《细胞死亡与分化》编辑团队为您带来的《细胞死亡与疾病》是转化细胞死亡领域的同行评审在线期刊。它旨在通过其专业（包括癌症、免疫和神经科学）促进实验和内科学的多样化和综合领域。它现在还接受一个新领域的文章：癌症代谢。

Cell Death and Disease is a peer-reviewed online journal launched by the editorial team of Cell Death and Differentiation, focusing on the field of translational cell death. The journal aims to promote diversity and integration in experimental and clinical sciences, covering specialized areas such as cancer, immunology, and neuroscience. Recently, it has also started accepting articles in the new area of cancer metabolism.

《细胞死亡与疾病》是由《细胞死亡与分化》编辑团队推出的同行评审在线期刊，专注于转化细胞死亡领域。期刊旨在促进实验科学与内科学的多样化与综合，涵盖癌症、免疫学和神经科学等专业领域。近期，期刊还开始接受关于癌症代谢的新领域文章。

Cell Death and Disease

Abstract Ferroptosis, a nonapoptotic form of programmed cell death characterized by significant iron-dependent peroxidation of phospholipids, is regulated by cellular metabolism, redox homeostasis, and various cancer-related signaling pathways. Recently, considerable progress has been made in demonstrating the critical role of lipid metabolism in regulating ferroptosis, indicating the potential of combinational strategies for treating cancer in the future. In this study, we explored the combinational effects of lipid metabolism compounds and ferroptosis inducers on renal cell carcinoma (RCC) cells. We found potent synergy of the fatty acid amide hydrolase (FAAH) inhibitor URB597 with ferroptosis inducer (1S, 3R)-RSL3 (RSL3) in inhibiting the growth and metastasis of RCC cells both in vitro and in vivo via induction of G1 cell cycle arrest and promotion of the production of lipid peroxides, malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), and cytosolic reactive oxygen species (ROS). In addition, inhibition of FAAH increased the sensitivity of RCC cells to ferroptosis. Genome-wide RNA sequencing indicated that the combination of URB597 and RSL3 has more significant effects on regulation of the expression of genes related to cell proliferation, the cell cycle, cell migration and invasion, and ferroptosis than either single agent alone. Moreover, we found that combinational treatment modulated the sensitivity of RCC cells to ferroptosis via the phosphatidylinositol 3 kinase (PI3K)-AKT signaling pathway. These data demonstrate that dual targeting of FAAH and ferroptosis could be a promising strategy for treating RCC.

Junfeng Hao

Qiguang Chen

Yongmin Feng

Qiyu Jiang

Huiwei Sun

Botian Deng

Xin Huang

Jibin Guan

Qiuping Chen

Xincheng Liu

Yanjin Wang

Peng Cao

Fan Feng

Xiaoyu Li

Combination treatment with FAAH inhibitors/URB597 and ferroptosis inducers significantly decreases the growth and metastasis of renal cell carcinoma cells via the PI3K-AKT signaling pathway

Abstract Necroptosis facilitates cell death in a controlled manner and is employed by many cell types following injury. It plays a significant role in various liver diseases, albeit the cell-type-specific regulation of necroptosis in the liver and especially hepatocytes, has not yet been conceptualized. We demonstrate that DNA methylation suppresses RIPK3 expression in human hepatocytes and HepG2 cells. In diseases leading to cholestasis, the RIPK3 expression is induced in mice and humans in a cell-type-specific manner. Overexpression of RIPK3 in HepG2 cells leads to RIPK3 activation by phosphorylation and cell death, further modulated by different bile acids. Additionally, bile acids and RIPK3 activation further facilitate JNK phosphorylation, IL-8 expression, and its release. This suggests that hepatocytes suppress RIPK3 expression to protect themselves from necroptosis and cytokine release induced by bile acid and RIPK3. In chronic liver diseases associated with cholestasis, induction of RIPK3 expression may be an early event signaling danger and repair through releasing IL-8.

