Cell Death Discovery最新文献

Dysregulated mitochondrial dynamics and macrophage-driven inflammation are essential contributors to the pathogenesis of acute kidney injury (AKI). Although the chemokine CX3CL1 has been associated with inflammatory responses, its role in AKI, particularly in regulating macrophage polarization and mitochondrial function, remains unclear. In this study, we investigated the therapeutic potential of CX3CL1 inhibition in a lipopolysaccharide (LPS)-induced AKI model. Our results found that CX3CL1 deficiency could significantly ameliorate renal dysfunction and attenuate inflammatory responses. RNA sequencing revealed that CX3CL1 deficiency alters macrophage subpopulations and gene expression profiles in the kidney, particularly affecting pathways related to immune responses and mitochondrial function. Mechanistically, the absence of CX3CL1 promotes macrophage polarization from a pro-inflammatory M1 phenotype toward an anti-inflammatory M2 phenotype. Furthermore, CX3CL1 inhibition improves mitochondrial dynamics, alleviates mitochondrial dysfunction, and reduces oxidative stress and mitochondrial DNA (mtDNA) leakage, thereby preserving mitochondrial integrity. Notably, CX3CL1 knockdown suppresses activation of the cGAS-STING pathway, a key mediator of inflammation triggered by cytosolic mtDNA. We also observed that these effects appear to be mediated through stabilization of mitochondrial transcription factor A (TFAM). Collectively, these findings identify CX3CL1 as an essential regulator of macrophage mitochondrial function and inflammation in AKI, offering a potential therapeutic target for mitigating kidney injury.

Non-small cell lung cancer (NSCLC) is characterized by the deregulation of the Hippo kinase NDR2 and high basal autophagic activity. NDR2 promotes autophagy-driven tumor growth in some cancers, but evidence in lung cancer is lacking. Human bronchial epithelial tumor cell (HBEC) lines H2030, H2030-BrM3, and H1299, with or without NDR2 depletion via siRNA or shRNA, were cultured for up to 24 h in the presence or absence of serum, and with or without the autophagosome-lysosome fusion inhibitor chloroquine (CQ). Autophagosome biogenesis, migration and Golgi apparatus functionality were analyzed. Serum deprivation of HBECs silences the expression of NDR1 but not NDR2. As shown by the increased expression of the autophagosome marker LC3-II, NDR2 participates to the formation and distribution of phagophores/autophagosomes in HBECs in an ATG9A-dependent manner. NDR2 is required for cargos degradation since its depletion disrupts lysosomal trafficking and/or fusion with autophagosomes. Finally, NDR2 silencing inhibits filopodia formation and cell polarization during HBEC migration under serum deprivation by disrupting Golgi repositioning to the leading edge, a process essential for cell migration. These data highlight NDR2's role in Golgi- and autophagy-regulated migration during starvation. Unlike NDR1, NDR2 is stabilized under starvation and promotes autophagy by regulating LC3 and ATG9A, thereby supporting NSCLC cell proliferation and migration. Routine staining for NDR2 and/or ATG9 could aid in diagnosing NSCLC with high migratory potential.

Parkinson's disease (PD) is histopathologically defined by the presence of Lewy bodies, which are intracellular proteinaceous inclusions that contain mainly aggregated alpha-synuclein (aSyn). It is believed that oligomeric intermediates between monomeric aSyn and large aggregates are neurotoxic, which would lead to the demise of dopaminergic neurons. Therefore, novel therapies preventing aSyn-induced cell death need to be developed. Therefore, we performed a genome-wide siRNA screening in an aSyn-induced dopaminergic cell death model and found the knockdown of three transforming growth factor-beta (TGFb) pathway-related genes to be protective. Hence, we hypothesized that a reduction in TGFb signaling would protect dopaminergic neurons from aSyn-induced toxicity. Thus, we validated the results of the genome-wide knockdown screening with the use of two different types of siRNAs. We confirmed that the knockdown of Activin receptor-like kinase 5 (ALK5) and Mothers against decapentaplegic homolog 2 (SMAD2), two genes of the TGFb pathway, protected dopaminergic neurons from aSyn-induced toxicity. An increase in TGFb signaling by treatment with TGFb ligands further exacerbated aSyn-induced toxicity, whereas this effect was mitigated by knockdown of ALK5, SMAD2, or Dynein light chain roadblock type-1 (DYNLRB1). Moreover, TGFb ligand treatment induced an up-regulation of SNCA mRNA expression in aSyn-overexpressing cells. Interestingly, consistent with the literature, we identified an up-regulation of the genes of the TGFb pathway in aSyn-overexpressing cells. Altogether, we identified a potential protective role by interference with the TGFb pathway against aSyn-induced toxicity. These findings provide a rationale for the development of novel strategies against PD.

