Apoptosis最新文献

{"title":"The impact of lipid metabolism on ferroptosis in myocardial ischemia-reperfusion injury.","authors":"Yuxin Li, Zekun Lou, Fang Liu, Yang Liu, Chaofan Wang, Yiwen Wang, Wei Qian, Dongye Li, Tongda Xu","doi":"10.1007/s10495-025-02192-z","DOIUrl":"https://doi.org/10.1007/s10495-025-02192-z","url":null,"abstract":"<p><p>Myocardial ischemia-reperfusion (I/R) injury remains a major challenge in cardiovascular interventions. Although conventional reperfusion therapies restore coronary blood flow, they can often exacerbate myocardial damage. In recent years, ferroptosis, a novel form of regulated cell death characterized by iron-dependent lipid peroxidation, has emerged as a pivotal contributor to myocardial I/R injury. Unlike apoptosis and necrosis, ferroptosis is driven by the accumulation of reactive iron and the peroxidation of membrane phospholipids enriched with polyunsaturated fatty acids (PUFAs), processes that are tightly regulated by lipid metabolism. However, the precise mechanisms linking lipid metabolic reprogramming to ferroptosis during myocardial I/R injury remain incompletely understood. To address this gap, this review systematically examines the interplay between lipid metabolism and ferroptosis in myocardial I/R injury. We highlight the roles of fatty acid uptake, β-oxidation, phospholipid remodeling, cholesterol metabolism, and mitochondria-lipid droplet interactions in forming a deleterious cycle of metabolic disruption, oxidative stress, and membrane damage. Key regulators, such as acyl-CoA synthetase long-chain family member 4 (ACSL4), lysophosphatidylcholine acyltransferase 3 (LPCAT3), and cluster of differentiation 36 (CD36), are emphasized for their roles in contributing to ferroptotic vulnerability. Moreover, the review also explores the protective roles of short-chain fatty acids (SCFAs) and 7-dehydrocholesterol (7-DHC) as emerging anti-ferroptotic agents. Novel yet understudied mechanisms with therapeutic potential are also discussed, including Rab8a-PLIN5-mediated lipid droplet trafficking and 7-DHC reductase (DHCR7) deficiency-induced 7-DHC accumulation. Collectively, this review provides a comprehensive framework for understanding the lipid metabolism-ferroptosis axis in myocardial I/R injury, offering insights for future mechanistic studies and clinical translation.</p>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231374","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":"Mechanism of glycolysis-pyrolysis crosstalk driving vicious circle of intervertebral disc degeneration.","authors":"Silong Gao, Tao Liu, Xianghan Hou, Chao Song, Yingjin Luo, Weiye Cai, Daqian Zhou, Jiale Lv, Yongliang Mei, Houyin Shi, Shiqin Wang, Yi Li, Zongchao Liu","doi":"10.1007/s10495-025-02194-x","DOIUrl":"https://doi.org/10.1007/s10495-025-02194-x","url":null,"abstract":"<p><p>The acidic and inflammatory microenvironment serves as a central pathological feature of intervertebral disc degeneration (IVDD), acting as a critical driving factor in disease progression. However, the interplay between acidic and inflammatory microenvironments remains largely unexplored. In this study, we revealed the molecular mechanism by which crosstalk between glycolysis and pyroptosis exacerbates IVDD. We observed that lactic acid stimulation triggers pyroptosis in NPCs by stimulating the NLRP3 inflammasome, activating the caspase-1 pathway, and upregulating the expressions of IL-1β and IL-18. Acid sensitive ion channel 1a (ASIC1a) expression is positively correlated with extracellular acidosis severity and NPC pyroptosis levels. Furthermore, the knockdown of ASIC1a via siRNA effectively alleviated pyroptosis. After treatment of NPCs with IL-1β, glycolysis levels were increased, accompanied by up-regulation of c-Myc (a key regulator of the Warburg effect) and nuclear translocation, the knockdown of c-Myc effectively alleviated glycolysis. Mechanistically, lactate activates acid-sensing ion channel 1a (ASIC1a), which mediates Ca²⁺ influx to promote pyroptosis in nucleus pulposus cells (NPCs) and IL-1β release. Secreted IL-1β subsequently induces the nuclear translocation of, thereby upregulating glycolytic enzyme expression, enhancing glycolysis, and accelerating lactate accumulation. This cascade establishes a vicious cycle that progressively aggravates IVDD. Our findings demonstrate that glycolysis‒pyroptosis crosstalk promotes acid‒inflammatory microenvironments in degenerated discs, driving disease progression. Targeted inhibition of this crosstalk improves disc biological function and mitigates IVDD progression.