Apoptosis最新文献

{"title":"Nutrient deficiency-induced downregulation of SNX1 inhibits ferroptosis through PPARs-ACSL1/4 axis in colorectal cancer","authors":"Li-Heng Qian,&nbsp;Kai-Ling Wen,&nbsp;Ying Guo,&nbsp;Ying-Na Liao,&nbsp;Ming-Yue Li,&nbsp;Zuo-Qing Li,&nbsp;Shu-Xin Li,&nbsp;Hui-Zhen Nie","doi":"10.1007/s10495-025-02088-y","DOIUrl":"10.1007/s10495-025-02088-y","url":null,"abstract":"<div><p>Colorectal cancer (CRC) is among the most prevalent and deadly gastrointestinal malignancies, with advanced-stage tumors often exhibiting resistance to both chemotherapy and targeted therapies, underscoring the urgent need for novel therapeutic targets to improve clinical outcomes. Sorting nexin 1 (SNX1), previously implicated in receptor trafficking between early and late endosomes/lysosomes in cancer studies, has an unclear role in CRC tumorigenesis and progression. Our study revealed that SNX1 expression was downregulated in CRC, and its low levels correlated with advanced tumor stages and unfavorable clinical outcomes. Functionally, SNX1 significantly inhibited tumor cell growth both in vitro and in vivo. Further experiments showed that SNX1 induced ferroptosis in CRC cells by modulating the PPARs-ACSL1/4 pathway downstream of EGFR signaling. Moreover, glucose deprivation suppressed the Hippo pathway, promoted YAP nuclear translocation, and activated the transcription factor Yin Yang 1 (YY1), leading to SNX1 downregulation. This subsequently activated EGFR signaling and ultimately suppressed ferroptosis in CRC cells. Notably, the combination of SNX1 overexpression and 5-fluorouracil (5-FU) treatment exhibited a synergistic anti-tumor effect in a cell-derived xenograft (CDX) model. These findings underscore the critical role of SNX1 in regulating ferroptosis and tumor progression in CRC and highlight its potential as a therapeutic target to enhance chemotherapy effectiveness in CRC.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"30 5-6","pages":"1391 - 1409"},"PeriodicalIF":8.1,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647165","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 oxeiptosis in disease mechanisms and therapeutic opportunities","authors":"K. Bhuvaneshwari,&nbsp;Kannan Harithpriya,&nbsp;Kumar Ganesan,&nbsp;Baojun Xu,&nbsp;Kunka Mohanram Ramkumar","doi":"10.1007/s10495-025-02087-z","DOIUrl":"10.1007/s10495-025-02087-z","url":null,"abstract":"<div><p>Cell death is a crucial mechanism through which cells respond to damage and stress, thereby maintaining homeostasis. Cell death pathways include both caspase-dependent and caspase-independent mechanisms, such as apoptosis, necrosis, autophagy, and ferroptosis. The recent discovery of oxeiptosis identifies a unique form of ROS-mediated, caspase-independent cell death with apoptotic-like features. This process is regulated by key molecules, including KEAP1, PGAM5, and AIFM1, and is characterized by distinct molecular and morphological features. These regulators contribute to cellular integrity by activating cytoprotective genes through Nrf2 stabilization by KEAP1 and maintaining cellular homeostasis via PGAM5-mediated AIFM1 Ser116 dephosphorylation. In this review, we discuss the broad spectrum of oxeiptosis-mediated regulation in disease pathogenesis by combating ROS-induced cellular damage. Modulating oxeiptosis helps in disease management by mitigating ROS-induced cellular damage, restoring redox balance, and preventing pathological inflammation. Additionally, we highlight modulators such as natural derivatives and lncRNAs that trigger oxeiptosis in various diseases, including vitiligo, psoriasis, and multiple cancer types. Modulating oxeiptosis presents significant clinical implications by offering novel therapeutic strategies to mitigate oxidative stress, restore cellular homeostasis, and prevent inflammation-driven diseases. This review emphasizes potential therapeutic advances for conditions characterized by aberrant ROS accumulation, offering innovative avenues for clinical intervention and treatment development.