Cell Death and Differentiation最新文献

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.

The Hippo pathway has been implicated in the onset and pathogenesis of inflammatory bowel disease (IBD), with Mammalian STE20-like kinase 1 (MST1), a core kinase in this pathway, playing significant roles in inflammation and immune regulation. However, the specific role of MST1 in IBD remains largely undefined. In this study, we observed that MST1 expression was significantly decreased in IBD patients and acute colitis mice. Intestinal epithelial cell-specific MST1 knockout mice exhibited heightened susceptibility to dextran sodium sulfate (DSS)-induced colitis, characterized by severe disruption of intestinal epithelial barrier and markedly increased epithelial cell pyroptosis, thus exacerbating intestinal inflammation. Pharmacological inhibition of caspase-1/GSDMD-mediated pyroptosis ameliorated the detrimental effects of MST1 deficiency in colitis. Consistently, MST1 deficiency exacerbated intestinal barrier disruption and pyroptosis in both in vivo and in vitro models under TNFα-induced inflammation and DNA damage. Mechanistically, MST1 depletion promoted YAP nuclear translocation and enhances its interaction with p73 in intestinal epithelial cells, leading to increased p73 stability and transcriptional activity. This, in turn, facilitated the recruitment of p73 to the caspase-1 promoter, upregulating caspase-1 expression and translating into increased pyroptosis under TNFα-induced inflammatory conditions. Altogether, our findings highlight the critical role of MST1 in maintaining intestinal mucosal barrier homeostasis by regulating epithelial cell pyroptosis via the YAP/p73 signaling pathway. Reduced MST1 expression may correlate with a better response to anti-TNF therapy in IBD patients. Consequently, MST1 could serve as a promising predictive biomarker for anti-TNF therapy responsiveness and a potential therapeutic target for IBD, offering valuable insights for personalized treatment strategies.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease worldwide, yet the molecular mechanisms underlying its pathogenesis are not fully understood. Here, we identify the deubiquitinating enzyme Ubiquitin-specific protease 2 (USP2) as a key regulator in hepatic lipid metabolism and MASLD progression. We show that USP2 expression is significantly upregulated in liver tissues from MASLD patients and high-fat diet (HFD)-induced mouse models. Usp2 knockout or pharmacological inhibition alleviates hepatic steatosis and improves systemic metabolic parameters both in vivo and in vitro. Strikingly, hepatocyte-targeted GalNAc-conjugated siRNA against Usp2 markedly attenuates MASLD in mouse models, highlighting therapeutic potential. Mechanistically, USP2 directly interacts with and stabilizes peroxisome proliferator-activated receptor γ (PPARγ) by removing K48-linked ubiquitin chains at lysine 161 within its DNA-binding domain, thereby preventing proteasomal degradation and enhancing its transcriptional activity. This USP2-PPARγ axis promotes hepatic lipid accumulation and drives MASLD progression. Our findings uncover a novel regulatory mechanism in MASLD pathogenesis and suggest that USP2 may represent a promising and druggable therapeutic target for metabolic liver disease.

Diabetic nephropathy (DN) is the primary cause of end-stage renal disease worldwide. Recent studies have revealed that lactate-mediated histone lactylation, which functions as a novel epigenetic modification, is involved in the occurrence and development of diabetes-related complications. However, little is known about the role of lactyltransferase in DN. Alanyl-tRNA synthetase 1 (AARS1) was identified as a novel lactyltransferase that modulates histone H3-lysine-18 lactylation (H3K18la). In the present study, we determined whether AARS1-mediated H3K18la participates in the pathogenesis of DN. More importantly, we explored the potential mechanism involved. A mouse DN model consisting of both wild-type and alanyl-tRNA synthetase (AARS1) heterozygote (AARS1^+/-) mice was utilized in this study. Transcriptomic and lipidomic analyses, combined with a variety of molecular biological methodologies, were employed to elucidate the potential mechanism by which AARS1 regulates ferroptosis in DN. Our results indicated that the increases in AARS1 and H3K18la expression were involved in kidney dysfunction and renal cell death via the modulation of ferroptosis in the DN model. Moreover, AARS1 induced lipid peroxidation by increasing fatty acid elongase-5 (ELOVL5) transcription, ultimately contributing to ferroptosis induction. Furthermore, AARS1 interacted with signal transducer and activator of transcription 1 (STAT1) to jointly regulate ELOVL5 transcription. Additionally, treatment with the STAT1-specific inhibitor fludarabine delayed DN progression. In addition, we observed that AARS1 modulated the lactylation of both STAT1 and H3K18 to regulate ELOVL5 transcription, thus triggering ferroptosis. Inhibition of AARS1-induced lactylation via β-alanine attenuated ferroptosis in DN model mice and hyperglycaemic cells. The present study showed that AARS1 induced the lactylation of H3K18 and STAT1 to regulate ELOVL5 transcription, thus triggering ferroptosis in a diabetic nephropathy model.