Cell Death Discovery最新文献

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.

Cerebral malaria (CM) is associated with dysregulated immune response against the blood stage of malaria parasite that often leads to serious organ damage, ultimately causing fatal pathological complications. Conventional treatments, although effective in controlling the parasite, often fail to address the severe immunopathology associated with the disease. Herein, we investigated the therapeutic potential of Mesenchymal stem cells (MSCs) in managing the excess proinflammatory response and maintaining immune homeostasis in Plasmodium berghei ANKA (PbA) infected C57BL/6 mice, an experimental cerebral malaria (ECM) disease model. Parasitemia and survival were monitored regularly, along with the neurological complications associated with the disease. Immunophenotyping, along with programmed cell death analysis of splenocytes, was also done via flow cytometry, and cytokine levels were analyzed at different time points in serum, as well as spleen, through bioplex assay and qRT-PCR. It was found that MSC effectively reduced parasitemia, increased survival, and decreased hemozoin accumulation in spleens of PbA-infected mice, along with improving brain pathology by preventing vascular leakage and protecting the blood-brain barrier (BBB). MSCs not only rescued the lymphocytes from apoptosis by downregulating PD-1/PD-L1 and ROS levels but also effectively modulated the Th17/Treg imbalance and maintained immune homeostasis by downregulating Interleukin-6 (IL-6) and Interleukin-17 (IL-17) cytokines and upregulating Interleukin-10 (IL-10) cytokine in infected mice. For the first time, we reported that MSCs were able to induce a dual phenotype effector Treg cell subset (Tr17), which are known to express both RoRγt and Foxp3 transcription factors, which were highly suppressive against pathogenic Th17 cells as they significantly downregulated IL-17 expression in Th17 cells. In conclusion, our findings offer insight into how the infusion of MSCs reduces the severity of experimental CM by modulating Th17/Treg balance and inducing Tr17 effector Treg response against Th17 cells. Thus, MSCs could potentially be used as an adjunct therapy for addressing the immunopathological complications of CM.

Hypopharyngeal squamous cell carcinoma (HPSCC) is a highly aggressive malignancy with a poor prognosis. This study elucidates the role of the E3 ubiquitin ligase Tripartite Motif Containing 15 (Trim15) and its substrate, mitochondrial voltage-dependent anion channel 3 (VDAC3), in regulating autophagy, mitophagy, and chemoresistance in HPSCC. We found that Trim15 is significantly downregulated in HPSCC tissues and inhibits cell proliferation and migration in FaDu and Detroit 562 cells. Trim15 stabilizes VDAC3 via K6-linked ubiquitination, thereby suppressing autophagy and mitophagy while elevating reactive oxygen species (ROS) levels. VDAC3 knockdown enhances autophagy and mitophagy, concomitantly reducing ROS and promoting cancer cell survival. High-concentration ethanol suppresses Trim15 and VDAC3 expression, suggesting an adaptive response to oxidative stress. Notably, chloroquine (CQ), an autophagy inhibitor, enhances HPSCC sensitivity to 5-fluorouracil (5-FU), with synergistic effects observed in xenograft models. These findings establish the Trim15-VDAC3-mitophagy axis as a critical regulator of HPSCC progression and chemoresistance, offering a novel therapeutic target for augmenting the efficacy of autophagy inhibitors in combination with standard chemotherapy.

Natural products have emerged as promising therapeutic agents for targeting redox vulnerabilities in cancer. Rottlerin, a bioactive polyphenol derived from Mallotus philippinensis, exhibits broad anticancer properties through autophagy and apoptosis induction. However, its capacity to modulate ferroptosis, a druggable form of iron-dependent cell death, remains unexplored in hepatocellular carcinoma (HCC). Here, we demonstrate that rottlerin potently inhibits HCC proliferation by triggering ferroptosis execution, as evidenced by lipid peroxidation accumulation and ferroptosis inhibitor (ferrostatin-1)-rescued cell death. Strikingly, subtherapeutic doses of rottlerin enhanced the efficacy of clinical ferroptosis inducers (RSL3 and sorafenib), and this chemosensitization effect persisted in PKCδ-depleted models, indicating a target-agnostic mechanism. Mechanistically, rottlerin orchestrates ubiquitin-proteasomal degradation of two central ferroptosis defense nodes: the cystine transporter SLC7A11 and glutathione peroxidase 4 (GPX4), thereby compromising cellular antioxidant capacity. This dual-degradation strategy distinguishes rottlerin from single-target phytochemicals and underlies its robust ferroptosis induction. Our work provides the first demonstration of rottlerin's ferroptotic activity in HCC, positioning it as a dual degrader capable of overcoming compensatory antioxidant adaptations. These findings advocate for rottlerin's clinical development either as monotherapy or in rational combinations to augment ferroptosis-targeted HCC treatment.