Cell Death Discovery最新文献

Hepatocellular carcinoma (HCC) has become the leading cause of global cancer-related mortality, which raises the demand for optimized therapeutic routes. The semi-essential micronutrient taurine has been gradually identified as a pivotal player linked to various diseases. Nevertheless, the metabolic impacts of taurine on hepatocellular carcinoma remain elusive. Here, we report that taurine is a negative regulator of urea cycle, thereby exerting a suppressive effect on growth of HCC tumors. Mechanistically, argininosuccinate lyase (ASL) is uncovered as the main target of taurine in repressing urea cycle of HCC cell lines. Furthermore, Fos proto-oncogene (FOS) functions as the transcription factor of ASL, which is significantly reduced upon taurine treatment. Physiologically, FOS-ASL axis is required for metabolic effects of taurine and contributes to growth of HCC tumors. Expression of ASL correlates with the inhibitory effect of taurine. Ultimately, synergistic blockade of glutaminolysis and urea cycle indicates that taurine is sufficient to substantially enhance the efficacy of the glutaminase GLS1 inhibitor in management of hepatocellular carcinoma. Collectively, these findings not only illustrate the metabolic mechanism of taurine in controlling growth of HCC tumors, but also create a promising route for utilization of taurine in clinic.

Drug resistance remains a major challenge in treating acute myeloid leukemia (AML), despite advancements in targeted therapies. We established cabozantinib-resistant FLT3-ITD⁺ AML cell lines (MV4-11-XR, Molm13-XR) from parental MV4-11 and Molm13 cells. In addition to resistance to cabozantinib, they also exhibited resistance to FDA-approved sorafenib and quizartinib with substantial increases in IC₅₀. The FLT3 D835Y mutation emerged in both cell lines, while an additional 1.3 kb deletion in FLT3 (FLT3¹^.³) was present in MV4-11-XR cells. Both resistant cells displayed higher proliferation rates and increased colony formation, as well as increased phosphorylation of FLT3 and its downstream signaling molecules, including ERK, STAT5, and AKT. Transcriptomic analysis identified 1113 and 1057 differentially expressed genes (DEGs) in MV4-11-XR and Molm13-XR, respectively, compared with their parentals, of which 81 and 74 DEGs are metabolic-related. Further metabolic assays confirmed that cabozantinib resistance was associated with significant metabolic alterations, including enhanced glycolysis with increased glucose uptake, lactate production, GAPDH activity, and glycolytic gene expression, as well as impaired oxidative phosphorylation and reduced mitochondria mass. Further in silico drug screening and in vitro experiments demonstrated that PI3K/mTOR dual inhibitor omipalisib and HSP90 inhibitor radicicol effectively reversed the metabolic reprogramming in cabozantinib-resistant cells. Moreover, both omipalisib and radicicol exhibited synergistic effects with cabozantinib, highlighting their therapeutic potential. Overall, we identified metabolic dysregulation as a hallmark of cabozantinib resistance and suggested that targeting metabolic vulnerabilities with PI3K/mTOR or HSP90 inhibitors could be an option to mitigate drug resistance.

Glioma, the most prevalent primary brain tumor, primarily arises from glial cells or their progenitors. Histologically, gliomas are classified into astrocytomas, oligodendrogliomas, and ependymomas. Due to their aggressive invasive nature and resistance to chemotherapy, gliomas exhibit high recurrence rates and poor clinical outcomes. Regulated cell death (RCD) refers to a set of genetically controlled cellular processes that significantly influence tumor behavior. RCD plays a dual role in cancer: under normal physiological conditions, it eliminates malignant cells to prevent tumorigenesis, while in pathological conditions, tumor cells evade RCD to gain survival advantages. Furthermore, distinct RCD pathways can modulate the tumor immune microenvironment, thereby affecting therapeutic outcomes. Targeting RCD mechanisms presents a promising strategy to overcome therapeutic resistance and advance innovative glioma immunotherapies. This review explores the molecular mechanisms of pyroptosis, ferroptosis, necroptosis, and autophagy in glioma, emphasizing their critical roles in tumor progression. It also examines therapeutic strategies targeting RCD, including recent advancements in glutathione peroxidase 4 (GPX4) inhibitors, oncolytic virotherapy, and other emerging agents. Furthermore, the review discusses the potential of nanoparticle-based drug delivery systems and multi-omics approaches to optimize personalized combination therapies, aiming to enhance multimodal, synergistic interventions for more effective glioma management.

