International Journal of Biological Sciences最新文献

{"title":"Comprehensive analytical approach identifies a subtype of CTCF+ tumor-associated neutrophils associated with CRC development and as a biomarker for immunotherapy.","authors":"Jie-Pin Li, Yuan-Jie Liu, Yi Zhang, Qian-Wen Ye, Guo Xu, Jin-Chen Chong, Yi Yin, Yang Li, Shuang-Shuang Wang, Jin-Yong Zhou, Jun Qian, Shen-Lin Liu, Xi Zou, Yu-Gen Chen","doi":"10.7150/ijbs.111529","DOIUrl":"10.7150/ijbs.111529","url":null,"abstract":"<p><p><b>Background:</b> Colorectal cancer (CRC) is an aggressive and heterogeneous tumor with limited therapeutic options. Tumor-associated neutrophils (TANs) play multifaceted roles in the tumor microenvironment (TME) depending on their polarization. Understanding TAN heterogeneity and the mechanisms underlying their tumor-promoting activities is critical for advancing CRC treatment. <b>Methods:</b> This study integrated single-cell RNA sequencing, spatial transcriptomics, bulk RNA sequencing, and in vivo/ex vivo experiments to characterize TANs in CRC. <b>Results:</b> We identified a distinct subpopulation of TANs characterized by high CCCTC-binding factor (CTCF) expression (CTCF+ TANs) enriched in hypoxic tumor regions. CTCF+ TANs exhibit enhanced migratory capacity and IL-1β secretion, correlating with poor prognosis and resistance to immunotherapy. Mechanistically, CTCF regulates the expression of Migration and Invasion Enhancer 1 (MIEN1), which promotes TAN recruitment and migration without triggering inflammation. Functional studies revealed that CTCF+ TANs suppress T-cell immunity, facilitate epithelial-to-mesenchymal transition (EMT), and contribute to CRC progression and metastasis. In vivo, targeting CTCF-MIEN1-IL-1β signaling rescued the immunosuppressive microenvironment and improved the efficacy of anti-PD-L1 therapy. <b>Conclusions:</b> CTCF+ TANs represent a novel TAN subtype that drives CRC progression and immunosuppression via the CTCF-MIEN1-IL-1β axis. These findings highlight the potential of targeting CTCF+ TANs to overcome immunotherapy resistance and improve patient outcomes.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 12","pages":"5305-5327"},"PeriodicalIF":10.0,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12435489/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075011","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":"YBX1/CD36 positive feedback loop: novel molecular target for MASLD treatment.","authors":"Yuxuan Jiang, Cristina Llorente","doi":"10.7150/ijbs.121866","DOIUrl":"10.7150/ijbs.121866","url":null,"abstract":"","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 12","pages":"5164-5166"},"PeriodicalIF":10.0,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12435216/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075241","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":"Targeting NINJ1-Mediated Plasma Membrane Rupture in Tubular Epithelial Cell Prevents Inflammatory Response in Acute Kidney Injury.","authors":"Siyan Zhou, Qigang Lan, Wang Xin, Yaqin Wang, Aihong Zhang, Jiachuan Xiong, Liangjing Lv, Yan Li, Ling Nie, Shaozong Qin, Jinrun Zhou, Shuiqin Gong, Shaobo Wang, Yinghui Huang, Jinghong Zhao","doi":"10.7150/ijbs.115364","DOIUrl":"10.7150/ijbs.115364","url":null,"abstract":"<p><p>Damage-associated molecular patterns (DAMPs)-induced sterile inflammation is considered as a typical feature of acute kidney injury (AKI). Plasma membrane rupture in renal tubular epithelial cells (RTECs) is the major cause of DAMP release and nerve injury-induced protein 1 (NINJ1) has recently emerged as an executor of plasma membrane rupture, while its role in AKI pathophysiology remains largely unknown. Here, we show upregulated NINJ1 expression and oligomerization in renal tubules among human biopsies and mouse models as well as in cultured RTECs after AKI, accompanied by plasma membrane rupture, increased DAMP release and inflammatory response. Furthermore, knockdown of NINJ1 or inhibition of its oligomerization effectively prevents plasma membrane rupture in