetes accompanied by inflammation and tubular fibrosis. Berberine (BBR), a plant alkaloid and traditional Chinese medicine, has been shown to have beneficial effects on DKD. However, its mechanism underlying its therapeutic effects in DKD remain to be fully elucidated. Herein, we investigated the protective effects of BBR on STZ/HFD-induced DKD mice and high glucose (HG)-treated renal tubular epithelial cells (TECs). Results showed that BBR reduced inflammation and tubular fibrosis in DKD mice. Meanwhile, BBR also reversed HG-induced inflammation and fibrosis in TECs. Mechanistically, qPCR and western blotting assays revealed that BBR abolished the HG-induced upregulation of ISG15 and the changes in the expression of pyroptosis-related proteins. Furthermore, overexpression of ISG15 in kidney and TECs significantly exacerbated renal tubular cell injury and abolished the protective effect of BBR against DKD. In conclusion, these results demonstrated that BBR can attenuate inflammation and tubular fibrosis in DKD by inhibiting ISG15 and pyroptosis, providing a new potential strategy for the treatment of DKD and highlighting the therapeutic potential of BBR in mitigating renal injury and fibrosis.