Apoptosis最新文献

Poly (ADP‒ribose) polymerase inhibitors (PARPis) are widely used in maintenance therapy for various platinum-sensitive cancers regardless of the occurrence of BRCA mutations. However, the mechanisms of action and treatment resistance associated with the use of PARPis for maintenance therapy in pancreatic cancer remain unclear. In this study, in addition to the induction of apoptosis, the use of PARPis (olaparib and niraparib) as maintenance therapies inhibited cell proliferation by causing cellular senescence to exert potent anticancer effects on Capan-1 (BRCA mutated) and PANC-1 (BRCA wild-type) cells. Mechanistically, the cellular senescence caused by PARPis relies on the Chk2‒p21 pathway but not in a p53-dependent manner. Interestingly, in addition to directly causing DNA damage, PARPis also exacerbate DNA damage through the generation of ROS via the positive feedback pathway, thereby inducing cellular senescence. Unfortunately, PARPis therapy-induced senescence is a reversible anticancer mechanism in which senescent cancer cells lose their senescence-like phenotype and continue proliferating upon drug withdrawal. This potentially explains the requirement for sustained PARPi therapy in the clinic. Furthermore, the expression of Bcl-2 was increased in PARPi-induced senescent cancer cells, providing a window for opportunistic elimination via synergistic senolytic drugs. The inhibition of Bcl-2 through the sequence-dependent combination of navitoclax enhanced the anticancer effects of PARPis by removing senescent cells. Collectively, data from our study demonstrate that the clinical application of PARPis as maintenance therapy could be achieved through the induction of cellular senescence. Furthermore, sequence-dependent combination with senescence-targeting drugs can potentiate pancreatic cancer treatment effects of PARPis regardless of the BRCA status.

Recently evidence has suggested that long non-coding RNAs (lncRNAs) play a pivotal role in the prognosis and treatment of leukemia. However, studies on their use in differentiation therapy of acute myeloid leukemia (AML) remain scarce. In this study, we found that AC098613.1 was significantly increased in differentiated THP-1 cells, while its expression was significantly lower in AML patients. Moreover, AC098613.1 overexpression inhibited proliferation and induced differentiation of THP-1 and HL-60 cells. Mechanistically, we found that AC098613.1 targeted cell division cycle 5-like protein (CDC5L) to increase its stability, thereby enhancing its abundance and nuclear localization, and promoted the transcription of ADP-ribosylation factor GTPase activating protein with dual PH domains 1 (ADAP1) and the expression of nardilysin (encoded by NRD1), which ultimately induced the differentiation of AML cells. We further demonstrated in vivo that AC098613.1 overexpression significantly inhibited tumor growth by affecting the stability of CDC5L and regulating the expression of ADAP1, NRD1 and cyclin-dependent kinase 1 (CDK1). The research demonstrates that AC098613.1 promotes AML cell differentiation by regulating the CDC5L/ADAP1/NRD1 axis, providing a new target for AML differentiation therapy.

Lysosomal associated membrane protein family member 5 (LAMP5), a recently identified member of the LAMP family, has been associated with poor prognosis in multiple cancer types; however, its precise oncogenic mechanisms remain unclear. This study systematically investigated the oncogenic and immunological functions of LAMP5 using multiple datasets. LAMP5 expression was significantly dysregulated in various cancers, highlighting its potential as a diagnostic and prognostic biomarker. GSVA indicated that LAMP5 expression is likely associated with enhanced cell proliferation and tumor invasive potential; it may also be correlated with alterations in anti-tumor immune responses. Immune infiltration analyses using Multi-database analyses revealed that high LAMP5 expression was associated with increased infiltration of immune cells including natural killer T cells and tumor-associated fibroblasts, accompanied by upregulation of immune checkpoint molecules and chemokines. Validation using various immunotherapy cohorts showed that elevated LAMP5 expression may be linked to reduced immunotherapy efficacy. A focused investigation in bladder cancer revealed that LAMP5 facilitates proliferation via regulation of the FBXW11/p27 axis. These findings identify LAMP5 as a multifunctional oncoprotein with both prognostic and therapeutic relevance in bladder cancer. This study provides insights into the molecular mechanisms by which LAMP5 promotes bladder cancer progression and offers potential targets for therapeutic intervention and clinical management.

