Experimental and Molecular Medicine最新文献

CD169⁺ macrophages, a unique subset of macrophages that cannot be simply defined as M1 or M2 macrophages, have been reported to be associated with various autoimmune diseases. However, the role of CD169⁺ macrophages in autoimmune hepatitis (AIH) is largely unknown. Here we found that the infiltration of CD169⁺ macrophages increased in the liver of patients with AIH and strongly positively correlated with inflammation degree. In a mouse model, depletion of CD169⁺ macrophages ameliorated ConA-induced acute liver injury. Immune homeostasis was also improved when CD169⁺ macrophages were depleted, as the infiltration of monocytes, macrophages and T cells decreased. Bone marrow-derived Ly6C^hiCD169⁺ macrophages were further identified as the crucial subset in AIH. Next, we found that CD169⁺ macrophages were IFNγ-responsive and IFNγ could induce the expression of CD169. In response to the IFNγ signal, CD169⁺ macrophages actively secrete chemokine (C-C motif) ligand (CCL12), thus recruiting CCR2⁺ monocytes and macrophages to exacerbate AIH. Finally, neutralizing CCL12 improved AIH. Our results suggest that bone marrow-derived CD169⁺ macrophages, the key subset of macrophages in AIH, actively secrete CCL12 in response to IFNγ to recruit CCR2⁺ monocytes and macrophages, thus exacerbating AIH. The CD169⁺ macrophages are a potential therapeutic target in AIH.

Although considerable research has focused on enhancing the apoptotic function of BAX for several decades, inhibition of its functionality remains relatively underexplored, despite intensive BAX activation occurring in various neurodegenerative diseases. Here we present a protein engineering approach to modulate BAX integration into the mitochondrial outer membrane, establishing a tunable strategy for antiapoptosis. Utilizing optogenetic methods that employ cryptochrome 2 and its binding partner cryptochrome-interacting basic helix loop helix 1, we achieved precise spatial control over BAX localization, a critical determinant of its function. Our results demonstrate that the engineered BAX variant is effectively incapacitated in its apoptotic function while also modulating endogenous BAX activity to enhance cellular resistance to apoptosis. These findings not only advance our understanding of BAX regulation but also offer promising prospects for the development of therapeutic strategies against apoptosis-related diseases.

The tumor microenvironment (TME) is often hypoxic. EGLN1, which encodes the oxygen sensor PHD2, plays a crucial role not only in the survival of cancer cells but also in regulating other cell types that reside in the TME. In this Review, we explore the role of this protein in some of the key components of the TME, focusing on the functions of EGLN1/PHD2 in endothelial, stromal and immune cells. So far, the activity of EGLN1/PHD2 has been characterized in different cell types, albeit with controversial outcomes in different cancer settings. This Review aims to discuss the role of EGLN1/PHD2 in the TME and the strategies targeting this protein that might be used to hit tumors.

Ferroptosis, a newly discovered type of regulatory cell death with iron-dependent accumulation of lipid peroxides, is widely discussed in a plethora of neurological disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, stroke, traumatic brain injury and spinal cord injury. There are many preclinical and clinical evidences supporting the critical role of ferroptosis in these neurologic conditions, despite the molecular machinery by which ferroptosis modulates brain dysfunction remains uncharacterized. Transcription factors (TFs) are core components of the machinery that manipulates ferroptosis process genetically. Until now, there is no report on the summarization of role of ferroptosis-associated TFs in neurological diseases. Therefore, here we provided the basic knowledge regarding the regulation of TFs on ferroptotic processes including iron metabolism, antioxidant defense and lipid peroxidation. In addition, we also discussed the recent advances in our understanding of ferroptosis-related TFs in the emerging hallmarks of neurological diseases. The fact that Nrf2 activator RTA-408 is approved for clinical evaluation (phase 2 clinical trial) of its efficacy and safety in patients with Alzheimer's disease supports this notion. Future research on proteolysis-targeting chimera (PROTAC) and gene therapy holds promise for optimization of neurological disease treatment.