Colorectal cancer (CRC) ranks as a leading cause of cancer-related mortality worldwide, yet its molecular mechanisms remain incompletely understood. The transcription factor LBX2 regulates morphogenesis of multiple organ systems in vertebrates, yet its role in CRC progression remains poorly understood. In the study, we found that LBX2 knockdown suppresses CRC proliferation in vitro and in vivo. ChIP-seq/RNA-seq identifies GFPT2 as a direct transcriptional target of LBX2. The LBX2/GFPT2 axis elevates UDP-GlcNAc levels and O-GlcNAcylation, promoting Raptor T700 glycosylation. This modification enhances mTORC1 activation by strengthening Raptor-Rag interactions, accelerating glycolysis and lactate production. Accumulated lactate induces histone H4K12 lactylation, which further upregulates LBX2 transcription, forming a positive feedback loop. Clinically, high LBX2 expression correlates with elevated PET-CT SUVmax values (indicating hyperglycolysis) in CRC patients. Patient-derived organoids with high LBX2 show increased sensitivity to the GLUT1 inhibitor. LBX2 thus serves as both a metabolic driver and a potential biomarker for CRC-targeted therapies.

Disulfiram (DSF), a clinically approved anti-alcoholism drug, exerts anti-tumor activity through its copper metabolite CuET by inhibiting the ubiquitin-proteasome system (UPS). However, its regulatory mechanisms on autophagy and potential for combination therapy remain to be clarified. Here, we revealed that DSF activates autophagy in colorectal cancer (CRC) cells via dual mechanisms: compensatory autophagy induction through proteasome inhibition by targeting the p97-NPL4 axis, and transcriptional upregulation of the autophagy-related gene BECN1 via FOS gene activation. Transcriptomic analysis identified that DSF enhances c-Fos expression, promoting c-Fos/AP-1 complex binding to the BECN1 promoter to drive beclin-1 expression. Furthermore, combining DSF with the autophagy inhibitor chloroquine (CQ) synergistically enhanced anti-tumor efficacy both in vitro and in vivo. DSF-induced autophagy may mitigate its pro-apoptotic effects, while autophagy inhibition fully blocks protein degradation pathways, leading to lethal protein accumulation. This study elucidates DSF's dual regulation of autophagy through UPS suppression and the c-Fos/beclin-1 axis, and validates the synergistic efficacy of DSF combination with CQ in CRC, providing a theoretical foundation and translational potential for DSF-based combination therapies.

Cancer cells rewire their metabolism to sustain the high proliferative rate. Metabolism is therefore a common vulnerability of cancer cells, successfully exploited for therapeutic purposes. Intrinsic tumor characteristics and adaptive responses of cancer cells can however reduce the short and long-term efficacy of such a strategy. Understanding the determinants of therapy response and the mechanisms of chemoresistance is crucial to maximize therapy efficacy. In cancer, lysosomes undergo massive changes in their localization, size, and composition that support tumor progression. Additionally, lysosomes are one of the crucial drivers of chemoresistance via the drug sequestration or by facilitating adaptations to stress conditions. In the last decades, several reports have shown that lysosomal membrane proteins, such as the lysosome-associated membrane proteins 1 and 2 (LAMP1 and LAMP2), are deregulated in different cancer types and their expression has been correlated to drug efficacy. We performed an in silico gene essentiality and drug sensitivity screenings, revealing that LAMP2 expression is one of the determinants of resistance to inhibitors of de novo purine synthesis. In vitro experiments confirmed the in silico data and also showed that purine synthesis inhibitors trigger a ROS- and transcriptional-dependent increase of LAMP2. Our results identify the upregulation of LAMP2 expression as an adaptive response to purine synthesis inhibition to preserve cell viability and, in those tumors showing high LAMP2 levels, could also be an indicator of intrinsic resistance to these drugs that may be taken into consideration during the selection of the most appropriate therapy.