</p>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145231409","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":"PANoptosis: potential new targets and therapeutic prospects in digestive diseases.","authors":"Minglin Zhang, Xuelin Zhao, Ting Cai, Fen Wang","doi":"10.1007/s10495-025-02186-x","DOIUrl":"https://doi.org/10.1007/s10495-025-02186-x","url":null,"abstract":"<p><p>PANoptosis, a newly defined, multifaceted programmed cell death (PCD) pathway, integrates key features of pyroptosis, apoptosis, and necroptosis. It is orchestrated by multiprotein complexes called PANoptosomes (ZBP1-, AIM2-, RIPK1-, and NLRP12-PANoptosomes), which assemble via domain interactions in response to specific pathogen- or damage-associated signals. This integrated pathway plays crucial roles in maintaining tissue homeostasis by eliminating infected and damaged cells and provides potent innate immune defence through the coordinated release of inflammatory cytokines and damage-associated molecular patterns (DAMPs), offering superior pathogen clearance compared with single PCD modes. Increasing evidence underscores the significant involvement of PANoptosis in digestive diseases. In gastric cancer, it modulates tumour progression, the immune microenvironment and chemoresistance. PANoptosis drives epithelial cell death in ulcerative colitis and Crohn's disease, contributing to mucosal barrier disruption and inflammation. It influences immune infiltration, metabolic reprogramming, and therapeutic response in colorectal cancer. PANoptosis also contributes to the pathogenesis of diverse liver conditions, including failure, fibrosis, metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carcinoma, and mediates pancreatic injury in acute pancreatitis. While research on oesophageal and pancreatic malignancies is nascent, PANoptosis-based molecular subtyping and therapeutic targeting demonstrate translational potential. This review synthesizes current evidence, highlighting PANoptosis as a critical regulator in digestive pathologies and as a promising target for intervention.</p>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197898","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":"ERO1A-positive tumor epithelial cells in colorectal cancer progression: a multi-omics perspective.","authors":"Shangshang Hu, Jinwei Lou, Yuhan Chen, Muzi Ding, Jian Qin, Junjie Nie, Yue Li, Zixuan Liu, Mu Xu, Huiling Sun, Qianni Xiao, Yuqin Pan, Shukui Wang","doi":"10.1007/s10495-025-02184-z","DOIUrl":"https://doi.org/10.1007/s10495-025-02184-z","url":null,"abstract":"<p><p>Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide. Tumor epithelial cells play a crucial role in shaping the tumor microenvironment (TME) and driving cancer progression. This study utilized a multi-omics approach, integrating data from 21 multi-center CRC cohorts (n = 2,767), including single-cell transcriptomics, bulk transcriptomics, spatial transcriptomics, and proteomics. Bioinformatic analyses were combined with in vitro and in vivo experiments for validation. A distinct epithelial subpopulation, ERO1A-positive epithelial cells (ERO1A + Epi), was identified and found to be significantly enriched in advanced-stage CRC, correlating with poor prognosis. ERO1A + Epi cells promoted proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) in vitro, while in vivo models confirmed their role in tumor growth and liver metastasis. Spatial and intercellular interaction analyses revealed that ERO1A + Epi cells interact with CTHRC1 + cancer-associated fibroblasts (CTHRC1 + CAFs) and SPP1 + macrophages via MDK-LRP1, MIF-(CD74 + CD44), and APP-CD74 signaling pathways, fostering a pro-tumorigenic TME. Co-culture experiments demonstrated that ERO1A + Epi enhances the expression of CTHRC1 and SPP1. A risk prediction model (ETSRM) based on the ERO1A + Epi_TME_Score demonstrated superior prognostic accuracy over 111 existing CRC models. Integrating ETSRM with TNM staging further enhanced survival prediction. Our findings identify ERO1A + Epi as a significant driver of colorectal cancer progression. The ERO1A + Epi_TME_Score-based ETSRM provides a robust prognostic tool, offering new insights into CRC pathogenesis and highlighting potential therapeutic targets for improved patient outcomes.