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"30 5-6","pages":"1182 - 1201"},"PeriodicalIF":8.1,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596025","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":"Melatonin attenuates inflammatory bone loss by alleviating mitophagy and lactate production","authors":"Zexin Lin,&nbsp;Yuan Gu,&nbsp;Yingsong Liu,&nbsp;Zilin Chen,&nbsp;Shuai Fang,&nbsp;Zhuan Wang,&nbsp;Zixian Liu,&nbsp;Qingrong Lin,&nbsp;Yanjun Hu,&nbsp;Nan Jiang,&nbsp;Bin Yu,&nbsp;Guanqiao Liu","doi":"10.1007/s10495-025-02096-y","DOIUrl":"10.1007/s10495-025-02096-y","url":null,"abstract":"<div><p>Mitochondrial homeostasis plays a major role in the progression of chronic inflammatory bone loss which has a complex pathogenesis with unsatisfactory therapeutic efficiency. Recently, melatonin has been shown to recipient mitochondrial function and bone formation. However, the effects and underlying molecular mechanism of melatonin in chronic inflammatory bone loss remain unclear. Here, we reported that melatonin ameliorated lipopolysaccharide (LPS)-induced inflammatory bone loss by improving osteogenesis. We found that melatonin rescued LPS-induced mitochondrial dysfunction and metabolic reprogramming in osteoblasts, resulting in reduced osteogenesis impairment. Mechanistically, melatonin inhibited mitochondrial reactive oxygen species (mtROS) production by suppressing LPS-induced mitophagy, which attenuated the activation of the mtROS/HIF-1α/pyruvate dehydrogenase kinase 1 (PDK1) axis. Moreover, melatonin restored pyruvate dehydrogenase (PDH) activity by inhibiting phosphorylation of PDH through the mtROS/HIF-1α/PDK1 axis and eventually downregulated lactate production. These findings indicate the therapeutic effects of melatonin against chronic inflammatory bone loss and demonstrated a potential treatment strategy against inflammatory osteogenic disorders through regulating mitochondrial dysfunction and metabolic reprogramming.</p><h3>Graphical abstract</h3><p>The present study reports that melatonin ameliorates LPS-induced bone loss by improving mitochondrial function in osteoblasts and demonstrates that melatonin inhibits LPS-induced mitophagy, which, in turn, suppressing the mtROS/HIF-1α/PDK1 axis, resulting in reduced lactate production and eventually promoting osteogenesis.</p>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"30 5-6","pages":"1351 - 1371"},"PeriodicalIF":8.1,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596023","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":"Magea13 attenuates myocardial injury in acute myocardial infarction by inhibiting the cAMP-PKA signaling pathway","authors":"Jialin Zheng,&nbsp;Xiaoyu Xu,&nbsp;Ziwei Zhang,&nbsp;Kanghui Ge,&nbsp;Yi Xiang,&nbsp;Hualei Dai","doi":"10.1007/s10495-025-02078-0","DOIUrl":"10.1007/s10495-025-02078-0","url":null,"abstract":"<div><h3>Object</h3><p>Acute myocardial infarction (AMI) is a serious cardiovascular disease for which there are still no effective therapeutic options available, and melanoma-associated antigen-A13 (Magea13), a member of the MAGE superfamily, has an unknown role in AMI. This study aims to investigate the potential role and molecular mechanisms of Magea13 in myocardial injury associated with AMI through in vivo and in vitro experiments.</p><h3>Methods</h3><p>Firstly, differentially expressed genes (DEGs) and signaling pathways were screened by RNA sequencing. Cardiac-specific Magea13 overexpression was achieved with the adeno-associated virus type 9 serotype system. Subsequently, these rats underwent left anterior descending coronary artery (LAD) ligation, followed by histopathological examination, biochemical assay, and Western blot analysis to evaluate the efficacy and feasibility of Magea13 in AMI. Meanwhile, the Magea13-overexpressing rat cardiomyocyte cell line (H9c2) was also subjected to hypoxia-glucose deficiency/reperfusion to mimic AMI injury to further validate its effects in vitro.</p><h3>Results</h3><p>The cardiomyocyte-specific overexpression of Magea13 was observed to attenuate myocardial injury in rats with acute myocardial infarction. Furthermore, Magea13 overexpression was demonstrated to attenuate OGD/R-induced H9c2 cell injury. Mechanistic studies have suggested that the protective effect of Magea13 may be mediated through the cAMP-PKA pathway.</p><h3>Conclusion</h3><p>Magea13 has been demonstrated to offer protection against AMI myocardial injury through the cAMP-PKA signaling pathway and is therefore a promising therapeutic and predictive target for AMI myocardial injury.