Apoptosis最新文献

{"title":"Autophagy-lysosomal dependency defines a vulnerable physiological state in drug-tolerant persister cells of triple-negative breast cancer.","authors":"Essha Chatterjee, Biswajit Dey, Anamika Sharma, Anil Dharavath, Aliva Naik, Hoshiyar Singh, Santanu Basak, Bhavna Pratyusha, Vigneshwar Reddy Ashireddygari, Prasad Tammineni, Harikrishna Adicherla, Ira Bhatnagar, Nandkumar Doijad, Rahul Kumar, Santosh Kumar Guru","doi":"10.1007/s10495-026-02310-5","DOIUrl":"https://doi.org/10.1007/s10495-026-02310-5","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC), a subtype of aggressive breast cancer, has limited treatment options. Recurrent disease caused by drug-tolerant persister cells (DTPs) that evade chemotherapeutic agents (e.g., doxorubicin hydrochloride (DOX) and paclitaxel (PTX)) is a significant challenge in treating TNBC. Recent studies highlight both autophagy and lysosomal function as key mechanisms supporting cancer cell survival; however, their precise roles in mediating drug tolerance in TNBC remain largely unexplored. This study aimed to elucidate the mechanisms by which autophagic and lysosomal activities support the survival of TNBC DTPs following exposure to DOX and PTX. Compared with parental cells in both 2D and 3D cellular topologies, our results showed that treatment with DOX and PTX produced a fraction of latent DTPs that exhibited increased autophagic induction and improved lysosomal protein expression. The results revealed that pharmacological inhibition of autophagy (hydroxychloroquine) or lysosomal activity (bafilomycin A1) compromised DTPs' survival. Similarly, disrupting lysosomal integrity with L-leucyl-L-leucine methyl ester (LLOME) decreased DTPs' viability. Additionally, knockdown of the lysosomal protein LAMP1 (lysosomal-associated membrane protein 1) significantly reduced persister cells' viability and enhanced the cytotoxic effects of DOX and PTX. In a xenograft model, depleting LAMP1 in TNBC cells slowed tumor proliferation and delayed tumor initiation. Our results demonstrated that increased autophagy-lysosomal process renders DTP cell survival in TNBC by maintaining mitochondrial reactive oxygen species (mROS) generation, which, in turn, contributes to chemotherapy resistance. A potential treatment strategy for eradicating DTP cells and preventing tumor recurrence in TNBC involves targeting these mechanisms.</p>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 5","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147863501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut microbiota-tryptophan-serotonin axis drives anxiety-like behavior via NLRP3-mediated neuronal pyroptosis in the medial prefrontal cortex.","authors":"Guiqiang Zhou, Xing Wang, Tongzhou Qin, Ling Guo, Jiajin Lin, Zhaowen Zhang, Peng Gao, Yan Zhou, Wei He, Jing Li, Guirong Ding","doi":"10.1007/s10495-026-02356-5","DOIUrl":"https://doi.org/10.1007/s10495-026-02356-5","url":null,"abstract":"<p><p>The gut-brain axis plays a critical role in anxiety disorders, yet the underlying mechanisms remain incompletely understood. Using a mouse model of radiofrequency radiation (RFR)-induced anxiety-like behaviors, we employed gut microbiota intervention, regulation of tryptophan metabolites, and other methods to investigate the impact of the gut-brain axis on brain function changes. It was found that gut microbiota dysbiosis disrupts tryptophan metabolism, leading to reduced serotonin (5-HT) levels and NLRP3 inflammasome-mediated neuronal pyroptosis in the medial prefrontal cortex (mPFC). Probiotic intervention restored microbial homeostasis, normalized central 5-HT metabolism, suppressed neuronal pyroptosis, and partially alleviated anxiety-like behaviors. Similarly, treatment with the selective serotonin reuptake inhibitor (SSRI) paroxetine increased brain 5-HT, attenuated NLRP3 activation and pyroptosis, and improved behavioral outcomes. These findings reveal that perturbations in gut-brain tryptophan metabolism are strongly correlated with anxiety-like behaviors via neuroinflammatory pyroptotic pathways, offering new mechanistic insights and potential therapeutic targets for anxiety disorders.</p>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 5","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147863502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PKCβ II antagonizes O-GlcNAcylated FOXO4 and inhibits lipid synthesis","authors":"Hua Fu,&nbsp;Yuqin Li,&nbsp;Pengzhou Li,&nbsp;Liyong Zhu,&nbsp;Shaihong Zhu,&nbsp;Guohui Wang","doi":"10.1007/s10495-026-02348-5","DOIUrl":"10.1007/s10495-026-02348-5","url":null,"abstract":"<div><h3>Background</h3><p>Obesity and associated metabolic disorders remain major public health challenges worldwide. The regulation of lipid synthesis represents a promising therapeutic target, yet the precise mechanisms remain elusive.