</p>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197917","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":"Regulated cell death environments drive fibroinflammatory reprogramming in surviving adipose-derived stem cells.","authors":"Wilfredo Oliva-Olivera, Tina Ravnsborg, Elisa Le Boiteux, Eduardo García-Fuentes, Lourdes Garrido-Sánchez, Ole N Jensen, Francisco J Tinahones","doi":"10.1007/s10495-025-02191-0","DOIUrl":"https://doi.org/10.1007/s10495-025-02191-0","url":null,"abstract":"<p><p>Adipose-derived stem cells (ASCs) can shift toward proinflammatory and fibrotic phenotypes, but factors triggering this transition are not fully understood. This study aimed to elucidate the impact of exposure to regulated cell death environments on the fibroinflammatory potential of surviving subcutaneous ASCs (sub-ASCs). Surviving sub-ASCs were characterized by transcriptional analysis of genes associated with inflammation and extracellular matrix remodeling. Phenotypical markers of fibroinflammatory progenitor cells were monitored by immunoblotting and flow cytometry. We determined post-translational modifications (PTMs) of histone proteins by immunoblotting and mass spectrometry, including individual and combinatorial histone marks. Four days after transient exposure to serum starvation- or tumor necrosis factor-alpha (TNFα)-induced cell death, surviving sub-ASCs cultured under hypoxic proliferative conditions showed elevated mRNA levels of inflammatory mediators, fibrillar collagens, matricellular proteins, and cytoskeletal components. This fibroinflammatory transcriptional activation was accompanied by decreased expression of fibroinflammatory progenitor cell markers. Surviving sub-ASCs exhibited variations in histone methylation marks associated with transcriptional regulation. Inhibiting calcium-dependent μ- and m-calpains during TNFα-induced cell death increased histone marks associated with gene activation and repression, altering surviving sub-ASCs transcriptional responses four days later. Middle-down mass spectrometry identified changes in specific histone mark combinations in surviving sub-ASCs following TNFα-induced cell death. These findings suggest that regulated cell death environments act as reprogramming agents for surviving ASCs, driving fibro-inflammatory transcriptional activation and histone PTM changes, likely as part of an inducible gene expression program promoting cell survival.</p>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197920","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":"Integrating pathology genomics and single-cell genomics to identify lactate metabolism-related prognostic features and therapeutic strategies for melanoma.","authors":"Songyun Zhao, Xiaoqing Liang, Jiaheng Xie, Zijian Lin, Zihao Li, Zhixuan Jiang, Wanying Chen, Hao Dai, Yucang He, Liqun Li","doi":"10.1007/s10495-025-02190-1","DOIUrl":"https://doi.org/10.1007/s10495-025-02190-1","url":null,"abstract":"<p><p>Cutaneous melanoma (SKCM) is highly malignant and prone to developing treatment resistance. Lactate metabolism in the tumor microenvironment (TME) plays a crucial role in SKCM progression, immune evasion, and therapy resistance. This study aimed to integrate multi-omics data to systematically characterize the molecular features of lactate metabolism in SKCM, construct an effective prognostic model, and explore potential therapeutic strategies. Quantitative pathological features were extracted using CellProfiler and combined with deep learning features obtained from a pre-trained ResNet50 convolutional neural network. Gene set variation analysis (GSVA) was used to calculate lactate metabolism scores and identify associated pathological features. Single-cell RNA sequencing was applied to assess lactate metabolic activity across different cell types. These data, together with spatial transcriptomics, genomic alterations, immune infiltration profiles, and immunotherapy response data, were integrated to construct a lactate metabolism signature (LMS) prognostic model (comprising 3 pathological features and 11 genes). The model was developed using 101 combinations of 10 machine learning algorithms. Furthermore, RAB32 knockdown experiments were performed to verify its effects on melanoma cell proliferation, migration, invasion, and metabolism. A total of 443 pathological imaging features significantly associated with lactate metabolism were identified. Single-cell analysis revealed that melanoma cells exhibited the highest lactate metabolic activity, with markedly