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"30 3-4","pages":"1042 - 1057"},"PeriodicalIF":6.1,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10495-025-02078-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143582165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: NF-κB contributes to Smac mimetic-conferred protection from tunicamycin-induced apoptosis","authors":"Behnaz Ahangarian Abhari,&nbsp;Nicole McCarthy,&nbsp;Patrizia Agostinis,&nbsp;Simone Fulda","doi":"10.1007/s10495-024-02056-y","DOIUrl":"10.1007/s10495-024-02056-y","url":null,"abstract":"","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"30 3-4","pages":"514 - 515"},"PeriodicalIF":6.1,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565852","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":"Novel impact of metal ion-induced cell death on diabetic cardiomyopathy pathogenesis and therapy","authors":"Jingjing Jiang,&nbsp;Shengnan Hu,&nbsp;Kaibo Hu,&nbsp;Leyang Xiao,&nbsp;Jitao Lin,&nbsp;Yixuan Chen,&nbsp;Deju Zhang,&nbsp;Yangliu Ou,&nbsp;Jing Zhang,&nbsp;Linhui Yuan,&nbsp;Wenting Wang,&nbsp;Peng Yu","doi":"10.1007/s10495-025-02090-4","DOIUrl":"10.1007/s10495-025-02090-4","url":null,"abstract":"<div><p>Diabetes mellitus is a common chronic metabolic disease, with its prevalence escalating annually. Diabetic cardiomyopathy is a leading cause of mortality among diabetic patients, characterized by intricate metabolic disturbances and myocardial cell demise. Various forms of cellular death pathways including apoptosis, pyroptosis, autophagic cell death, necroptosis, ferroptosis, and entosis have been identified in diabetic cardiomyopathy. Inhibiting myocardial cell death pathways has shown promise in mitigating diabetic cardiomyopathy progression. However, there are still gaps in understanding the role of metal ions in diabetic cardiomyopathy pathogenesis. Recent research endeavors have found that iron, copper, zinc, calcium, manganese and other metal elements related to cell death play an intricate and critical role in the pathogenesis and progression of diabetic cardiomyopathy. Notably, many animal studies have shown that the development and progression of diabetic cardiomyopathy can be alleviated by inhibiting the cell death process induced by these metal ions. Therefore, we review the molecular mechanisms underlying the death of various metal ions and the potential pathophysiological roles they play in diabetic cardiomyopathy. In addition, the value of these metal ions in the treatment of diabetic cardiomyopathy is also described.</p><h3>Graphic abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"30 5-6","pages":"1152 - 1181"},"PeriodicalIF":8.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555659","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":"Neutrophils: a new target for postoperative cognitive dysfunction","authors":"Jianxin Cheng,&nbsp;Jin Gao,&nbsp;Jianjun Li,&nbsp;Hao Tian","doi":"10.1007/s10495-025-02098-w","DOIUrl":"10.1007/s10495-025-02098-w","url":null,"abstract":"<div><p>Postoperative cognitive dysfunction (POCD) is a prevalent complication affecting the central nervous system after surgery, manifesting as a decline in cognitive abilities, particularly common among elderly patients. Surgical stress and anesthesia can activate systemic inflammation, prompting immune cells, including neutrophils, to infiltrate the brain, thereby triggering neuroinflammation and resulting in cognitive impairment. Neutrophils, as crucial effector cells in innate immunity, have been increasingly recognized in recent years for their significant role in the pathogenesis of POCD due to their vital function in inflammatory responses. They are not only rapidly activated in peripheral blood, secreting a range of cytokines, chemokines, and neutrophil extracellular traps (NETs), but also possess the capacity to alter the permeability of the blood-brain barrier (BBB), further facilitating the development of neuroinflammation. This paper systematically reviews the recent findings on the diverse functions of neutrophils and their role in POCD, aiming to provide novel theoretical foundations and cutting-edge perspectives for advancing foundational research and optimizing clinical intervention strategies for POCD.