Autophagy plays a dual role in cancer, acting as a tumor suppressor and promoter depending on tumor stage and context. While Atg5 and Atg7 are well established core autophagy genes, the role of Unc-51-like kinase 1 (ULK1)-a key autophagy initiator-remains poorly understood in pancreatic ductal adenocarcinoma (PDAC). Here we investigated the role of ULK1 using tissue-specific deletion in genetically engineered mouse models. Although ULK1 messenger RNA levels remained unchanged between normal and tumor cells in The Cancer Genome Atlas dataset, multiplex immunohistochemistry revealed elevated ULK1 activity, marked by pATG14, in high-grade human PDAC tissues. Genetic deletion of Ulk1 impaired autophagy and reduced cell proliferation, colony formation and invasiveness of pancreatic cancer cells. In vivo, both syngeneic orthotopic and KPC (LSL-Kras^G12D/+; LSL-Trp53^R172H/+; Pdx1-Cre) mouse models with tissue-specific Ulk1 deletion exhibited significant delayed tumor progression, reduced tumor burden and extended survival. Importantly, Ulk1 deficiency remodeled the tumor immune microenvironment by reducing tumor-promoting polymorphonuclear myeloid-derived suppressor cells and neutrophils while substantially enhancing recruitment of cytotoxic CD8⁺ T cells and major histocompatibility complex II⁺ antigen-presenting cells. Chemokine and cytokine profiling revealed that downregulation of Cxcl2, Ccl2 and G-CSF might lead to polymorphonuclear myeloid-derived suppressor cell and neutrophil recruitment and survival, with concurrent upregulation of GM-CSF for dendritic cell infiltration, thereby inducing antitumor immunity. These findings provide insights into the role of ULK1 in PDAC progression through tumor-intrinsic metabolic support by autophagy activation and immune modulation by tumor-derived cytokines. Targeting ULK1 may represent a promising therapeutic strategy by inhibiting autophagy and enhancing antitumor immune responses in pancreatic cancer.

Atherosclerosis is the underlying cause of cardiovascular disease. Recent studies have shown that N⁶-methyladenosine (m⁶A) modification in macrophages is associated with atherosclerosis progression. However, there is a lack of systemic research on the role of m⁶A modification in macrophage differentiation and activation during atherosclerosis. Here we conducted multiomics analysis (MeRIP-seq and RNA-seq) of macrophages during their differentiation and activation to elucidate the regulatory network of the m⁶A spectrum at different stages. Western blot, quantitative PCR (qPCR), RNA-seq and RNA immunoprecipitation (RIP)-qPCR results demonstrated that m⁶A modification modulates KDM6B expression during macrophage activation. Through co-immunoprecipitation, RIP‒qPCR and genetic perturbation experiments, we revealed that Mettl3/Rbm15 regulates the stability of Kdm6b mRNA and that Kdm6b is required for interacting with and demethylating Jak1 to induce its phosphorylation-mediated macrophage activation. Next, through the analysis of single-cell RNA-seq data and coculture experiments, we revealed that Kdm6b-mediated macrophage activation promoted cytotoxic T lymphocyte cytotoxicity following atherosclerosis progression. Moreover, the systemic use of STM2457, a METTL3 inhibitor, revealed the importance of m⁶A modification in immune cell infiltration and plaque activation. Finally, we utilized macrophage-specific Kdm6b-knockout mice to determine whether Kdm6b facilitates macrophage and cytotoxic T lymphocyte activation and atherosclerosis. Our findings revealed that m⁶A modification plays a pivotal role in the upregulation of Kdm6b in response to IFN-γ stimulation, which is essential for the phosphorylation of Stat1-induced macrophage activation-mediated atherosclerosis development.