The pathological hallmark of schistosomiasis is egg-induced granulomatous inflammation and the subsequent fibrosis in the liver; and mesenchymal stem cells have been explored for the treatment of schistosomiasis fibrosis. However, the underlying mechanisms are largely unknown. We demonstrated here that IFN-γ/ LPS-primed MSCs alleviate schistosomiasis fibrosis through promoting conversion of Ly6C^hiCX3CR1^lo to pro-resolving Ly6C^loCX3CR1^hi. Importantly, primed MSCs promoted macrophage efferocytosis in the infected mice, and in vitro experiments confirmed the direct role of primed MSC on enhancement of macrophage efferocytosis, as well as its conversion to pro-resolving type. Mechanistically, primed MSC promoted β2 integrins(Itgb2) expression within macrophages; and Itgb2 blockade not only inhibited GTPase Rac1 activity, a key regulator of actin filament organization during efferocytosis, but also abolished the enhancement of primed MSCs on macrophage efferocytosis, suggesting that primed MSCs enhance efferocytosis via Itgb2-Rac1 axis. Moreover, either Itgb2 blockade or Rac1 inhibition within macrophages reversed the regulation of primed MSCs on macrophage subset switching, suggesting that primed MSCs promote macrophage subset conversion dependent on efferocytosis pathway. Taken together, this study demonstrates that primed MSCs attenuate schistosomiasis liver fibrosis by enhancing macrophage subset switch and efferocytosis via Itgb2-Rac1 axis, which offers novel insights into the therapeutic targets of MSC-based anti-fibrotic therapy.

Polypyrimidine Tract Binding Protein 2 (Ptbp2) binds to polypyrimidine clusters in pre-mRNA molecules and plays a vital role in alternative splicing, especially during neuronal development and maturation. Our study shows that Ptbp2 binds to the 3' UTR of DNA polymerase kappa (Polk), leading to its stabilization and increased expression. While Polk's role in DNA repair is known, its post-transcriptional regulation remains largely unclear. We observed a correlation between increased Ptbp2 levels and higher Polk expression in clinical samples of Chronic Myeloid Leukemia (CML). Knocking out Ptbp2 in CML cell lines and patient samples decreased Polk levels; when treated with hydroxyurea, these samples exhibited increased DNA damage, evidenced by long comet tails and elevated γH2AX foci, a DNA damage marker; however, re-expressing Polk in Ptbp2-KO cells restored the phenotype. Disruption of the DNA repair pathway is a hallmark of cancer and is closely linked to genomic instability. Polk was found to interact with MRE11 of the MRN complex, regulating the activation of the ATM-CHK2 signaling pathway. Cells with high levels of Ptbp2 and Polk showed increased sister chromatid exchanges and BrdU incorporation in ex vivo tests, while multinucleated cells with multipolar spindles appeared in in vivo tests. Our results confirm the key role of the Ptbp2-Polk-MRE11 axis in promoting genomic instability and supporting the survival of cells with higher malignancy.

Metastasis remains the primary cause of mortality in colorectal cancer (CRC), with a 5-year survival rate of ~14%, despite therapeutic advances. SPP1⁺ tumor-associated macrophages (TAMs) are implicated in promoting tumor progression, angiogenesis, and immune evasion. Osteopontin (OPN), encoded by the SPP1 gene, is a critical regulator of TAMs M2 polarization and CRC metastasis when derived from TAMs. However, it remains unclear whether CRC-derived OPN interacts with M2-like TAMs to promote metastasis and what the underlying mechanisms are. Here, we found that OPN is highly expressed in metastatic CRC and is associated with poor prognosis. Contrary to prior reports, neither knockdown nor overexpression of OPN in CRC cells directly altered tumor cell invasion and migration. Rather, OPN expression levels were positively correlated with M2-like TAMs infiltration. The co-culture system revealed bidirectional chemotactic interactions between CRC cells-derived OPN and M2-like TAMs. Mechanistically, high OPN expression activates the PI3K/AKT signaling pathway in macrophages, promoting the secretion of CSF1, which induces M2-like polarization of macrophages to facilitate tumor metastasis. Finally, in a mouse metastasis model, blocking the CSF1/CSF1R axis with a CSF1R inhibitor reduced the M2-like TAMs recruitment and CRC tumor metastasis burden. Our study demonstrates that the OPN/PI3K/AKT/CSF1-CSF1R axis plays a crucial role in CRC metastasis. Blocking the CSF1/CSF1R axis reduces M2-like TAMs infiltration and tumor metastasis, offering a promising strategy for metastatic CRC.

Pancreatic ductal adenocarcinoma (PDAC) presents significant treatment challenges, primarily due to its propensity for developing resistance to therapeutic interventions. While the underlying mechanisms remain elusive, they are closely associated with mitochondrial adaptation in response to treatment. Mitophagy, a selective subtype of autophagy that eliminates damaged or surplus mitochondria, is crucial for tumorigenesis, progression, and treatment resistance in cancers. This review discusses the intricate regulatory pathways of mitophagy in PDAC, focusing on the PINK1/Parkin pathway and receptor-mediated pathways. Furthermore, it explores the therapeutic potential of targeting mitophagy to increase the effectiveness of existing treatments and improve patient survival. Current evidence indicates that combining mitophagy inhibition with conventional chemotherapy yields promising yet inconsistent results, which may be attributed to the context-dependent functions of mitophagy and a lack of specific inhibitors. This review highlights the therapeutic potential of targeting mitophagy in PDAC and underscores the necessity for biomarker-driven patient stratification and the development of pathway-specific modulators in future clinical efforts.