Graphical abstract

Acute pancreatitis (AP) is a potentially life-threatening inflammatory disease whose severity is fundamentally shaped by the mode of pancreatic acinar cell death. Crucially, this cell fate decision is primarily governed by genetically encoded programs known as regulated cell death (RCD), including apoptosis, necroptosis, pyroptosis, ferroptosis, and autophagy-dependent death. Unlike accidental necrosis, RCD proceeds via specific signaling cascades. In AP, excessive RCD in pancreatic acinar cells drives local tissue injury and systemic inflammation, potentially leading to systemic inflammatory response and organ failure. Mitochondria are central integrators of these interconnected RCD pathways: pathological calcium overload and oxidative stress disrupt mitochondrial function, causing ATP depletion. These organelle failures precipitate cell death cascades and amplify inflammation. Damaged mitochondria release damage-associated molecular patterns (DAMPs), which further promote cytokine release and pancreatic injury. This review highlights key RCD signaling mechanisms in AP and their pathophysiological significance. Emerging therapeutic strategies include agents that stabilize mitochondrial integrity or inhibit RCD signaling, which have shown efficacy in experimental models. Therefore, targeting RCD—especially via mitochondrial protection—represents a promising approach to limit pancreatic damage and improve outcomes. To realize this potential, we conclude by outlining translational challenges, such as biomarker validation, and proposing future research directions to advance AP therapeutics.

Ferroptosis represents an iron-dependent form of regulated cell death, distinguished by the accumulation of lipid peroxides. This process holds significant implications for tumor progression and resistance to therapeutic interventions. Cell adhesion molecules (CAMs), which facilitate interactions between cells and between cells and the extracellular matrix, have emerged as pivotal regulators of ferroptosis sensitivity within the cancerous milieu. Accumulating evidence underscores the capacity of CAMs to modulate key ferroptotic pathways. This includes the system Xc⁻/GSH/GPX4 antioxidant axis and iron metabolism through endocytic uptake mechanisms. Depending on the cellular context, CAMs can either promote or suppress ferroptosis. This review offers a systematic summary of the roles played by major CAM families—namely, the immunoglobulin superfamily, cadherins, and integrins—in the regulation of ferroptosis. Such regulation is achieved through diverse mechanisms, including signal transduction, lipid peroxidation, and iron homeostasis. Furthermore, we delve into the therapeutic potential of targeting CAMs, either as standalone treatments or in conjunction with ferroptosis inducers, as a novel and promising strategy for cancer management. These insights not only enhance our comprehension of the regulatory mechanisms governing ferroptosis mediated by CAMs but also pave the way for innovative combination therapies in the field of oncology.

Immunotherapy has drawn attention in the current era; CAR T cells and STING agonists are emerging as novel approaches for cancer treatment. Advances in STING agonist development are ongoing, and many remain in the preclinical stage. At the same time, it is now clear that dysregulated or chronic activation of the cGAS–STING pathway contributes to a broad spectrum of human pathological conditions. Classically, cGAS, as a sensor of dsDNA, recognizes the cytoplasmic dsDNA and, due to the enzymatic activity, generates a di-nucleotide molecule as the 2′3′ cGAMP. 2′3′ cGAMP behaves as the natural activator of STING and further facilitates the downstream pathway via TBK1 to IRF-3 and NF-κB. Conventionally, this pathway is explored in the context of the antiviral immune response. The agonists of STING have a distinct role in immunotherapy, but the cGAS–STING pathway is also associated with other molecular mechanisms that deviate from its canonical pathway and activate its non-canonical pathway, which leads to different molecular patterns, and this is associated with many diseases and cancer survival. Here, we discussed the various pathways that regulate the cGAS–STING activation in chronic and non-canonical ways. Chronic and non-canonical pathways associated with human disease and cancer. We also discussed the therapeutic opportunities.

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has been increasingly recognized as a key mechanism in salivary gland disorders. Initially identified in postmenopausal xerostomia, evidence now extends to autoimmune diseases, radiation-induced injury, hormonal regulation, and malignant tumors such as adenoid cystic carcinoma. Rather than being a secondary consequence of oxidative stress, ferroptosis actively contributes to epithelial damage, inflammatory amplification, and resistance to therapy. In Sjögren’s disease, interferon-γ promotes ferroptotic death of salivary epithelial cells through suppression of antioxidant defenses. Radiation accelerates ferritinophagy, iron release, and GPX4 loss, driving acinar injury that can be alleviated by radioprotective agents. Estrogen deficiency enhances ferroptosis via altered iron handling and hormone receptor signaling, while pharmacological inhibitors and natural compounds restore salivary function in experimental models. In malignant salivary tumors, inhibition of NOTCH1 or the use of iron-based nanomedicine induces ferroptosis and overcomes apoptosis resistance, highlighting its therapeutic promise. Beyond treatment, saliva and exosomal cargo have emerged as non-invasive sources of ferroptosis-related biomarkers, offering opportunities for disease monitoring and patient stratification. Despite these advances, challenges remain in validating biomarkers, characterizing alternative defense systems, and translating preclinical insights into clinical trials. Collectively, current findings position ferroptosis as both a mechanistic driver and a tractable therapeutic target in salivary gland biology, with broad implications for precision medicine.