RTECs, thereby alleviating DAMP-induced inflammatory response and renal tubular injury. Mechanistically, the ETS transcription factor (ELK1) is identified as a novel transcription factor for NINJ1 during AKI, especially ELK1 phosphorylation at Ser³⁸³ significantly enhances its transcriptional activity. Importantly, genetic silencing of NINJ1 or pharmacological inhibition of Ser³⁸³-phosphorylated ELK1 can protect against AKI and improve AKI prognosis. Collectively, these findings highlight the ELK1-NINJ1 axis as a pivotal regulator of plasma membrane rupture in RTECs upon AKI, suggesting that it may serve as a potential target for AKI treatment and prognosis improvement.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 12","pages":"5223-5239"},"PeriodicalIF":10.0,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12435343/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075243","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":"Senescent Tumoral HLA-E Reshapes Microenvironment through Impairing NK Cell-Dendritic Cell-T Cell Network in Malignant Pleural Effusion from Lung Cancer.","authors":"Ying-Ming Tsai, Jen-Yu Hung, Yu-Yuan Wu, Hung-Pei Tsai, Kuan-Li Wu, Tai-Huang Lee, Hung-Hsing Chiang, Wei-An Chang, Hsiao-Chen Lee, Sheng-Feng Pan, Kai-Chien Chuang, Shu-Fang Jian, Ling-Yu Wu, Ya-Ling Hsu","doi":"10.7150/ijbs.116499","DOIUrl":"10.7150/ijbs.116499","url":null,"abstract":"<p><p><b>Background:</b> Malignant pleural effusion (MPE) is ominous in lung cancer patients. However, comprehensive studies of both innate and adaptive immune responses within the pleural tumor microenvironment remain limited. <b>Methods:</b> We collected samples from patients with heart failure and lung cancer-MPE. By single-cell RNA sequencing, we analyzed alternations in cancer cells, NK cells, DCs, and T cells. Key cytokines involving in cell-cell interactions were quantified using Luminex or ELISA, while HLA-E and aging markers were assessed via immunohistochemistry. <b>Results:</b> Our findings revealed that CD56⁺CD16⁺ and CD56⁻CD16⁻ NK cells exhibited reduced cytotoxicity, mainly through HLA-E-expressing senescent cancer cells interacting with NK cells inhibitory receptor, leading to NK cell dysfunction and reduced XCL2 expression, which might impair cDC1 recruitment. Consequently, aDC2 cells evolved into exhausted phenotype, resulting in inadequate T cell activation. In CD8 T cells, transcription factors such as <i>FOXO1</i> contributed to diminished cytotoxicity. Despite presence of GZMA CD4 T cells, their cytotoxicity was suppressed in MPE. Th1-like and Th2-like regulatory T cells further inhibited CD4 T cell responses. Key molecules, CXCL16, BAG6, and IL-7, bridging innate and adaptive immunity conferred poor prognosis. <b>Conclusions:</b> Our study demonstrates that senescent cancer cells promote immunoevasion through HLA-E, suppressing NK cell cytotoxicity, impairing DC function, and disrupting T cell activation. Cell-cell interaction and imbalanced Th1/Th2 contribute to microenvironmental remodeling, driving disease progression. These findings provide insights into the immunological landscape and therapeutic targets for intervention.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 12","pages":"5240-5257"},"PeriodicalIF":10.0,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12435339/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075173","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":"ANXA6 Overexpression Causes Abnormal Decidual Macrophage-Trophoblast Crosstalk in Recurrent Spontaneous Abortion.","authors":"Xin Chen, Xue Yao Li, Xue Qin Ma, Yan Zhang, Qian Lin Song, Jing Yang","doi":"10.7150/ijbs.111791","DOIUrl":"10.7150/ijbs.111791","url":null,"abstract":"<p><p>ANXA6 is involved in numerous biological processes; however, its association with recurrent spontaneous abortion (RSA) remains poorly understood. In this study, we observed significant upregulation of ANXA6 expression in decidual macrophages from RSA patients. Functional analysis revealed that ANXA6 overexpression enhanced