</p><h3>Methods</h3><p>RT-qPCR and western blot measured gene expression. Lipid droplets were evaluated by Nile Red staining. TC, HDL-C, LDL-C, TG and NEFA levels were detected by ELISA kits. The interaction between proteins or genes was analyzed by ChIP, Dual-luciferase reporter, and Co-IP assays. Subcellular localization was analyzed by nuclear/cytoplasmic fractionation and immunofluorescence.</p><h3>Results</h3><p>FOXO4 was downregulated after bariatric surgery and directly decreased the transcription of lipogenic enzymes ACACA and HMGCR. Nuclear localization of FOXO4 was regulated by a previously uncharacterized interplay between O-GlcNAcylation and phosphorylation. Specifically, O-GlcNAcylation at S261 promoted FOXO4 nuclear translocation and enhanced lipogenic gene expression, while PKCβII-mediated phosphorylation at T451 antagonized this modification. Functionally, FOXO4 deletion suppressed lipid synthesis under HFD conditions. OGA or PKCβII knockdown promoted lipid synthesis by regulating FOXO4.</p><h3>Conclusion</h3><p>Elevated OGA inhibited FOXO4’s nuclear translocation via O-GlcNAcylation, and subsequent PKCβII-mediated phosphorylation-induced degradation. This process decreased ACACA and HMGCR expression, thereby attenuating lipid synthesis.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 5","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147829422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A multi-targeted therapeutic strategy for triple-negative breast cancer: the tumor-targeting peptide p28 enhances chemotherapy, induces apoptosis, crosses the blood–brain barrier, and suppresses metastasis","authors":"Haniyeh Abuei,&nbsp;Pei Pei Chong,&nbsp;Mohammad Hossein Malekzadeh,&nbsp;Anahita Mojiri,&nbsp;Mohammad Amin Mosleh Shirazi,&nbsp;Sedigheh Sharifzadeh,&nbsp;Ali Farhadi","doi":"10.1007/s10495-026-02346-7","DOIUrl":"10.1007/s10495-026-02346-7","url":null,"abstract":"<div><p>Triple-negative breast cancer (TNBC) is an aggressive and molecularly heterogeneous subtype of breast cancer characterized by limited targeted treatment options, frequent chemoresistance, and a strong propensity for metastasis, particularly to the central nervous system (CNS). These challenges highlight the need for multi-targeted therapeutic strategies. The tumor-targeting peptide p28, which exhibits antitumor activity and potential blood–brain barrier (BBB) penetration, represents a promising candidate for enhancing therapeutic efficacy in TNBC through distinct mechanisms of action. In this study the effects of p28, five standard chemotherapeutic agents, and their low-dose combinations with p28 were systematically evaluated in TNBC models in vitro and in vivo. Cellular responses, including BBB permeability, viability, proliferation, apoptosis, cell cycle distribution, oxidative stress, DNA damage, and metastatic potential, were assessed. Integrated transcriptomic and systems biology analyses were performed to identify dysregulated pathways, and selected targets were subsequently evaluated at the transcript and protein levels. In xenograft models, tumor growth, apoptosis, metastasis-related features, histopathology, toxicity, and overall survival were comprehensively assessed. p28 reduced TNBC cell viability while sparing normal cells, demonstrated favorable BBB permeability, and significantly enhanced the antitumor activity of chemotherapeutic agents at reduced doses. These combinations showed synergistic effects, resulting in markedly enhanced tumor suppression, increased apoptosis, reduced invasion and metastasis, reduced toxicity, and prolonged survival. Collectively, these findings support p28 as a promising preclinical combination strategy in TNBC, distinguished by its synergistic interaction with chemotherapy, and justify further investigation of its therapeutic potential in metastatic breast cancer.