Cell Death and Differentiation最新文献

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.

Prostate cancer is one of the most prevalent malignancies in men, with increasing incidence and mortality largely attributed to treatment resistance and metastasis. The effectiveness of current therapies for advanced cases is hindered by intricate genetic and microenvironmental factors, emphasizing the urgent need for novel therapeutic targets. Chimeric RNAs have emerged as promising biomarkers in cancer research, among which CCDC7_19-13, a circular chimeric RNA, is frequently identified in prostate cancer. Our study reveals that CCDC7_19-13 expression is markedly reduced in advanced and recurrent prostate cancer, where its low levels serve as an independent predictor of poor prognosis. Functional experiments demonstrate that CCDC7_19-13 overexpression inhibits cell proliferation, induces apoptosis, and suppresses tumor growth in vivo, whereas its knockdown reverses these effects. Mechanistically, CCDC7_19-13 encodes a novel protein, CCDC7_241aa, which triggers ferroptosis by interacting with SLC7A11 and facilitating its TRIM21-mediated ubiquitination and degradation. Notably, treatment with recombinant CCDC7_241aa effectively suppresses tumor growth in patient-derived xenograft models without toxicity and enhances the efficacy of docetaxel and enzalutamide in vitro. These findings establish CCDC7_19-13 as a significant prognostic marker and potential therapeutic target in prostate cancer, with the recombinant CCDC7_241aa protein offering promise for combination therapies in advanced cases.

SPOP, the most frequently mutated gene in prostate cancer, has been implicated in the aberrant activation of stress granules, presenting significant challenges in disease management. However, the mechanistic link between SPOP mutations and cellular energy stress remains inadequately explored. In this study, we demonstrate that ULK1 expression is positively correlated with both loss-of-function mutations in SPOP and the upregulation of the E3 ubiquitin ligase TRIM24 in human prostate cancer specimens. Mechanistically, SPOP mutations induce the upregulation of TRIM24, which subsequently binds to ULK1 and catalyzes its non-degradative K27-linked polyubiquitylation. This post-translational modification enhances the stability of ULK1, facilitating cellular adaptation to energy stress and consequently promoting prostate cancer progression. Notably, pharmacological inhibition of TRIM24 using TRIM24-PROTAC (proteolysis-targeting chimera) effectively suppressed tumor growth in mice bearing SPOP-mutant prostate cancer cells. Collectively, these findings elucidate a pivotal role of SPOP mutations in modulating energy stress responses via TRIM24-mediated ULK1 ubiquitylation and underscore the therapeutic potential of targeting TRIM24 in SPOP-mutant prostate cancers.