Voltage-dependent anion channel 2 (VDAC2) is a pivotal β-barrel protein located in the mitochondrial outer membrane (MOM), playing a central role in metabolite transport, ion homeostasis, and the determination of cell fate. Compared to other isoforms in the same family, VDAC2 possesses unique structural features—including an N-terminal extension, an enrichment of cysteine residues, and a distinct β-barrel conformation—which underlie its non-redundant functional roles. Notably, VDAC2 acts as a “dual regulatory hub” in apoptosis: it suppresses apoptosis by directly binding and inhibiting BAK, while also being essential for BAX-mediated apoptosis, demonstrating marked context-dependency. Furthermore, VDAC2 is deeply involved in tumor progression through its regulation of metabolic reprogramming, reactive oxygen species (ROS) homeostasis, ferroptosis, and mitochondrial quality control. Dysregulation of VDAC2 expression is closely associated with prognosis in multiple cancers, highlighting its promise as a diagnostic and prognostic biomarker, as well as a therapeutic target. This review systematically consolidates current knowledge on VDAC2 in oncology, identifies limitations and challenges in existing research, and aims to offer strategic insights to guide future investigations.

Abdominal aortic aneurysm (AAA) progression is closely linked to inflammation and endothelial dysfunction. Our previous study has demonstrated that increased CD95 ligand (CD95L) and its downstream effector Caspase-8 in the aortic tissue, contributed to AAA by modulating inflammation. However, how the CD95L/Caspase-8 modulated aneurysmal inflammation remains poorly understood. This study investigates how CD95L/Caspase-8 signaling drives endothelial pyroptosis to exacerbate AAA. Using a CaCl₂-induced AAA murine model and primary mouse aortic endothelial cells (MAECs), we demonstrate that CD95L triggers endothelial pyroptosis, characterized by NLRP3 inflammasome activation, Gasdermin D N-terminal (GSDMD-N) cleavage, and Caspase-8/Caspase 1 activation. Electron microscopy confirmed pyroptotic morphology, while flow cytometry excluded apoptosis or necrosis. CD95L elevated IL-1β/IL-18 secretion, which was abolished by Caspase-8 siRNA or inhibitor Z-IETD-FMK. Mechanistically, CD95L suppressed Caspase-8 phosphorylation at Tyr380, enabling its activation of GSDMD-dependent pyroptosis. In vivo, CaCl₂-induced AAA mice exhibited aortic dilation, elastin degradation, and endothelial-specific pyroptosis, all attenuated by endothelial-targeted Caspase-8 knockdown via AAV9-shRNA. This intervention reduced NLRP3 and GSDMD-N expression while preserving vascular integrity. Similarly, SRC kinase activation mitigated pyroptosis markers and aortic damage. These findings establish CD95L as a key mediator of endothelial pyroptosis in AAA via Caspase-8 dephosphorylation and NLRP3/GSDMD-N activation. Targeting Caspase-8 or enhancing SRC activity represents a promising therapeutic strategy to curb AAA progression by preserving endothelial homeostasis.

Beige adipocytes play a key role in non-shivering thermogenesis. SEMA3E, a member of the class 3 semaphorin family, is involved in various pathological processes, but its role in adipocyte differentiation and thermogenesis remains unclear. Here, we found SEMA3E expression increased in inguinal white adipose tissue (iWAT) following cold exposure or β-adrenergic agonist CL316,243 stimulation. In vitro, loss- and gain-of-function experiments revealed that SEMA3E promoted beige adipocyte differentiation and enhanced thermogenic genes expression. In vivo, fat transplantation experiments indicated that SEMA3E promoted adipogenesis. Furthermore, adeno-associated virus (AAV)-mediated SEMA3E knockdown in iWAT impaired thermogenesis in mice exposed to cold or CL316,243. RNA-Seq analysis linked SEMA3E to mitochondrial oxidative phosphorylation, and its knockdown reduced mitochondrial respiration by downregulating respiratory chain components expression and lowering mitochondrial oxygen consumption rate. Mechanistically, gene set enrichment analysis suggested SEMA3E regulated beige adipocyte differentiation via the Wnt/β-catenin pathway. SEMA3E knockdown delayed β-catenin degradation, while inhibiting this pathway with IWR-1 rescued the suppressed differentiation and thermogenic genes expression. In conclusion, these findings highlight the crucial role of SEMA3E in beige adipocyte differentiation and thermogenesis.