Placenta-derived extracellular vesicles (EVs) are emerging as critical regulators of maternal-fetal communication during pregnancy. These lipid bilayer-enclosed particles, primarily secreted by trophoblasts, transport bioactive cargos-including RNAs, proteins, lipids and neurotransmitters-that influence a wide range of developmental and immunological processes. While much attention has been given to their roles in maternal adaptation and health outcomes, recent studies highlight their direct impact on fetal development, particularly fetal brain development. Emerging evidence suggests that placental EVs may traverse both the placental and blood-brain barriers, thereby contributing to signaling processes that influence neurogenesis, cell fate specification and regional brain patterning. Their cargo composition is dynamic, modulated by gestational age and environmental factors such as air pollution, viral infection and chemical toxicants. These stressors can alter EV secretion and molecular content, contributing to adverse fetal outcomes including impaired organogenesis and neurodevelopmental delays. In this review, we synthesize current knowledge on placental EV biology, examine their roles in maternal and fetal health with an emphasis on neurodevelopment and evaluate how environmental exposures reshape EV-mediated signaling. We also discuss emerging technologies and translational opportunities, including EV-based diagnostics and therapeutic delivery systems. Collectively, placenta-derived EVs represent a vital yet underexplored mechanism in fetal programming, offering novel insights into the developmental origins of health and disease.

In recent years, cryo-electron microscopy structures of ion channels in complex with G proteins have been resolved, providing insights into the molecular mechanisms underlying the crosstalk between G protein-coupled receptors (GPCRs) and ion channels. Downstream signaling initiated by GPCR activation can indirectly modulate ion channel activity. Alternatively, the direct binding of Gα or Gβγ subunits to ion channels can directly regulate their ion conduction activity. Recent cryo-electron microscopy structures, such as TRPC5-Gα_i3, GIRK-Gβγ and TRPM3-Gβγ, have elucidated these direct interactions and advanced our understanding of how Gα or Gβγ subunits activated by GPCRs modulate ion channel activity. In addition, the structure of the TRPV4-RhoA complex has revealed that small G proteins can also directly modulate ion channels. Understanding the physiological roles of these complexes will be critical for their potential use as pharmacological targets. Here we summarize the current knowledge of the interactions between ion channels and G proteins.

Despite therapeutic advances, ovarian cancer remains a major clinical challenge owing to its frequent metastasis and chemoresistance, which are often driven by cancer stem cells (CSCs) and proangiogenic signaling. Here we demonstrated that dihydroartemisinin (DHA), a derivative of the antimalarial drug artemisinin, inhibits CSC characteristics, tumor neovascularization and resistance to carboplatin via a microRNA-dependent mechanism in ovarian cancer. DHA substantially inhibited CSC properties, tumorigenicity and vascular endothelial growth factor A (VEGF-A)-mediated tumor neovascularization in ovarian cancer. Moreover, the combined treatment with DHA and carboplatin produced a synergistic effect that reduced tumor burden, chemoresistance and peritoneal dissemination in vivo. Mechanistically, DHA downregulated BMI-1 and VEGF-A/vascular endothelial growth factor receptor 2 (VEGFR2), which are critical factors in CSC maintenance and metastasis, via the upregulation of miR-200b. An analysis of ovarian tumor tissues collected from patients enrolled in our clinical cohort revealed that dual positivity for BMI-1 and VEGF-A was associated with poor progression-free survival. Overall, DHA targets the miR-200b-BMI-1/VEGF-A axis to suppress cancer stemness and metastatic potential, highlighting its therapeutic promise in overcoming the limitations of standard chemotherapy for ovarian cancer. The clinical trial number for this study is not applicable.

Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of the polycomb repressive complex 2 (PRC2), which mediates transcriptional repression through histone H3 lysine 27 trimethylation (H3K27me3), is highly expressed in aggressive triple-negative breast cancer (TNBC). However, despite the elevated EZH2 expression, H3K27me3 levels remain unexpectedly low, suggesting a potential noncanonical role for EZH2 in TNBC. Here we demonstrate that EZH2 directly binds to the transcription factor E2F1, and this interaction is critical for modulating chromatin accessibility by disrupting H3K27me3 deposition. This noncanonical function of EZH2, which operates independently of its methyltransferase activity, is linked to enhanced tumor cell proliferation and inhibition of apoptosis. Our findings reveal that EZH2 functions in a chromatin context-dependent manner by cooperating with E2F1 in TNBC, highlighting that the EZH2-E2F1 interaction, independent of PRC2, plays a key role in remodeling chromatin structure and facilitating TNBC proliferation.