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"30 5-6","pages":"1117 - 1132"},"PeriodicalIF":8.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555658","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 the USP family in autophagy regulation and cancer progression","authors":"Congcong Liu,&nbsp;Yalin Yuan,&nbsp;Yuxin Zhan,&nbsp;Mi Zou,&nbsp;Linqian Wu,&nbsp;Chunfang Zhang,&nbsp;Bofan Chen,&nbsp;Haimin Zeng,&nbsp;Ruhui Yang,&nbsp;Tianheng Hu,&nbsp;Jie Peng,&nbsp;Liang Hao","doi":"10.1007/s10495-025-02095-z","DOIUrl":"10.1007/s10495-025-02095-z","url":null,"abstract":"<div><p>Autophagy is a vital pathway for recycling and degrading intracellular materials, closely linked to tumorigenesis and progression. The ubiquitin-specific protease (USP) family, as a critical group of deubiquitinating enzymes, plays a complex part in regulating autophagy, metabolism, immune responses, and tumor cells’ resistance to drugs. By modifying autophagy-associated proteins through deubiquitination, the USP family influences tumor cell proliferation, survival, and metabolism. Additionally, these enzymes are involved in modulating immune responses within the tumor microenvironment, thereby impacting tumor immune escape. Regarding drug resistance, the USP family enhances the tolerance of tumor cells to chemotherapeutic agents by promoting autophagy. Therefore, targeting USP family members and their regulated autophagy processes may offer new avenues for cancer therapy. This review examines the function of the USP family in tumor autophagy regulation and its implications for tumor progression. The goal of future studies should be to clarify the molecular mechanisms underlying USP-autophagy interactions and their specific roles in various tumor types to establish a theoretical framework for developing novel cancer therapeutic strategies.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"30 5-6","pages":"1133 - 1151"},"PeriodicalIF":8.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555660","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":"CCDC134 enhances ovarian reserve function and angiogenesis by directly interacting with INHA in a mouse model of premature ovarian insufficiency","authors":"Xiangrong Cui,&nbsp;Huihui Li,&nbsp;Xinyu Zhu,&nbsp;Xia Huang,&nbsp;Tingting Xue,&nbsp;Shu Wang,&nbsp;Xuan Jing","doi":"10.1007/s10495-025-02092-2","DOIUrl":"10.1007/s10495-025-02092-2","url":null,"abstract":"<div><p>Premature ovarian insufficiency (POI) is a multifactorial condition characterized by diminished ovarian function, granulosa cell (GC) apoptosis, and impaired ovarian angiogenesis, leading to infertility and long-term health complications. Despite its prevalence, effective therapeutic targets for POI remain limited. This study investigates the role of CCDC134 in maintaining ovarian reserve and promoting angiogenesis and its interaction with INHA in a mouse model of POI. Ovarian granulosa cells from POI patients and unaffected women were analyzed for apoptosis and CCDC134 expression. A cisplatin-induced mouse model of POI was used to evaluate the therapeutic potential of AAV-mediated ovary-specific overexpression of CCDC134. Ovarian morphology, hormonal levels, follicular development, granulosa cell viability, and angiogenesis were assessed. The interaction between CCDC134 and INHA was examined using co-immunoprecipitation, immunofluorescence, and molecular pathway analyses. CCDC134 expression was significantly downregulated in ovarian tissues and granulosa cells of POI patients and cisplatin-induced POI mice. CCDC134 overexpression improved ovarian morphology, restored follicular development across all stages, and enhanced reproductive outcomes in POI mice. Hormonal imbalances, including decreased AMH and E2 and elevated FSH and LH, were reversed following CCDC134 overexpression. Moreover, CCDC134 treatment significantly reduced GC apoptosis by downregulating pro-apoptotic markers (Caspase-3 and Bax) and upregulating anti-apoptotic Bcl-2. Angiogenesis was enhanced, as indicated by increased expression of CD34 and vWF, improved endothelial cell viability, and restored VEGF levels. Mechanistic studies revealed a direct interaction between CCDC134 and INHA, with CCDC134 promoting INHA expression and modulating apoptotic and angiogenic pathways. CCDC134 plays a critical role in maintaining ovarian reserve and promoting angiogenesis by directly interacting with INHA. Its overexpression restores ovarian function, mitigates granulosa cell apoptosis, and enhances angiogenesis in a mouse model of POI. These findings highlight the therapeutic potential of the CCDC134-INHA axis as a novel strategy for treating POI.