Cell Death and Differentiation最新文献

Osteoclasts are essential for bone remodeling; however, their hyperactivity leads to pathological bone loss. While inflammasome-activated caspases are known to influence osteoclastogenesis, the role of caspase-11, beyond its conventional function in pyroptosis, remains unclear. Here, we identified caspase-11 as a pivotal regulator of RANKL-induced osteoclast differentiation. Caspase-11 expression and activity were elevated in bone tissues exhibiting excessive resorption and in RANKL-stimulated bone marrow-derived macrophages. Unlike inflammasome activation, RANKL-induced caspase-11 did not trigger typical inflammasome-associated inflammatory responses. Caspase-11 knockout mice displayed increased bone mass and resistance to RANKL-induced bone resorption; in parallel, genetic or pharmacological inhibition of caspase-11 impaired osteoclast differentiation in vitro. Notably, mechanistic studies revealed that RANKL-activated caspase-11 translocates to the nucleus, where it cleaves and inactivates poly(ADP-ribose) polymerase 1 (PARP1), a transcriptional repressor of osteoclastogenesis. In addition, using the caspase-11 inhibitor, VX-765, substantially reduced ovariectomy-induced bone loss. These findings collectively reveal a novel, non-inflammatory function of caspase-11 in osteoclastogenesis, positioning it as a promising therapeutic target for osteolytic diseases.

Ubiquitin removal by deubiquitinating enzymes (DUBs) is a crucial cellular process. Among the DUBs, ubiquitin-specific protease 13 (USP13) is overexpressed in multiple cancers and is associated with tumorigenesis and poor prognosis. However, its involvement in the cell death pathway is poorly understood. Thus, we describe the novel function of USP13 as a crucial regulator of necroptosis. USP13 interacts with cellular IAP2 (cIAP2), stabilizing cIAP2 proteins in colorectal cancer (CRC) cells. The TCGA-COAD and GEO databases revealed USP13 upregulation in CRC patients and its association with poor clinical outcomes. The loss of USP13 significantly potentiates TNF-α/SMAC mimetic birinapant/pan-caspase inhibitor Z-VAD-FMK (TBZ)-induced necroptosis in CRC cells and diminishes tumor growth in a xenograft model. Thereby, USP13 may serve as a potential therapeutic target for anticancer treatment of CRC.

Regulated cell death is integral to sculpting the developing brain, yet the relative contributions of extrinsic apoptosis and necroptosis remain unclear. Here, we leverage single-cell mass cytometry (CyTOF) to characterize the cellular landscape of the mouse telencephalon in wild-type (WT), RIPK3 knockout (RIPK3 KO), and RIPK3/Caspase-8 double knockout (DKO) mice. Strikingly, combined deletion of RIPK3 and Caspase-8 leads to a 12.6% increase in total cell count, challenging the prevailing notion that intrinsic apoptosis exclusively governs developmental cell elimination. Detailed subpopulation analysis reveals that DKO mice display selective enrichment of Tbr2⁺ intermediate progenitors and endothelial cells, underscoring distinct, cell type-specific roles for extrinsic apoptotic and necroptotic pathways. These findings provide a revised framework for understanding the coordinated regulation of cell number during telencephalic development and suggest potential mechanistic links to neurodevelopmental disorders characterized by aberrant cell death.

Elevated glycolysis in lung tissue is a hallmark of sepsis-induced acute lung injury (SI-ALI), yet the role of glycolytic reprogramming and lactate-derived protein modifications in damaging epithelial cells remains poorly understood. In this study, we reveal that PDK4-driven glycolytic reprogramming promotes excessive lactate production in lung tissue during SI-ALI. Mechanistically, AARS1 in epithelial cells selectively enhances lactylation modification at the K375 site of LPCAT2, which suppresses STAT1 acetylation and facilitates STAT1 phosphorylation, nuclear translocation, and transcriptional repression of SLC7A11. This cascade ultimately triggers epithelial cells ferroptosis. Pharmacological inhibition of PDK4 attenuates lactate accumulation and LPCAT2 lactylation, thereby restoring STAT1 acetylation and SLC7A11 expression. Furthermore, AARS1 knockdown or mutation of the LPCAT2-K375 lactylation site rescues STAT1-mediated SLC7A11 suppression and mitigates ferroptosis in vitro and septic mice. Our findings revealed that elevated expression of PDK4 is a critical factor contributing to the increased lactate production in lung tissue during sepsis, and established a novel LPCAT2-K375/STAT1/SLC7A11 axis driving epithelial cells ferroptosis in SI-ALI, highlighting the crosstalk between metabolic reprogramming, post-translational modifications (PTM), and ferroptosis. Targeting the PDK4 or LPCAT2 lactylation may offer therapeutic potential for SI-ALI. In sepsis-induced acute lung injury (SI-ALI), PDK4 hyperactivation drives excessive lactate production in epithelial cells, triggering AARS1/HDAC9-mediated LPCAT2 lactylation. This modification suppresses STAT1 acetylation while enhancing phosphorylation, driving its nuclear translocation and subsequent SLC7A11 transcriptional downregulation. The resultant glutathione synthesis deficiency promotes ferroptosis, exacerbating SI-ALI progression.