Jessica Hoff

Ling Xiong

Tobias Kammann

Sophie Neugebauer

Julia M. Micheel

Nikolaus Gaßler

Michael Bauer

Adrian T. Press

RIPK3 promoter hypermethylation in hepatocytes protects from bile acid-induced inflammation and necroptosis

Embryonal carcinoma (EC), characterized by a high degree of stemness similar to that of embryonic stem cells, is the most malignant subtype within non-seminomatous testicular germ cell tumors (TGCTs). However, the mechanisms underlying its malignancy remain unknown. In this study, we employed single-cell RNA sequencing to analyze four non-seminoma samples. Our differential expression analysis revealed high expression of SERPINB9 in metastatic EC cells. We conducted in vitro experiments to further investigate SERPINB9's role in the progression of EC. Functionally, the knockdown of SERPINB9 in NCCIT and NTERA-2 leads to a diminished migratory capability and decreased cis-platin resistance, as demonstrated by Transwell migration assay and drug sensitivity assay. Moreover, embryoid bodies showed reduced size and lower OCT4 expression, alongside heightened expression of differentiation markers AFP, ACTA2, and CD57 in shSERPINB9 cells. In vivo, the role of SERPINB9 in maintaining cancer stemness was validated by the limiting dilution assay. Mechanistically, Bulk RNA-seq further showed downregulation of ERK1/2 signaling and WNT signaling pathways with concomitant upregulation of differentiation pathways subsequent to SERPINB9 knockdown. Additionally, the analysis indicated increased levels of cytokines linked to tertiary lymphoid structures (TLS), such as IL6, IL11, IL15, CCL2, CCL5, and CXCL13 in shSERPINB9 cells, which were further validated by ELISA. Our research indicates that SERPINB9 plays a key role in driving tumor progression by enhancing tumor stemness and suppressing TLS. This study stands as the first to elucidate the molecular signature of non-seminomas at a single-cell level, presenting a wealth of promising targets with substantial potential for informing the development of future therapeutic interventions.

Zhouliang Bian

Biying Chen

Guohai Shi

Haihua Yuan

Yue Zhou

Bin Jiang

Long Li

Hengchuan Su

Yanjie Zhang

Single-cell landscape identified SERPINB9 as a key player contributing to stemness and metastasis in non-seminomas

单细胞图谱揭示SERPINB9在非精原细胞瘤的干细胞性和转移中的关键作用

Abstract Melatonin is a well-known natural hormone, which shows a potential anticancer effect in many human cancers. Bladder cancer (BLCA) is one of the most malignant human cancers in the world. Chemoresistance is an increasingly prominent phenomenon that presents an obstacle to the clinical treatment of BLCA. There is an urgent need to investigate novel drugs to improve the current clinical status. In our study, we comprehensively explored the inhibitory effect of melatonin on BLCA and found that it could suppress glycolysis process. Moreover, we discovered that ENO1, a glycolytic enzyme involved in the ninth step of glycolysis, was the downstream effector of melatonin and could be a predictive biomarker of BLCA. We also proved that enhanced glycolysis simulated by adding exogenous pyruvate could induce gemcitabine resistance, and melatonin treatment or silencing of ENO1 could intensify the cytotoxic effect of gemcitabine on BLCA cells. Excessive accumulation of reactive oxygen species (ROS) mediated the inhibitory effect of melatonin on BLCA cells. Additionally, we uncovered that PPARγ was a novel upstream regulator of ENO1, which mediated the downregulation of ENO1 caused by melatonin. Our study offers a fresh perspective on the anticancer effect of melatonin and encourages further studies on clinical chemoresistance.