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"30 5-6","pages":"1311 - 1330"},"PeriodicalIF":8.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555657","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":"Bushen Jianpi Tiaoxue Decoction (BJTD) inhibits the LIF-mTOR signaling axis to regulate mitochondrial function and alleviate cyclophosphamide-induced diminished ovarian reserve","authors":"Hangqi Hu,&nbsp;Jiacheng Zhang,&nbsp;Xiyan Xin,&nbsp;Yuxin Jin,&nbsp;Yutian Zhu,&nbsp;Haolin Zhang,&nbsp;Ruiwen Fan,&nbsp;Yang Ye,&nbsp;Yong Jiang,&nbsp;Dong Li","doi":"10.1007/s10495-025-02093-1","DOIUrl":"10.1007/s10495-025-02093-1","url":null,"abstract":"&lt;div&gt;&lt;p&gt;Diminished ovarian reserve (DOR) is a challenging obstacle impacting women’ fertility globally with limited treatment option. Bushen Jianpi Tiaoxue Decoction (BJTD) has shown significant efficacy and safety in treating DOR patients, yet the molecular mechanisms behind its effect remain uncertain. Our study aimed to uncover the pharmacology and signaling pathway of BJTD in cyclophosphamide (Cy)-provoked DOR mice and 4-hydroperoxy cyclophosphamide (4-HC)-irritated KGN cells (human granulosa-like cell line) damage models. Granulosa cells from DOR patients and Cy-induced models were reanalyzed utilizing transcriptomics to predict differentially expressed genes and crucial signaling pathways. Validation experiments were conducted in vitro using KGN cells treated with 4-HC, a Cy metabolite, to establish a DOR model. Cell viability, apoptosis, oxidative stress, mitochondrial function, and ferroptosis markers were assessed using the cck8 assay, flow cytometry, fluorescence staining, RT-qPCR, and western blotting analyses. BJTD-serum was evaluated for its protective effects on 4-HC-triggered KGN damages. In vivo, a Cy-induced DOR mouse model was treated with BJTD to evaluate ovarian morphology, estrous cycle, follicle counts, hormone markers, mitochondrial apoptosis and ferroptosis levels, respectively via the vaginal smear, histological analysis, immunostaining, gene and protein expression experiments. The UPLC-MS analysis and network pharmacology were applied to identify BJTD’s active ingredients, followed by molecular dockings to assess interactions with the target protein. To confirm the BJTD’s mechanism of action, mTOR signaling modulation was analyzed using a specific inhibitor or activator in vitro. Transcriptomic reanalysis revealed significant gene expression differences, with &lt;i&gt;LIF&lt;/i&gt; identified as a key target associated with apoptosis pathway. In vitro, 4-HC exposure induced apoptosis, mitochondrial dysfunction, and ferroptosis in KGN cells, accompanied by upregulation of LIF, mTOR, and FoxO3a signalings. BJTD-serum treatment significantly improved cell viability, reduced apoptosis, and alleviated oxidative stress by modulating mitochondrial function and ferroptosis markers, such as Nrf2, HO-1, and GPX4. In vivo, BJTD alleviated Cy-induced ovarian damage, improving ovarian index, estrous cycle, follicle development, and hormone levels, while reducing follicular atresia and granulosa cells apoptosis. Mechanically, BJTD suppressed Cy-induced activation of the LIF-mTOR axis and downstream mitochondrial apoptosis markers, including Cleaved Caspase 9/3, BAX, and γH2AX, while enhancing OPA1 and Bcl-2 expressions. The UPLC-MS outcome combining with network pharmacology identified mainly 20 active compounds in BJTD, with astragaloside IV exhibiting the strongest binding to the mTOR protein. The mTOR pathway modulation experiments confirmed that BJTD’s protective effects are mediated through inhibition of hyperactivated mTOR phosphorylation a","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"30 5-6","pages":"1331 - 1350"},"PeriodicalIF":8.1,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555685","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}