reactive oxygen species (ROS) generation and reduced mitochondrial membrane potential, thereby promoting pyroptosis and upregulating M1 macrophage polarization markers. Mechanistically, inhibition of NLRP3 rescued ANXA6 overexpression-induced elevation of M1 polarization and pyroptosis in macrophages. In addition, inhibition of ROS alleviated the decreased mitochondrial membrane potential, aggravated macrophage pyroptosis, and exacerbated inflammatory response, as well as the promoted macrophage M1 polarization caused by ANXA6 overexpression. Further mechanisms suggest that overexpression of ANXA6 in macrophages could promote the accumulation of mitochondrial ROS and inhibit mitochondrial membrane potential through the NF-κB signaling pathway, exacerbating macrophage pyroptosis and amplifying the resulting inflammatory response, thereby promoting macrophage M1 polarization. Besides, ANXA6 overexpressing macrophages showed an inhibitory effect on trophoblast function <i>in vitro</i>, a process mediated through TNF-α inhibition of the PI3K/AKT axis. Collectively, our study reveals that ANXA6 is a key mediator of immune dysregulation at the maternal-fetal interface in RSA patients.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 12","pages":"5206-5222"},"PeriodicalIF":10.0,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12435268/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074894","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":"Recent Advances of Trained immunity in Macrophages.","authors":"Peizhi Li, Manman Liu, Yakun Liu, Jing Guo, Jingfeng Jiang, Guidan Wang, Chenlong Cao, Xinru Wang, Junxing Qu, Zhiheng Sun","doi":"10.7150/ijbs.115515","DOIUrl":"10.7150/ijbs.115515","url":null,"abstract":"<p><p>Trained immunity (TI), also known as innate immune memory, is the long-term change in the functional program of innate immune cells after transient stimulation through epigenetic and metabolic alterations. This reprogramming augments the response to secondary challenges fueled by various stimulus and contributes to the resistance of cancer, infectious diseases, auto-inflammatory disorders, and other diseases. Macrophages, which are versatile innate immune cells with remarkable plasticity, can adapt to different microenvironments and perform diverse functions. TI of macrophages has been deeply involved in pathogen infection. However, current understandings in the effect of TI are still incomplete and require further investigation and summarization. In this review, we summarized the existing knowledge in this field including the hallmark and mechanism of TI, its impact on health and disease, as well as the potential as a therapeutic tool. This study provides new perspectives for a comprehensive insight of TI.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 12","pages":"5258-5283"},"PeriodicalIF":10.0,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12435229/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075141","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":"Lipin3 deficiency aggravates cisplatin induced acute kidney injury via activating Sirt1-p21-Caspase 3-GSDME pyroptosis pathway.","authors":"Yu-Xing Liu, Hao Huang, Fang Wang, Mei-Fang Zhao, Jie-Yuan Jin, Yi Dong, Qian Wang, Liang-Liang Fan, Rong Xiang","doi":"10.7150/ijbs.110125","DOIUrl":"10.7150/ijbs.110125","url":null,"abstract":"<p><p>Lipin proteins, including Lipin 1, Lipin 2 and Lipin3, play a vital role in lipid metabolism. Despite their significance, there is limited understanding of the involvement of Lipin proteins in kidney diseases. This study aims to elucidate the specific functions of Lipin 3 in the context of acute kidney injury (AKI). In the present study, Lipin3 levels were analyzed in AKI public database, kidney tissues from AKI patients and cisplatin induced mice models, as well as cisplatin induced HK2 cells. A <i>Lipin3</i> knockout (<i>Lipin3</i>-KO) mouse model was generated to investigate the pathophysiological roles of Lipin3 in the kidneys. The underlying mechanisms were further examined