Dexin Shen

Zhao Deng

Wei Liu

Fenfang Zhou

Yayun Fang

Danni Shan

Gang Wang

Kaiyu Qian

Mengxue Yu

Yi Zhang

Lingao Ju

Yu Xiao

Xinghuan Wang

Cell Death Dis

Melatonin inhibits bladder tumorigenesis by suppressing PPARγ/ENO1-mediated glycolysis

褪黑素通过抑制PPARγ/ENO1介导的糖酵解抑制膀胱肿瘤发生

Abstract Metabolic reprogramming to glycolysis is closely associated with the development of chronic kidney disease (CKD). Although it has been reported that phosphofructokinase 1 (PFK) is a rate-limiting enzyme in glycolysis, the role of the platelet isoform of PFK (PFKP) in kidney fibrosis initiation and progression is as yet poorly understood. Here, we investigated whether PFKP could mediate the progression of kidney interstitial fibrosis by regulating glycolysis in proximal tubular epithelial cells (PTECs). We induced PFKP overexpression or knockdown in renal tubules via an adeno-associated virus (AAV) vector in the kidneys of mice following unilateral ureteral occlusion. Our results show that the dilated tubules, the area of interstitial fibrosis, and renal glycolysis were promoted by proximal tubule-specific overexpression of PFKP, and repressed by knockdown of PFKP. Furthermore, knockdown of PFKP expression restrained, while PFKP overexpression promoted TGF-β1-induced glycolysis in the human PTECs line. Mechanistically, Chip-qPCR revealed that TGF-β1 recruited the small mothers against decapentaplegic (SMAD) family member 3-SP1 complex to the PFKP promoter to enhance its expression. Treatment of mice with isorhamnetin notably ameliorated PTEC-elevated glycolysis and kidney fibrosis. Hence, our results suggest that PFKP mediates the progression of kidney interstitial fibrosis by regulating glycolysis in PTECs.

Shu Yang

Han Wu

Yanchun Li

Lixin Li

Jiaqing Xiang

Lin Kang

Guangyan Yang

Zhen Liang

Inhibition of PFKP in renal tubular epithelial cell restrains TGF-β induced glycolysis and renal fibrosis

肾小管上皮细胞中PFKP的抑制抑制TGF-β诱导的糖酵解和肾纤维化

Abstract The TGFβ signaling pathway is known for its pleiotropic functions in a plethora of biological processes. In melanoma, TGFβ signaling promotes invasiveness and metastasis formation. However, its involvement in the response to therapy is controversial. While several studies have linked TGFβ signaling to elevated resistance to targeted therapy in melanoma, separate findings have indicated a favorable treatment response through TGFβ-mediated increase of cell death. We now found that the outcome of TGFβ signaling in the context of targeted therapy is dose dependent. Unlike low doses, high levels of TGFβ signal activation induce apoptosis upon simultaneous MAPK pathway inhibition, even in targeted therapy resistant melanoma cell lines. Using transcriptomic analyses, combined with genomic target identification of the critical TGFβ signaling effector SMAD4, we demonstrate that parallel activation of TGFβ signaling and MAPK pathway inhibition causes a complete switch of TGFβ target genes from promoting pro-invasive processes to fueling pro-apoptotic pathways. Investigations of underlying mechanisms identified a novel apoptosis-inducing gene signature. Functional validation of signature members highlighted a central role of the pro-apoptotic BCL2 family member BCL2L11 (BIM) in mediating apoptosis in this condition. Using a modified, synthetic version of the TGFB1 mRNA for intra-tumoral injections, we additionally showcase a potential therapeutic application of this treatment combination.

Benjamin Loos

Adrian Salas-Bastos

Anna Nordin

Julien Debbache

Salome Stierli

Phil F. Cheng

Stefanie Rufli

Conrad Wyss

Mitchell P. Levesque

Reinhard Dummer

Wendy Wei-Lynn Wong

Steve Pascolo

Claudio Cantù

Lukas Sommer

TGFβ signaling sensitizes MEKi-resistant human melanoma to targeted therapy-induced apoptosis