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 5","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147829151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"QD394 induces ferroptosis and suppresses the proliferation of colorectal cancer via the SP1/JNK pathway","authors":"Ruixue Zhang,&nbsp;Haiyan Quan,&nbsp;Wenjing Xiao,&nbsp;Zhenhua Lin,&nbsp;Aihua Jin","doi":"10.1007/s10495-026-02290-6","DOIUrl":"10.1007/s10495-026-02290-6","url":null,"abstract":"<div><p>Lipid peroxidation triggers ferroptosis, a type of regulated cell death that is iron-dependent. Owing to its important role in tumor suppression, ferroptosis represents an extremely promising therapeutic target for cancer. QD394, a quinazolinone-based compound, was recently identified as a novel redox regulator with demonstrated cytotoxic and proapoptotic effects in pancreatic and breast cancer models. Preliminary RNA sequencing analysis suggested potential associations between QD394 treatment and ferroptosis, mitogen-activated protein kinase (MAPK) signaling, and angiogenic pathways. Cell Counting Kit-8 (CCK-8), colony formation assay, and 5-ethynyl-2'-deoxyuridine (EdU) assays, as well as annexin V/PI staining, revealed that QD394 inhibited cell proliferation and induced apoptosis. Microtubule assembly, chick chorioallantoic membrane (CAM), and scratch assays demonstrated that QD394 suppressed angiogenesis. Notably, QD394-treated colorectal cancer (CRC) cells exhibited decreased levels of glutathione (GSH), solute carrier family 7 member 11 (xCT), and glutathione peroxidase 4 (GPX4), and increased levels of malondialdehyde (MDA) and lipid reactive oxygen species (ROS), suggesting that QD394 induces ferroptosis. Mechanistically, QD394 treatment reduced specific protein 1 (SP1) levels through ubiquitin-mediated proteolysis. Notably, overexpression of SP1 counteracted QD394-induced ferroptosis. Moreover, QD394 treatment significantly increased the ratio of p-JNK to total JNK in CRC cells, whereas SP1 overexpression effectively reversed this effect. In a xenograft model, QD394 significantly inhibited tumor growth and decreased tumor weight, and the expression of Ki-67, GPX4, and SP1. In contrast, 4-hydroxynonenal (4-HNE) and p-JNK levels were markedly elevated. Collectively, our findings reveal that QD394 triggers ferroptosis in CRC through the SP1/JNK signaling axis, highlighting its potential as a novel anticancer agent.</p><h3>Graphical Abstract</h3><div><figure><div><div><picture><source><img></source></picture><span>The alternative text for this image may have been generated using AI.</span></div></div></figure></div></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 5","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147829224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Celecoxib potentiates ribociclib-induced apoptosis and anti-tumor activity by co-targeting COX-2/NF-κB and PI3K/AKT/mTOR pathways in hormone receptor-positive/HER2-negative breast cancer","authors":"Sanghee Han,&nbsp;Hail Kim,&nbsp;Minji Choi,&nbsp;Bo-Hyung Kim,&nbsp;Sumin Chae,&nbsp;Seok-Geun Lee","doi":"10.1007/s10495-026-02340-z","DOIUrl":"10.1007/s10495-026-02340-z","url":null,"abstract":"<div>\u0000 \u0000 <p>Hormone receptor‐positive/HER2‐negative (HR⁺/HER2⁻) breast cancer accounts for the majority of breast tumours, and cyclin‑dependent kinase 4/6 (CDK4/6) inhibitors such as ribociclib have improved patient outcomes. However, their benefit is limited by resistance and dose‑limiting toxicities, while COX‑2-associated inflammatory signaling and downstream NF‑κB and PI3K/AKT/mTOR pathways contribute to cancer cell survival. We therefore examined whether the clinically available COX‑2 inhibitor celecoxib enhances ribociclib’s anti‑tumour activity in preclinical HR⁺/HER2⁻ models, primarily through in vitro mechanistic evaluation. HR⁺/HER2⁻ breast cancer cells were treated with celecoxib, ribociclib or both, and cell viability, clonogenic growth, cell‑cycle distribution and apoptosis were assessed alongside RT‑qPCR and western blotting. Drug interactions were analyzed using Chou–Talalay synergy analysis. Celecoxib plus ribociclib significantly reduced proliferation and colony formation compared with single agents and yielded combination index values &lt; 1 in multiple dose pairs, indicating synergy. The combination increased sub-G₁ and Annexin V-positive cells, reduced mRNA levels of <i>CDK1</i>, <i>CDK6</i>, <i>CCND1</i>, <i>CCNE1/E2</i>, and <i>CDC25A</i>, and lowered p-Rb, cyclin D1, CDK4, CDK1, and E2F1 protein expression. BAX increased and BCL-2 decreased. <i>IL1B</i>, <i>IL6</i>, and <i>TNF</i> transcripts, p-p65, COX-2, p-PI3K, p-AKT, and p-mTOR were also reduced. In an orthotopic MCF7 xenograft model, combined treatment was associated with greater tumour growth suppression and lower Ki‑67, p‑Rb, COX‑2 and p‑AKT expression than monotherapy, without additional toxicity under the experimental conditions tested. These findings show that celecoxib is associated with enhanced ribociclib‑induced apoptosis and anti‑tumour activity, accompanied by coordinated modulation of cell-cycle, apoptotic, inflammatory, and survival pathways. To our knowledge, this is the first report of a celecoxib–CDK4/6 inhibitor combination in HR⁺/HER2⁻ breast cancer, providing a mechanistic basis for further evaluation in more biologically robust preclinical models.