Cell Death Discovery最新文献

Several microRNAs play vital roles in placental development. miR-155 has been implicated in placental development and can directly interact with a variety of targets, including angiotensin type II receptor 1 (AT₁R) (Agtr1) mRNA. The AT₁R is pro-proliferative and promotes early placental development. We therefore tested the hypothesis that miR-155 downregulates Agtr1 mRNA expression and impairs placental development. Placentae and fetuses from wild-type C57Bl/6 mice (miR-155^+/+, control) and C57Bl/6 mice with a null mutation in miR-155 (miR155^-/-) were mated with males of the same genotype and analyzed on gestational day 18.5, when placental morphology and miR-155 and AGTR1 expression were assessed. Additionally, HTR8/SVneo cells were cultured with a miR-155 mimic to determine the effects on trophoblast proliferation, migration and invasion. miR-155^-/- dams produced significantly heavier pups with unchanged placental weights and fetal-to-placental weight ratios. Placentae from miR-155^-/- dams had significantly larger labyrinth zones and labyrinth-to-placental area ratios than controls, with altered stereological parameters. Placental Agtr1 mRNA and AGTR1 protein levels were significantly increased in miR-155^-/- dams. Finally, in vitro treatment in human HTR-8/SVneo cells with the miR-155 mimic increased miR-155 expression, decreased AGTR1 mRNA levels and decreased the rates of trophoblast cell proliferation, migration and invasion. Thus, miR-155 is demonstrated to attenuate placental development in mice. We propose that this is at least partly due to its effects on the AT₁R.

Mitochondrial dysfunction is one of the core drivers of aging. It is manifested by reactive oxygen species (ROS) accumulation, mitochondrial DNA (mtDNA) mutations, imbalanced energy metabolism, and abnormal biosynthesis. Mitochondrial autophagy maintains cellular homeostasis by selectively removing damaged mitochondria through mechanisms including the ubiquitin-dependent pathway (PINK1/Parkin pathway) and the ubiquitin-independent pathway (mediated by receptors such as BNIP3/FUNDC1). During aging, the decrease in mitochondrial autophagy efficiency leads to the accumulation of damaged mitochondria, forming a cycle of mitochondrial damage-ROS-aging damage and aggravating aging-related diseases such as neurodegenerative diseases and cardiovascular pathologies. The targeted regulation of mitochondrial autophagy (drug modulation and exercise intervention) can restore mitochondrial function and slow aging. However, autophagy has a double-edged sword effect; moderate activation is anti-aging, but excessive activation or dysfunction accelerates the pathological process. Therefore, targeting mitochondrial autophagy may be an effective anti-aging technique; however, future focus should be on the tissue-specific regulatory threshold and the dynamic balance mechanism to achieve precise intervention.

Monkeypox virus (MPXV) is a globally reemerging pathogen that poses a significant threat to public health, representing the most impactful Orthopoxvirus infection in humans since the eradication of smallpox. Macroautophagy (hereafter referred to as autophagy) is an evolutionarily conserved catabolic process essential for maintaining cellular homeostasis, and it can exert either pro-viral or anti-viral effects during infections. Poxviruses interaction with the autophagy machinery remains poorly understood, and the specific interplay between MPXV and autophagy has not been documented. In this study, we infected Calu-3 cells with MPXV and observed that the virus significantly impairs autophagic flux by upregulating Rubicon, a known negative regulator of autophagy. Notably, silencing Rubicon restored autophagic flux and led to a marked reduction in MPXV replication. Overall, our findings reveal a novel mechanism by which MPXV inhibits autophagy through the modulation of Rubicon, suggesting that autophagy activation may be a potential therapeutic strategy for MPXV.

Loss-of-function variants in the ferredoxin reductase (FDXR) gene result in a primary mitochondrial disease in humans, involving abnormal mitochondrial iron accumulation. However, the molecular mechanism is not fully understood. To better understand the underlying pathology of FDXR-related disease, we generated a mouse model corresponding to the hotspot variant found in humans. We demonstrated increased lipid peroxidation in the inner mitochondrial and plasma membranes, resulting in susceptibility to ferroptosis. Closer examination revealed that disruption of the NRF2 pathway and its target gene SLC7A11 appear to play important roles in this pathogenic process. Finally, administration of the NRF2 activator omaveloxolone, which was recently approved by the FDA for treatment of Friedreich's ataxia, helps mitigate the pathogenesis. Together, our results suggest that ferroptosis is a novel underlying mechanism of FDXR-related disease and that activation of NRF2 could be an immediate, viable treatment option for individuals with FDXR-related disease and other conditions involving aberrant iron metabolism.

Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive malignancy with limited therapeutic options. Although targeted therapies like pemigatinib provide partial clinical benefits, acquired resistance remains a significant challenge. Through integrative bioinformatics analysis of public datasets and immunohistochemical validation, we identified the retinoid-related orphan receptor gamma (RORγ) as markedly upregulated in iCCA. Genetic silencing and pharmacological inhibition of RORγ (GSK805/XY101) suppressed proliferation, induced apoptosis in vitro, and significantly reduced xenograft tumor growth in vivo. Mechanistically, RORγ promoted fibroblast growth factor receptor 2 (FGFR2) signaling via two complementary mechanisms: direct transcriptional activation of FGFR2 and induction of fibroblast growth factor 1 (FGF1) expression and secretion, which in turn activated FGFR2. Inhibition of RORγ markedly decreased FGF1 levels in conditioned media, whereas exogenous FGF1 restored tumor growth. Notably, RORγ antagonists synergized with pemigatinib to overcome resistance in pemigatinib-refractory models. Collectively, these findings identify the RORγ-FGF1-FGFR2 axis as a critical oncogenic driver in iCCA and highlight RORγ inhibition as a promising therapeutic strategy to suppress tumor progression and enhance sensitivity to FGFR inhibitors.

Parkinson's disease (PD) is a challenging neurodegenerative disorder. Recently, therapy of neural stem cells (NSCs) derived from human induced pluripotent stem cells (hiPSCs) has emerged as a significant advancement in regenerative medicine. Melatonin (MT), acting as a mitochondrial targeting hormone, exhibits neuroprotective properties in neurodegenerative diseases and modulates stem cell differentiation through mitochondrial dynamics. However, the precise mechanism by which MT influences dopaminergic (DA) neuronal differentiation in hiPSCs through regulating mitochondrial dynamics remains unclear. In this study, we developed and optimized a technical protocol for the in vitro functional neuronal differentiation of hiPSCs. Our findings demonstrate that MT enhances the differentiation potential of hiPSCs toward neuroectoderm and significantly improves the efficiency of NSCs differentiation into DA neurons by more than three times within hiPSCs. Using the specific MT receptor inhibitor, Luzindole, we confirmed its inhibitory effect on MT-mediated promotion of neural differentiation. Mechanistically, we propose that MT enhances functional DA neuron differentiation from hiPSCs by activating mitochondrial dynamics-mediated WNT/β-catenin signaling pathways. Additionally, we elucidated the critical role of mitofusin2 (MFN2) in enhancing the directed differentiation of DA neurons from hiPSCs. In vivo studies validated the efficacy of MT-treated hiPSC-derived DA progenitor cells in regenerating tyrosine hydroxylase (TH)-positive DA neurons and improving motor function in a MPTP-induced mouse model of Parkinson's disease. In conclusion, this study highlights the potential clinical relevance of MT-enhanced differentiation of hiPSCs into DA neurons, offering promising implications for the treatment of PD. Melatonin orchestrates mitochondrial fusion dynamics-mediated WNT/β-catenin signaling to promote dopaminergic neuronal differentiation of human iPS and nerve regeneration in a MPTP-induced mouse model of Parkinson's disease.

RecQ family of DNA helicases play pivotal roles in DNA replication, repair and responses to DNA damage or replication stress. Several human RecQ helicases are defective in diseases associated with chromosomal instability, premature aging and cancer. We recently discovered novel mutations in the RECQL4 gene in glioblastoma (GBM), the most malignant brain tumor in adults. Transcriptomic profiles of GBMs with REQCL4 mutations resembled those in REQCL4 KO glioma cells. We employ structural modelling and biochemical approaches to elucidate impacts of novel mutations on RECQL4 helicase activities. Using recombinant RECQL4_P532S and RECQL4_R766Q proteins we demonstrate that P532S substitution reduces the RECQL4 ability to unwind DNA and disrupts DNA-coupled ATP-hydrolysis activity. WT and mutated RECQL4 were overexpressed in RECQL4 KO glioma cells to study interactions with BLM helicases, cell viability and specific responses to UVC- and chemotherapy-induced DNA damage/repair. Overexpression of RECQL4_P532S or RECQL4_R766Q variants affected DNA repair and responses to chemotherapeutics in glioma cells, and RECQL4_R766Q disturbed interactions with the BLM helicase. Our results reveal deleterious consequences of novel RECQL4 mutations in GBMs. The newly identified RECQL4 mutations affect RECQL4 helicases and their interactions with BLM contributing to glioma progression.