The tumor microenvironment is an immunosuppressive niche that contributes to tumor growth by downregulating immune cell functions or restraining immune cell infiltration. The underlying mechanisms are not still poorly understood. Here, we demonstrate that O-linked N-acetylglucosamine (O-GlcNAcylation), a prevalent form of protein glycosylation, contributes to establishing the immunosuppressive niche through regulating the metabolic and non-metabolic functions of uridine diphosphate glucose dehydrogenase (UGDH). Tumor cells carrying O-GlcNAcylation-deficient UGDH showed reduced xenograft tumor growth and improved survival in mice. Cytometry by time-of-flight (CyTOF) analysis suggests UGDH O-GlcNAcylation negatively correlates with cytotoxic CD8⁺ T cell infiltration. O-GlcNAcylation on serine 350 of UGDH is located within the UDP-binding domain, and the subsequent extensive all-atom molecular dynamics simulations reveal that O-GlcNAcylation reinforces hydrogen-bonding interaction and enzymatic activity of UGDH, leading to enhanced hyaluronic acid (HA) synthesis in the extracellular matrix. Moreover, O-GlcNAcylation of UGDH reduces CD8⁺ T cell infiltration by decreasing the chemokine CXCL10 expression. Specifically, O-GlcNAcylation enhances UGDH interaction with KPNA2 to compete with STAT1, and suppresses translocation of STAT1 into the nucleus, thereby transcriptionally downregulating CXCL10 expression. Thus, our study identifies UGDH O-GlcNAcylation as a key regulator of tumor immunity and further suggests a potential strategy for enhancing immunotherapy.

The function of cytosolic aldolase A (ALDOA) in glycolysis is well recognized. However, the cytosol-to-nucleus redistribution of ALDOA and its nuclear function is poorly understood. Here, we uncover inflammatory factor-stimulated nuclear function of ALDOA in augmenting pancreatic carcinogenesis by activating NF-κB signaling in a ubiquitination-dependent manner. TNF-α-triggered K11- and K29-linked ubiquitination of ALDOA at Lys200 promotes its interaction with RelA/p65 and facilitates importin-β-dependent nuclear translocation, establishing a positive feedback regulation in the tumor microenvironment by elevating the TNF-α expression in pancreatic ductal adenocarcinoma (PDAC). USP4 is identified as a negative regulator that deubiquitinates ALDOA. Instead of broadly targeting ALDOA, which causes glycolysis impairment, the specific elimination of ALDOA ubiquitination enhances chemosensitivity and the synergistic effect of chemotherapy combined with p65-specific anti-inflammatory therapy by selectively suppressing inflammation-induced proliferation in cancer cells. Collectively, we unveil the multifaceted mechanisms by which ALDOA promotes PDAC carcinogenesis, from metabolic to gene regulatory perspectives, providing potential therapies combatting cancer.

Neural activity drives blood vessel (BV) formation and energy substrate delivery in the developing brain to meet rising metabolic demands; however, the underlying mechanisms remain poorly understood. In this study, we exposed neonatal mice to chronic whisker stimulation (WS), a paradigm known to enhance BV formation in the somatosensory (S1) cortex. Transcriptomic (RNA-seq) and spatial (RNA-scope) analyses revealed that WS upregulated monocarboxylate transporter 2 (MCT2) in cortical neurons and MCT1 in endothelial cells (ECs). These changes coincided with increased cortical lactate levels, elevated astrocytic vascular endothelial growth factor A (VEGFa), and enhanced angiogenesis. Functional experiments demonstrated that neuronal MCT2 is essential for mediating WS-induced angiogenic and metabolic responses. Mechanistically, MCT2 facilitates _L-lactate influx into the cortex with or without WS, promoting lactate uptake by neurons and astrocytes. This, in turn, induces MCT2 expression in neurons and activates hypoxia-inducible factor 1α (HIF1α) and VEGFa expression in astrocytes. Together, these findings uncover a previously unrecognized role for neuronal MCT2 in regulating lactate flux, signaling, and vascular remodeling, thereby linking neural activity to metabolic adaptation and vascular development in the neonatal mouse neocortex.

The von Hippel-Lindau (VHL) protein (pVHL) functions as a potent tumor suppressor by mediating the degradation or inactivation of various substrates, including HIFα and Akt. However, pVHL is frequently downregulated in numerous cancers harboring wild-type VHL, and underlying mechanisms remains elusive. Aberrant glucose metabolism is a hallmark of cancer, driving tumor progression and therapeutic resistance. Despite this, the connection between glucose homoeostasis and pVHL turnover and functions has yet to be defined. In this study, we demonstrate that dysregulated glucose metabolism destabilizes pVHL in pancreatic ductal adenocarcinoma (PDAC), colorectal, and ovarian cancer cells. Mechanistically, energy stress induced by glucose starvation, 2-deoxyglucose (2-DG), or metformin activates AMP-activated protein kinase (AMPK), which subsequently phosphorylates and activates BAP1, a deubiquitinase whose specific function in targeting pVHL for deubiquitination and stabilization had not been previously characterized. Specifically, AMPKα phosphorylates BAP1 at residues S123, S469, and S583, enhancing the interaction between BAP1 and pVHL and promoting pVHL stabilization and tumor-suppressive function both in vitro and in vivo. Conversely, disrupting BAP1 phosphorylation through AMPKα depletion or reconstitution with a phosphorylation-defective BAP1 mutant (S123A/S469A/S583A) abolishes the BAP1-pVHL interaction, leading to impaired pVHL stabilization and accelerated tumor progression in cancer cell lines and patient-derived xenograft models. Clinically, our analysis reveals a positive correlation between levels of phosphorylated AMPKα (p-AMPKα), phosphorylated Ser123-BAP1 (pSer123-BAP1), and pVHL levels in PDAC, colorectal cancer, and ovarian cancer specimens. Collectively, these findings elucidate a novel mechanism linking dysregulated glucose metabolism to compromised function of the BAP1-pVHL tumor-suppressive axis. Our results suggest that therapeutic strategies designed to activate this pathway may represent a promising approach for treating cancers characterized by downregulated wild-type VHL and aberrant glucose metabolism.