in primary tubular epithelial cells (PTECs) and HK2 cells <i>in vitro</i>. The findings indicated that (1) Lipin3 was obviously increased in AKI patients, as well as cisplatin induced mice and cells; (2) Lipin3-null mice presented with more severe AKI symptoms compared to WT mice after cisplatin treatment; (3) Lipin3 played crucial role in regulating cell death and mitochondrial function after cisplatin treatment; (4) In terms of mechanism, Lipin3 regulated these phenotypes through its interaction with Sirt1, which activated the p21-Caspase 3-GSDME pathway. Our study suggests that Lipin3 could be pivotal in pyroptosis and AKI. Decreased Lipin3 levels in the kidney may potentially contribute as a risk factor for exacerbating AKI.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 12","pages":"5185-5205"},"PeriodicalIF":10.0,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12435314/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075116","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":"Recovery of FAM134A-mediated ER-phagy through BRD4 inhibition alleviates ethanol-induced neurodegeneration.","authors":"Jae Ryong Lim, Chang Woo Chae, Jee Hyeon Yoon, Ji Hyeon Cho, Ji Yong Park, Su Jong Han, Han Seung Chang, Su Yeol Kim, Ha Jin Kim, Young Hyun Jung, Ho Jae Han","doi":"10.7150/ijbs.116673","DOIUrl":"10.7150/ijbs.116673","url":null,"abstract":"<p><p>Endoplasmic reticulum (ER) stress is a major contributor to ethanol-induced neurodegeneration. ER-phagy, the selective elimination of specific ER domains, has emerged as a protective mechanism against ER stress. However, its regulation in ethanol-related neurological disorders remains unclear. Here, we investigated the effects and underlying mechanisms of ethanol on ER-phagy in neuronal cells and ethanol-fed mice. Our findings demonstrate that ethanol-induced ER stress is chronically sustained due to impaired ER-phagy. Among ER-phagy receptors, FAM134A expression was notably reduced by ethanol. Ethanol metabolism contributes to the downregulation of SIRT1 activity, leading to increased acetylation of histone H4 lysine 16 (H4K16ac) and enhanced recruitment of bromodomain-containing protein 4 (BRD4) to the FAM134A promoter. The BRD4/G9a complex-mediated increase in histone H3 lysine 9 dimethylation (H3K9me2) downregulates FAM134A expression by restricting the access of unfolded protein response (UPR)-associated transcription factor XBP1s. BRD4 inhibition or FAM134A overexpression restored ethanol-decreased ER-phagy, alleviating ER stress and preventing synaptic loss and neuronal cell death. In ethanol-fed mice, pharmacological inhibition of BRD4 restored hippocampal ER-phagy, resulting in improved cognitive function. In conclusion, recovering FAM134A-mediated ER-phagy through BRD4 inhibition may be a promising strategy to prevent ethanol-induced neurodegeneration.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 12","pages":"5167-5184"},"PeriodicalIF":10.0,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12435209/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075124","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":"<i>MALAT1</i> promotes malignancy of HBV-related hepatocellular carcinoma by regulating IGF2BP3-mediated nuclear-cytoplasmic shuttling.","authors":"Ze-Bang Du, Xin-Mou Wu, Tun Han, Yu-Xin Cai, Bo Qian, Yu-Shi Shen, Han-Yu Zhang, Jia-Shen Wu, Jie He, Xiao-Xuan Chen, Dong-Bei Guo, Hang-Tian Zhong, Xiong Li, Lei Zhang, Xiao-Ming Luo, Wen-Gang Li, Yu-Chun Lin, Zhong-Ning Lin","doi":"10.7150/ijbs.112133","DOIUrl":"https://doi.org/10.7150/ijbs.112133","url":null,"abstract":"<p><p>Hepatitis B virus (HBV) X protein (HBx) plays a critical role in the progression of HBV-related hepatocellular carcinoma (HCC). Long non-coding RNAs (lncRNAs) regulate various biological processes and contribute to HCC development, with their therapeutic potential in disease progression recently gaining significant attention. However, the involvement of lncRNAs in HBx-related hepatocarcinogenesis and the underlying regulatory mechanisms remain