Osteosarcoma (OS) is the most common primary malignant bone tumor mainly affecting children and young adults. Despite current treatments combining polychemotherapy and surgery, survival rates have remained unchanged for decades, highlighting the need to identify novel therapeutic approaches. NXP800, a newly developed orally available molecule, represents a promising therapeutic option. The therapeutic efficacy of NXP800 was evaluated in vitro and in a preclinical murine xenograft model of OS. RNA-seq analysis and functional assays were conducted to investigate the mechanisms of action and molecular target of NXP800. NXP800 decreases the viability of OS cell lines by blocking proliferation and inducing apoptosis. Mechanistically, NXP800 activates the Unfolded Protein Response (UPR), as demonstrated by eIF2α phosphorylation and ATF4 upregulation. This effect is mediated through the engagement of the Integrated Stress Response (ISR) via the activation of GCN2 kinase. Inhibition of GCN2, either through molecular or pharmacological approaches, abolishes NXP800-induced eIF2α phosphorylation and partially restores OS cell viability. Furthermore, NXP800 activates the IRE1α/JNK/c-Jun pathway while increasing the expression of the pro-apoptotic protein Puma. Finally, NXP800 delays tumor growth in preclinical OS model by promoting apoptosis. This study is a preclinical proof-of-principle of therapeutic efficacy of NXP800 both in vitro and in vivo, highlighting the relevance of targeting GCN2, and consequently activating the ISR and UPR, to induce apoptosis and inhibit tumor progression in OS.

While androgen receptor (AR) pathway inhibitors such as enzalutamide have demonstrated significant therapeutic efficacy in prostate cancer (PCa) treatment, the inevitable development of acquired resistance continues to pose a major clinical challenge in managing advanced PCa. We characterized Neurexophilin 4 (NXPH4) as a contributor to enzalutamide resistance (EnzR). Gain- and loss-of-function studies were conducted in PCa cell lines and mouse subcutaneous xenograft models to elucidate the role of NXPH4 in castration-resistant prostate cancer (CRPC). Additionally, the regulatory mechanisms of gene expression were assessed using a series of molecular and biochemical experiments. Our study demonstrates that AR as a transcriptional activator of NXPH4. Elevated NXPH4 expression facilitated PCa proliferation under enzalutamide treatment through mitochondrial metabolic reprogramming. We identified that NXPH4 partially localizes to mitochondria and physically interacts with aldehyde dehydrogenase 1 family member L2 (ALDH1L2), a critical enzyme in one-carbon metabolism. Androgen deprivation stimulated NXPH4 mitochondrial translocation and enhanced its binding to ALDH1L2. NXPH4-mediated metabolic reprogramming promotes PCa progression. Notably, the combination of NXPH4 knockdown and enzalutamide treatment showed potent synergistic effects, significantly suppressing cell proliferation in vitro and substantially inhibiting tumor growth in vivo. These findings reveal a previously unrecognized mechanism of EnzR and identify the NXPH4-ALDH1L2 complex as a promising therapeutic target for CRPC treatment.

Regulatory T (Treg) cells perform immunosuppressive functions in rapid response to genetic and environmental stress for maintaining the immune balance, which play a physiological role in preventing autoimmune and inflammatory diseases. Given the highly dynamic and reversible nature of small ubiquitin-like modifier (SUMO) modification, along with the predominant nuclear localization of SUMO paralogs and their associated enzymes, SUMOylation is essential for the flexible regulation of key nuclear processes in Treg cells, such as membraneless organelle formation, genome integrity, and cell cycle progression. Notably, SUMO:SUMO-interacting motif (SIM) interactions facilitate the formation of regulatory complexes that govern cellular processes, and enable crosstalk with other post-translational modifications (PTMs), particularly ubiquitination, phosphorylation, acetylation, and methylation, which are globally harnessed by Treg cells in various contexts to regulate key processes of protein stability, signaling pathways, transcriptional reprogramming, and epigenetic modifications, thereby fine-tuning their immune-regulatory responses. This review explores the multifaceted roles of SUMOylation in Treg cell biology, emphasizing its influence on differentiation, maturation, transcriptional and epigenetic regulation, and metabolic reprogramming. By delineating these pathways, we aim to uncover how dysregulation of SUMOylation may be destined to Treg cells mediated immune disorders, providing a foundation for therapeutic interventions.