enhanced intercellular communication in the high-metabolism group. The LMS model demonstrated excellent prognostic performance in both the TCGA training and validation cohorts. Patients in the high-LMS group had significantly shorter survival, showed immune evasion features, and exhibited activation of melanoma-related metabolic and signaling pathways (e.g., oxidative phosphorylation). In contrast, the low-LMS group had stronger immune infiltration and higher expression of immune checkpoint molecules. The key gene RAB32 was significantly correlated with all lactate metabolism-related pathological features, was highly expressed in the tumor core, and its high expression predicted poor prognosis. RAB32 knockdown markedly inhibited melanoma cell proliferation, migration, and invasion; reduced lactate production; suppressed the expression of glycolytic enzymes and lactate transporters; and decreased extracellular acidification rate (ECAR) and oxygen consumption rate (OCR). In addition, it significantly inhibited tumor growth in mouse xenograft models. This study developed a multi-omics-integrated prognostic model (LMS) based on lactate metabolism, providing a novel tool for risk stratification and therapeutic decision-making in SKCM patients. It also identified RAB32 as a central player in tumor metabolic reprogramming and invasiveness, with promising potential as a therapeutic target.</p>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145172418","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":"Role of PANoptosis in cancer: Molecular mechanisms and therapeutic opportunities.","authors":"Wen-Qing Wang, Zi Zhou, Feng-Xin Ge, Mukaddas Tayir, Meng-Yuan Hao, Dong-Dong Wu","doi":"10.1007/s10495-025-02173-2","DOIUrl":"https://doi.org/10.1007/s10495-025-02173-2","url":null,"abstract":"<p><p>PANoptosis is an inflammatory programmed cell death pathway. It integrates apoptosis, pyroptosis, and necroptosis via PANoptosome complexes, thereby coordinating immune responses and remodeling tumor microenvironment (TME). By overcoming limitations of therapies targeting a single-pathway (e.g., those targeting apoptosis), PANoptosis suppresses cancer progression, reverses drug resistance, and synergizes with radiotherapy through immune activation. Mechanistic insights are driving therapeutic strategies that target key regulators (ZBP1, RIPK3) and disease-specific miRNAs to modulate caspase-dependent and caspase-independent cascades. Its pathological duality-acute hyperactivation in tissue injury versus chronic dysregulation in degenerative diseases-highlights the need for context-dependent modulation. PANoptosis activation shows prognostic biomarker potential and universal therapeutic promise for drug-resistant cancers and inflammatory disorders, though clinical translation remains exploratory. This framework positions PANoptosis as a transformative paradigm bridging cell death dynamics and immune regulation.</p>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145172403","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":"VDAC1-interacting proteins: binding site mapping and their derived peptides induce apoptosis and multifaceted cellular effects.","authors":"Manikandan Santhanam, Venkatadri Babu, Anna Shteinfer-Kuzmine, Ran Zalk, Varda Shoshan-Barmaz","doi":"10.1007/s10495-025-02185-y","DOIUrl":"https://doi.org/10.1007/s10495-025-02185-y","url":null,"abstract":"<p><p>The mitochondrial voltage-dependent anion channel-1 (VDAC1) protein plays a central role in regulating mitochondrial metabolism, energy production, and apoptosis. VDAC1 interacts with over 100 proteins across the cytosol, endoplasmic reticulum, plasma membrane, and mitochondrial membranes. These interactions coordinate metabolism, cell death, and signal transduction, integrating mitochondrial and cellular functions. To identify VDAC1 binding sites, we designed a peptide array of 768 peptides from 19 selected VDAC1-interacting proteins. We focused on three partners: GAPDH, gelsolin, and actin. Their VDAC1-binding sequences as peptides interacted with purified VDAC1 and, as cell-penetrating peptides, induced cell death, and elevated intracellular Ca²⁺ and ROS levels. Despite sequence diversity, the peptides converged on enhancing transcription factors p53 and c-Jun, upregulating VDAC1, promoting its oligomerization, and triggering apoptosis. Other effects related to their originated protein's function include no significant effect of the GAPDH-derived peptide on its catalytic activity, indicating its effects are independent of glycolysis. The gelsolin-derived peptide altered actin organization, increasing filopodia and focal adhesion, and actin-derived peptides reduced actin, gelsolin, and tubulin expression. This study is the first to identify VDAC1 binding sites on 19 interacting partners and to demonstrate their use as cell-penetrating peptides to modulate the VDAC1 network. These findings highlight VDAC1's multifaceted regulatory role and offer a novel approach for targeting VDAC1-protein interactions for therapeutic purposes.