</p>\u0000 </div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 5","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147760446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Necroptosis in pancreatic cancer: Molecular mechanisms and therapeutic implications","authors":"Yu-Jie Fan,&nbsp;Wei-Jia Liu,&nbsp;Chang Liu,&nbsp;Yi-Wen Zhu,&nbsp;Ti Chu,&nbsp;Hang-Shen Han,&nbsp;Dong-Dong Wu","doi":"10.1007/s10495-026-02284-4","DOIUrl":"10.1007/s10495-026-02284-4","url":null,"abstract":"<div><p>Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal cancer due to its strong resistance to chemotherapeutic agents that induce apoptosis. As conventional treatments gradually lose their effectiveness over time, necroptosis has become a key therapeutic target worth exploiting. Necroptosis is a regulated cell death independent of caspases. It is driven by the receptor-interacting protein kinase 1/3 (RIPK1/3) and mixed lineage kinase domain-like pseudokinase (MLKL) signaling axis. This systematic review summarizes the complex role of necroptosis in PDAC. We clarify how necroptosis can be triggered or manipulated pharmacologically, and how it can be induced by accumulating reactive oxygen species (ROS). We also critically analyze its tumor-promoting side. Persistent necroptotic signaling reshapes the tumor microenvironment (TME) by releasing damage-associated molecular patterns (DAMPs) and activating inflammatory cascades. We also highlight the growing clinical significance of necroptosis-related genes (NRGs), long non-coding RNAs (lncRNAs), and specific biomarkers such as fermitin family member 1 (FERMT1). Finally, we propose a new, context-dependent therapeutic framework. This framework proposes a combination of strategies for controlling necroptosis induction and immunomodulatory agents, offering a reasonable strategy for PDAC management.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 5","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147714862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor suppressor candidate 1 (TUSC1) drives oxidative phosphorylation and tumor cell death in colorectal cancer","authors":"Janvie Manhas,&nbsp;Ruchi Bhardwaj,&nbsp;Sagar Tyagi,&nbsp;Ramani Shyam Kapuganti,&nbsp;Anushree Bharadwaj,&nbsp;Jaydeep Sharma,&nbsp;Gunjan Sharma,&nbsp;Diksha Joshi,&nbsp;Ayushi Jain,&nbsp;Priyanka Mani,&nbsp;S. V. S. Deo,&nbsp;Rajinder Parshad,&nbsp;Prasenjit Das,&nbsp;Archna Singh,&nbsp;Sam J. Mathew,&nbsp;Sudip Sen,&nbsp;Jayanth Kumar Palanichamy","doi":"10.1007/s10495-026-02336-9","DOIUrl":"10.1007/s10495-026-02336-9","url":null,"abstract":"<div><p>Tumor Suppressor Candidate-1 (TUSC1), located at chromosome 9p21.2, resides within a region frequently deleted in human malignancies, yet its role in colorectal cancer (CRC) remains undefined. We investigated TUSC1 expression and function using integrated clinical, transcriptomic, metabolic, and in-vivo approaches. Immunohistochemical analysis of 145 CRC specimens revealed a significant loss of TUSC1 protein compared to normal colon, concordant with TCGA-COAD/READ RNA-Seq datasets. DepMap CRISPR fitness screens demonstrated that TUSC1 is non-essential for baseline proliferation, supporting a tumor suppressor–like profile. Lentiviral re-expression of TUSC1 in low-expressing CRC cell lines (HCT116, SW480) induced broad transcriptomic remodeling, including suppression of PI3K–Akt–mTOR signaling and stemness programs, with concomitant enrichment of oxidative phosphorylation (OXPHOS) pathways. Quantitative proteomics and phospho-western analyses confirmed attenuation of PI3K–Akt signaling. TUSC1 overexpression led to increased mitochondrial respiration, Complex I activity, and mitochondrial mass without significant changes in glycolytic flux. It also led to elevated mitochondrial ROS levels and induced G2/M arrest and apoptosis. Antioxidants partially rescued mitochondrial ROS–dependent cytotoxicity in HCT116 cells, whereas SW480 cells displayed a more limited redox rescue. TUSC1 also reduced cancer stem cell markers, impaired clonogenicity, enhanced 5-fluorouracil sensitivity, and suppressed tumor growth in xenograft models. These findings establish TUSC1 as a metabolic tumor suppressor in CRC that attenuates PI3K–Akt signaling, enhances mitochondrial oxidative metabolism, and promotes ROS-mediated tumor cell death. This study provides the first mechanistic insight into TUSC1’s function in cancer, and its restoration or therapeutic induction of oxidative metabolic stress may represent a strategy for targeting CRCs.