Bone regeneration is a tightly coordinated process involving multiple cellular and molecular components, with emerging evidence highlighting the pivotal role of the nervous system, especially the sympathetic nervous system, in modulating skeletal repair. However, the mechanistic details of neuro-skeletal interactions during bone healing remain elusive. Here, we inhibited peripheral sympathetic nerves using 6-hydroxydopamine (6-OHDA) in a murine calvarial defect model and performed single-cell RNA sequencing on the injury sites at 7 and 14 days post-injury to delineate the cellular landscape underlying regeneration. Our analyses revealed activation of neurogenesis-associated pathways and dynamic crosstalk between neural and skeletal cells following injury. Sympathetic nerve inhibition significantly enhanced calvarial bone repair, characterized by downregulation of Capn6 in suture mesenchymal cells, increased formation of H-type blood vessels, and the emergence of a distinct macrophage subset exhibiting senescence-associated phenotypes. Importantly, pharmacological clearance of senescent cells by senolytic agents abrogated the regenerative benefits conferred by sympathetic blockade. Mechanistically, sympathetic inhibition promoted angiogenesis and osteogenesis by facilitating interactions between suture mesenchymal cells and endothelial cells, while the senescent-like macrophages contributed to bone repair via secretion of osteogenic cytokines. Collectively, these findings uncover a critical role of sympathetic nerves in regulating the bone healing niche and identify potential therapeutic targets to enhance skeletal regeneration. These insights may pave the way for the development of neuromodulatory or senescence-targeted therapies to promote bone repair in challenging clinical scenarios such as cranial bone defects, non-union fractures, or aging-associated impaired healing.

Circulating tumor cells (CTCs) play a critical role in the metastatic cascade and have emerged as promising biomarkers for cancer diagnosis, prognosis, and therapeutic monitoring. In breast cancer, CTCs mediate bone metastasis through intricate interactions with the bone microenvironment, regulating process such as homing, dormancy, reactivation, and colonization. Advances in CTC detection and characterization have deepened our understanding of their physical and biological properties, yet significant technical and biological challenges remain. This review provides a comprehensive overview of the roles of CTCs in breast cancer bone metastasis and highlighting their clinical significance, current limitations, and future applications.

Endothelial dysfunction-driven vascular inflammation underlies sepsis and atherosclerosis. Piezo1 serves as a central mediator for endothelial mechanotransduction and inflammatory homeostasis. Nevertheless, the transcriptional pathways linking mechanical sensing to anti-inflammatory protection and the exact composition of its downstream signaling cascade remain incompletely resolved. Here, we identify BHLHE40 as an endothelial mechanosensitive transcription factor induced by Piezo1 that coordinates ferroptosis resistance and inflammation suppression. Mechanistically, shear stress activates Piezo1, triggering Ca²⁺ influx and calcineurin-dependent NFAT2 nuclear translocation. NFAT2 recruits HDAC1 to form a transcriptional complex that directly drives BHLHE40 expression. BHLHE40 then binds the SLC7A11 promoter, upregulating this cystine transporter to inhibit ferroptosis. Rescued mitochondrial integrity, reduced ROS, and reversed lipid peroxidation demonstrated this phenomenon. Crucially, mice with endothelial-specific BHLHE40 overexpression attenuate LPS-induced lung vascular leakage, neutrophil infiltration, and pro-inflammatory cytokine release. Our work establishes the Piezo1/Ca²⁺/calcineurin/NFAT2-HDAC1/BHLHE40/SLC7A11 axis as a master mechanotransduction pathway that transcriptionally maintains endothelial homeostasis.

Tobacco use, including both traditional and electronic cigarettes, profoundly alters host-microbiota interactions, contributing to the pathogenesis of various systemic diseases. Smoking-induced microbial dysbiosis impacts multiple anatomical sites, including the oral cavity, respiratory tract, and gastrointestinal system, driving disease progression through mechanisms such as immune modulation, chronic inflammation, and metabolic dysregulation. This review examines the disruption of microbial ecosystems by smoking, with a focus on the imbalance between beneficial and pathogenic microorganisms. In the oral cavity, smoking is strongly linked to diseases such as periodontitis and oral cancer, marked by shifts in microbial diversity and functional profiles. Similar dysbiotic changes are observed in the respiratory and gastrointestinal systems, where smoking impairs mucosal immunity, increases oxidative stress, and compromises barrier integrity, thereby enhancing susceptibility to chronic diseases. Additionally, the review addresses the challenges in establishing causality between microbial changes and disease outcomes, emphasizing the need for more comprehensive research utilizing multi-omics approaches and longitudinal studies. By exploring the potential for microbiota-based interventions, this review underscores the critical role of microbial dysbiosis in smoking-related health risks, providing valuable insights for the development of targeted therapeutic strategies to mitigate the global health burden of tobacco use.