</p>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145172427","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":"Endothelial SPRY1 deficiency associates with angiogenic-metabolic reprogramming in pulmonary arterial hypertension: a multi-omics analysis of bulk and single-cell transcriptomic profiles.","authors":"Yanfei Mo, Desheng Wang, Zhenkun Deng, Pingping Zhao, Zhen Gou, Xiaoyun Sun, Yunrui Zhang, Yang Bai","doi":"10.1007/s10495-025-02175-0","DOIUrl":"https://doi.org/10.1007/s10495-025-02175-0","url":null,"abstract":"<p><p>The mechanism underlying vascular remodeling in pulmonary arterial hypertension (PAH) involves complex interactions among various cell types, with dysregulation of endothelial cells (ECs) homeostasis considered a crucial pathological factor. However, their local cellular changes still need to be fully identified during PAH. This study utilized single-cell RNA sequencing data from the GEO database to analyze lung tissue samples from PAH patients and normal controls, revealing significant heterogeneity in lung ECs and dysregulated metabolic pathways. We identified a significant expansion of capillary ECs in PAH patients, linked to dysregulated angiogenesis and glycolysis-tricarboxylic acid cycle metabolic pathways. Through integrative high-dimensional weighted gene co-expression network analysis (hdWGCNA) and machine learning, we identified SPRY1 as a novel key biomarker in PAH pathogenesis and validated its significant downregulation in a monocrotaline-induced PAH rat model. These findings establish capillary ECs expansion and SPRY1 deficiency as pivotal drivers in PAH pathogenesis, providing a foundation for precise therapeutic targeting.</p>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145172351","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":"His-tagged pro-apoptotic peptides: enhancing cell internalization and anticancer effect in vitro.","authors":"Aldo O González-Cruz, José Juan Pérez-Trujillo, Isaías Balderas-Rentería, Sheila Adela Villa-Cedillo, Ulises Edgardo De-León-Covarrubias, Eder Arredondo-Espinoza","doi":"10.1007/s10495-025-02180-3","DOIUrl":"https://doi.org/10.1007/s10495-025-02180-3","url":null,"abstract":"<p><p>Epidermal growth factor receptor (EGFR) overexpression is commonly found in various solid tumors, including non-small cell lung cancer, where it is associated with poor prognosis and resistance to treatment. Despite the availability of EGFR-targeted therapies, overcoming drug resistance remains a challenge. Tumor-homing cell-penetrating peptides can selectively target cancer cells and improve drug delivery. In this study, we evaluated the anticancer potential of EGFR-targeted pro-apoptotic peptides, specifically NRPD-KLAK-H and NRPD-CTMP4-H, designed to enhance internalization and overcome drug resistance in EGFR-positive cancers, and compared their effects with those of the free His-tagged peptides NRPD-H, KLAK-H, and CTMP4-H. MTT assays showed that KLAK-H and NRPD-KLAK-H exhibited the strongest anticancer effects, significantly inhibiting cell growth in A-549 cell line, with IC₅₀ values of 33.3 µM and 40.9 µM, respectively. TUNEL assays suggested that KLAK-H and NRPD-KLAK-H induced apoptosis in the tested cell lines. Immunofluorescence revealed successful internalization of KLAK-H/NRPD-KLAK-H, but poor uptake of CTMP4-H/NRPD-CTMP4-H. The His-tag modification improved peptide internalization, suggesting that short poly-histidine sequences can enhance cellular uptake of pro-apoptotic KLAK-derived peptides, particularly in cancer cells. Although the proposed EGFR-targeted proapoptotic peptides did not show the expected effect, our findings indicate that His-tagged pro-apoptotic peptides, especially KLAK-H, hold promise as potential cancer treatments.</p>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079542","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}