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 5","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147714861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The ATG14: multi-layer autophagy control and an emerging therapeutic target in cancer","authors":"Wenbo Wang,&nbsp;Chujuan Yu,&nbsp;Fulin Sun,&nbsp;Ruofeng Wang,&nbsp;Weikai Xia,&nbsp;Qinghang Song,&nbsp;Huhu Zhang,&nbsp;Zhenzhen Jia,&nbsp;Min Zhang,&nbsp;Haoran Wang,&nbsp;Zhenxiang Wang,&nbsp;Rong Fu,&nbsp;Lina Yang","doi":"10.1007/s10495-026-02302-5","DOIUrl":"10.1007/s10495-026-02302-5","url":null,"abstract":"<div><p>ATG14 (ATG14L/Barkor) is the autophagy-specific subunit of class III phosphatidylinositol 3-kinase complex I (PI3KC3-C1) and functions as a pivotal node linking autophagosome formation to autophagosome-lysosome fusion. Functionally, ATG14 regulates cell fate through multiple mechanisms. Under hypoxic or nutrient-deprived conditions, ATG14 maintains tumor cell survival and drug resistance, remodels cellular metabolism via lipophagy and mitophagy, and can either suppress or promote programmed cell death depending on the cellular context. Moreover, ATG14 plays protective roles in maintaining neuronal and hepatic homeostasis and is involved in the development of inflammatory and metabolic disorders. Here, we discuss the multi-layered regulation of ATG14, including post-translational modifications (phosphorylation, ubiquitination, palmitoylation), epitranscriptomic and non-coding RNA regulation, and competitive complex interactions, all of which fine-tune its autophagic output and functional plasticity. We further highlight the central roles of ATG14 during the autophagic process, summarize recent advances in cancer-related ATG14 research, and review ongoing drug development efforts as well as potential therapeutic strategies targeting ATG14. Our goal is to provide a comprehensive understanding of the physiological and pathological functions of ATG14 and to explore its potential as a druggable signaling hub. Given its bidirectional regulatory capacity to either suppress cytoprotective autophagy or enforce lethal autophagy-ATG14-targeted interventions must be strategically designed based on the disease stage and autophagy dependence.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 4","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147715670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Programmed cell death in lung cancer: mechanisms, immune responses, and therapeutics","authors":"Yang Liu,&nbsp;Qingxin Chen,&nbsp;Jiayu Xu,&nbsp;Hao Chi","doi":"10.1007/s10495-026-02298-y","DOIUrl":"10.1007/s10495-026-02298-y","url":null,"abstract":"<div><p>Lung cancer remains the leading cause of cancer‐related mortality worldwide, with an estimated 2.2 million new cases and 1.8 million deaths in 2020. Despite improvements achieved through cytotoxic chemotherapy and immune checkpoint blockade, survival outcomes for many patients remain unsatisfactory, largely due to tumour immune-evasion and resistance to immunotherapy. In this context, programmed cell death (PCD) pathways—especially apoptosis, pyroptosis, ferroptosis and necroptosis—play central roles in shaping tumour cell fate, modulating the tumour immune microenvironment, and influencing therapeutic response. Apoptosis typically proceeds via caspase-mediated dismantling and is often immune-tolerogenic, whereas pyroptosis, ferroptosis and necroptosis provoke danger signals, inflammation and potent dendritic cell and T-cell activation, thus serving as immunogenic cell death modalities. Reciprocal crosstalk between these PCD types and the immune system determines whether lung tumours remain “cold” (immune‐excluded) or become “hot” (immune‐inflamed). Importantly, targeting these classical PCD mechanisms—either alone or in combination with immunotherapy—emerges as a promising strategy to overcome immune resistance in lung cancer by converting non-responsive tumours into immune-sensitive states. This review synthesises mechanistic insights into how apoptosis, pyroptosis, ferroptosis and necroptosis regulate antitumour immunity in lung cancer and outlines therapeutic opportunities for targeting PCD to enhance immunotherapy efficacy and overcome immune-resistant phenotypes.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 4","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147715705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}