In response to DNA damage or DNA replication stress, cells activate signaling pathways dependent on the kinase, ATR (Ataxia Telangiectasia and Rad3-Related). ATR signaling leads to induction of cell cycle checkpoints, a pause in DNA replication, and upregulation of DNA repair activities. In response to replication stress, ATR is activated by TOPBP1 (Topoisomerase II beta-Binding Protein 1) associated with the 9-1-1 (Rad9-Hus1-Rad1) complex. The three proteins that make up the 9-1-1 complex form a ring encircling DNA at damage sites and help localize TOPBP1 and ATR to signal the presence of damage or replication stress. RHNO1 (Rad9, Hus1, and Rad1-associated Nuclear Orphan 1) was identified as a protein that binds to components of the 9-1-1 complex to promote ATR signaling. Previous studies in cell lines have revealed that RHNO1 activity is required for maintenance of the G₂M cell cycle checkpoint after ionizing radiation treatment, and for DNA repair in mitotic cells. In this study, we report a loss-of-function mouse model, in which Rhno1 is deleted in B lymphocytes, allowing us to test the function of RHNO1 in primary cells. We find that RHNO1 is broadly expressed in mouse tissues but is dispensable for B cell growth under normal conditions. RHNO1-deficient B cells nevertheless show altered checkpoint responses and reduced ability to repair DNA damage in M phase. Whereas initial ATR activation after ionizing radiation treatment appears normal in RHNO1-deficient cells, ATR/CHK1 signaling is reduced at later timepoints. Joining of DNA breaks during class switch recombination, which is dependent on nonhomologous end-joining, is not significantly affected by loss of RHNO1. These results demonstrate that RHNO1, unlike other proteins required for ATR-CHK1 signaling, is not essential for growth of primary cells, but has specific roles in regulating responses to cell stress.

Endoplasmic reticulum stress (ERS) dynamically regulates cell fate decisions within the tumor microenvironment (TME) through the PERK, IRE1α, and ATF6 pathways of the unfolded protein response (UPR), forming an "ERS-Death Axis" interconnected with apoptosis, autophagy, pyroptosis, and ferroptosis. Its molecular network involves CHOP-mediated apoptotic imbalance, NLRP3 inflammasome-activated pyroptosis, the ATF4-CHAC1 axis-driven ferroptosis, and the dual roles of autophagy (protective or pro-death). Oxidative stress further amplifies the biological functions of this network. The ERS-Death Axis exhibits significant heterogeneity across different tumors. Therapeutic strategies targeting this axis have demonstrated clear potential, including specific modulation of core UPR molecules, pathway activation by natural compounds, synergistic combinations with immune checkpoint inhibitors and metabolic interventions, and enhanced targeting and efficacy through nanodelivery systems. However, clinical translation faces key challenges such as tumor heterogeneity, drug delivery efficiency, and complex resistance mechanisms. In-depth elucidation of the tumor-specific mechanisms underlying the ERS-Death Axis will provide crucial theoretical support for overcoming bottlenecks in cancer therapy and optimizing combination treatment regimens, propelling this axis to become a core target for precision oncology.

Members of the evolutionarily conserved homeodomain-interacting protein kinase (Hipk) family play a critical role in regulating essential signalling pathways involved in growth, differentiation, and apoptosis. While vertebrates have multiple hipk genes, Drosophila contains a single hipk ortholog, what facilitates functional analysis. We find that hipk is necessary for the stabilization of the initiator caspase Dronc, thus enhancing the two Dronc activities in apoptotic scenarios: the induction of the caspase cascade, and the reinforcement of JNK signalling pathway. Conversely, our data suggest that Dronc also raises the expression levels of Hipk, thereby reinforcing the apoptotic response. These findings significantly enhance our understanding of caspase regulation and position Hipk as a promising target for modulating caspase activity in a variety of biological contexts.