unclear. In this study, we conducted a comprehensive analysis of multi-database sequencing data to identify metastasis-associated lung adenocarcinoma transcript 1 (<i>MALAT1</i>) as an HBx-associated lncRNA and observed its upregulation in HBV-related HCC tissues and cells upon HBx expression. Additionally, high <i>MALAT1</i> expression was correlated with poor prognosis and advanced HCC progression. <i>MALAT1</i> overexpression significantly promoted the proliferation, migration, and invasion of HCC cells. Mechanistic investigations revealed that <i>MALAT1</i> was transported to the cytoplasm and enhanced RNA stability in a N6-methyladenosine (m6A)-dependent manner through direct interaction with and recruitment of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3). Targeting <i>MALAT1 in vivo</i> with antisense oligonucleotides (ASO)-<i>MALAT1</i> treatment effectively suppressed the progression of xenograft tumors and orthotopic liver tumors in HBx-related HCC. Moreover, hydrodynamic-based gene delivery (HGD) was utilized to introduce anti-HBx transposon plasmids into murine hepatocytes, thereby suppressing <i>MALAT1</i>-m6A-mediated HBV-related hepatocarcinogenesis in HBx transgenic (HBx-Tg) mice. Overall, our findings shed novel light on the regulatory role of IGF2BP3-mediated <i>MALAT1</i> nuclear-cytoplasmic shuttling and RNA stabilization via m6A modification during HCC progression. These results suggest that m6A-based <i>MALAT1</i> expression serves as a novel diagnostic and prognostic biomarker for targeted epigenetic intervention in HBV-related HCC.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 11","pages":"4942-4960"},"PeriodicalIF":10.0,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374813/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144952973","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":"Hino-Fe Chelate Suppresses Osteosarcoma Progression through Dual Induction of Ferroptosis and NLRC4-mediated Pyroptosis: Mechanisms and Therapeutic Implications.","authors":"Yuxing Chen, Yong Tao, Qiu Huang, Jingtao Xu, Zhenxin Wang, Ye Zhang, Guangxu Fu, Fuqiang Tan, Keyi Feng, Yunsheng Ou","doi":"10.7150/ijbs.113785","DOIUrl":"https://doi.org/10.7150/ijbs.113785","url":null,"abstract":"<p><p>Osteosarcoma remains a challenging malignancy with poor prognosis, particularly in metastatic cases. This study investigates the therapeutic potential and molecular mechanisms of the Hinokitiol-iron complex (Fe(hino)₃) against osteosarcoma. Fe(hino)3 induced dose-dependent cell death in osteosarcoma cell lines (HOS, 143b, and K7M2) through multiple pathways. At moderate doses, Fe(hino)3 triggered ferroptosis by disrupting mitochondrial function, enhancing ROS generation and lipid peroxidation, downregulating GSS and GPX4, and upregulating HO1 and Ferritin expression. At higher doses, Fe(hino)₃ activated the NLRC4/Caspase-1/GSDMD pathway, leading to pyroptosis and the release of inflammatory factors. Mechanistically, Fe(hino)3 acted as a dual-mode cell death inducer through iron overload-mediated ferroptosis and NLRC4-dependent pyroptosis while modifying the immunosuppressive tumor microenvironment. In actual clinical application, Fe(hino)3 might be used as an alternative to chemotherapy or other targeted therapies for advanced osteosarcoma at a relatively low dose to improve biosafety and reduce side effects. However, when considering it in combination with immunotherapy for advanced osteosarcoma, a relatively safe high dose is more appropriate due to the pyroptosis-mediated inflammatory response but it still needs to consider the biosafety of combination therapy. These findings provide new insights into the development of Fe(hino)3 dose-dependent therapeutic strategies for advanced osteosarcoma treatment.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 11","pages":"4872-4894"},"PeriodicalIF":10.0,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374815/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144953121","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}