TGFβ信号增强对靶向治疗诱导凋亡的MEKi耐药人黑色素瘤的敏感性

Abstract In recent years, targeting mitochondrial apoptosis has emerged as a promising therapeutic strategy for Acute Myeloid Leukemia (AML). The SLC25 family of mitochondrial carriers plays a critical role in maintaining mitochondrial function and regulating apoptosis. However, the role of SLC25A21 , an oxodicarboxylate carrier, in AML progression and its potential as a prognostic biomarker remain underexplored. This study aimed to further investigate the role, molecular mechanism, and potential clinical value of SLC25A21 in AML progression. The transcript levels of SLC25A21 in bone marrow specimens were analyzed using real-time quantitative polymerase chain reaction. The correlation between SLC25A21 expression and the prognosis of AML was assessed through survival analysis. Findings revealed that SLC25A21 was downregulated in adult AML, and the low expression of SLC25A21 was correlated with worse prognosis for AML patients. Furthermore, overexpression of SLC25A21 inhibited cell proliferation and cell cycle progression, and was correlated with apoptosis through mitochondrial apoptosis signaling pathway. C-X-C motif chemokine ligand 8 ( CXCL8 ) was identified as a downstream target of SLC25A21 . These functions of SLC25A21 could be rescued by the overexpression of CXCL8 . Moreover, SLC25A21 overexpression significantly suppressed the growth of xenograft tumors. In conclusion, the low SLC25A21 expression is correlated with poor clinical outcome. The overexpression of SLC25A21 inhibited the AML cell survival and proliferation by dysregulating the expression of CXCL8 . SLC25A21 might be a potential prognostic marker and a treatment target for AML.

Yu Liu

Yan Xu

Qianqian Hao

Luyao Shi

Yufei Chen

Yajun Liu

Mengya Li

Yu Zhang

Tao Li

Yafei Li

Zhongxing Jiang

Yanfang Liu

Chong Wang

Zhilei Bian

Lu Yang

Shujuan Wang

SLC25A21 correlates with the prognosis of adult acute myeloid leukemia through inhibiting the growth of leukemia cells via downregulating CXCL8

SLC25A21通过下调CXCL8抑制白血病细胞生长，从而与成人急性髓性白血病预后相关

Chen Feng

Wei Mao

Chenyang Yuan

Pin Dong

Yuying Liu

Correction: Nicotine-induced CHRNA5 activation modulates CES1 expression, impacting head and neck squamous cell carcinoma recurrence and metastasis via MEK/ERK pathway

更正：尼古丁诱导的CHRNA5激活通过MEK/ERK途径调节CES1表达，影响头颈鳞状细胞癌的复发和转移

Abstract Chemoresistance poses a significant clinical challenge in the treatment of gastric cancer (GC), while its underlying molecular mechanisms are still not fully understood. Post-translational protein modification and abnormal activation of nuclear factor-kappa B (NF-κB) are critical regulators of tumor chemoresistance. This study investigates the role of TNF receptors-associated factors 6 (TRAF6) in 5-Fluorouracil (5-FU) resistant GC. Utilizing short hairpin RNA (shRNA) to suppress TRAF6 expression in 5-FU resistant GC cells across both in vivo and in vitro models, we observed a marked reduction in cell proliferation and tumor growth. Low expression of TRAF6 inhibited nuclear translocation of NF-κB-p65, which was achieved by promoting the expression of Interferon regulatory factor 3 (IRF3). Importantly, TRAF6, an E3 ubiquitin ligase, bound to the IRF3-Δ (SR + IAD) (1-190aa) domain, inducing Lys70 ubiquitination of IRF3 to regulate its protein stability, with ubiquitin K48 residue playing a crucial role in this process. In conclusion, our study reveals the mechanism by which the TRAF6/IRF3 axis decreases GC’s cells sensitivity to 5-FU by promoting nuclear translocation of NF-κB-p65, offering valuable insights into overcoming chemoresistance in GC.

Shitong Chen

Dong Zhang

Yi Du

Junbo Shi

Sikuan Gu

Xujun Zhou

Huijuan Yu

Feng Wang

Jinfei Chen

Hongjuan Cui

Targeting TRAF6/IRF3 axis to inhibit NF-κB-p65 nuclear translocation enhances the chemosensitivity of 5-FU and reverses the proliferation of gastric cancer

靶向TRAF6/IRF3轴抑制NF-κB-p65核转位增强5-FU的化疗敏感性并逆转胃癌的增殖

Abstract Lipid metabolism disorder is a critical feature of Crohn’s disease (CD). Phosphatidylinositol (PI) and its derivative, phosphatidylinositol bisphosphate (PIP2), are associated with CD. The mechanisms underlying such association remain unknown. In this study, we explored the role played by the major PI derivative, phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], in CD pathogenesis. The relationship between CD activity and PI or PIP2 was analyzed via lipidomics. The mucosal expression of PI(4,5)P2 in patients with CD was measured using immunofluorescence. The function and mechanism of PI(4,5)P2 were examined in dextran sulfate sodium (DSS)-induced colitis mice and lipopolysaccharide (LPS)-induced Caco-2 cell models, along with MeRIP and mRNA sequencing. The results suggested lipid PI and PIP2 were substantially negatively associated with disease activity and high-sensitivity C-reactive protein. PI(4,5)P2 was substantially downregulated in the inflamed mucosa of patients with CD. PI(4,5)P2 alleviated mouse colitis, with improvements in survival rate, colon length, weight, and disease activity index. PI(4,5)P2 also alleviated DSS-induced tissue damage, tight junction loss, and intestinal epithelial cell (IEC) pyroptosis. In the in vitro LPS-induced cell model, PI(4,5)P2 inhibited pyroptosis, as well as NLRP3, and caspase-1 expression, in addition to reducing interleukin (IL)-18, IL-1β, and lactate dehydrogenase (LDH) secretion. PI(4,5)P2 mediated NNMT upregulation in mice and Caco-2 cells and suppressed pyroptosis in IECs. NNMT knockdown restricted the inhibitory effect of PI(4,5)P2 on IEC pyroptosis. NNMT inhibited the stability of RBP4 mRNA via m6A modification, thereby preventing pyroptosis following PI(4,5)P2 treatment. Significant correlations were also observed between PI(4,5)P2 and NNMT, NNMT and RBP4, and RBP4 and GSDMD expression in the intestinal tissues from patients with CD. Our results indicated that PI(4,5)P2 ameliorates colitis by inhibiting IEC pyroptosis via NNMT-mediated RBP4 m6A modification. Thus, PI(4,5)P2 shows potential as a therapeutic target in CD.

Qingfan Yang

Na Diao

Fei Ma

Zicheng Huang

Minzhi Lin

Xinyu Liu

Qin Guo

Pan Li

Jian Tang

Xiang Gao

Kang Chao

PI(4,5)P2 alleviates colitis by inhibiting intestinal epithelial cell pyroptosis through NNMT-mediated RBP4 m6A modification

PI(4,5)P2通过NNMT介导的RBP4 m6A修饰抑制肠道上皮细胞焦亡从而缓解结肠炎

Abbreviation	Cell Death Dis
Journal Impact	8.18
Quartiles(Global)	CELL BIOLOGY(Q1)

ISSN	2041-4889
h-index	164
Top Journals	Yes

Publication Information	Publisher: Springer Nature，Publishing cycle: ，Journal Type: journal，Open Access Journals: Yes
Basic data	Year of publication: 2010，Proportion of original research papers: 94.53%，Self Citation Rate:2.50%， Gold OA Rate: 99.69%
Journal Fees	$4790Details
Average review cycle	网友分享经验：平均2月
Average recruitment ratio	网友分享经验：较难

Cell Death and Disease

Journal Citation Format

A journal article with 1 author

A journal article with 2 authors

A journal article with 3 authors

A journal article with 5 or more authors

Books Citation Format

Thesis Citation Format

Web sites Citation Format

Patent Citation Format

Staying up late manually editing references? ivySCI automatically matches journals and helps you generate references with a single click.

Share Submission Experience