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信号转导与靶向治疗（英文）
信号转导与靶向治疗（英文）
信号转导与靶向治疗（英文）/Journal Signal Transduction and Targeted TherapyCSTPCDSCI
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    Characterization of ferroptosis-triggered pyroptotic signaling in heart failure

    Xukun BiXiaotian WuJiaqi ChenXiaoting Li...
    4653-4666页
    查看更多>>摘要：Pressure overload-induced cardiac hypertrophy is a common cause of heart failure(HF),and emerging evidence suggests that excessive oxidized lipids have a detrimental effect on cardiomyocytes.However,the key regulator of lipid toxicity in cardiomyocytes during this pathological process remains unknown.Here,we used lipidomics profiling and RNA-seq analysis and found that phosphatidylethanolamines(PEs)and Acsl4 expression are significantly increased in mice with transverse aortic constriction(TAC)-induced HF compared to sham-operated mice.In addition,we found that overexpressing Acsl4 in cardiomyocytes exacerbates pressure overload-induced cardiac dysfunction via ferroptosis.Notably,both pharmacological inhibition and genetic deletion of Acsl4 significantly reduced left ventricular chamber size and improved cardiac function in mice with TAC-induced HF.Moreover,silencing Acsl4 expression in cultured neonatal rat ventricular myocytes was sufficient to inhibit hypertrophic stimulus-induced cell growth.Mechanistically,we found that Acsl4-dependent ferroptosis activates the pyroptotic signaling pathway,which leads to increased production of the proinflammatory cytokine IL-1β,and neutralizing IL-1β improved cardiac function in Acsl4 transgenic mice following TAC.These results indicate that ACSL4 plays an essential role in the heart during pressure overload-induced cardiac remodeling via ferroptosis-induced pyroptotic signaling.Together,these findings provide compelling evidence that targeting the ACSL4-ferroptosis-pyroptotic signaling cascade may provide a promising therapeutic strategy for preventing heart failure.
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    GRP75 triggers white adipose tissue browning to promote cancer-associated cachexia

    Xu ChenQingnan WuWei GongShaolong Ju...
    4667-4682页
    查看更多>>摘要：Cachexia,which affects 50-80％of cancer patients,is a debilitating syndrome that leads to 20％of cancer-related deaths.A key feature of cachexia is adipose tissue atrophy,but how it contributes to the development of cachexia is poorly understood.Here,we demonstrate in mouse models of cancer cachexia that white adipose tissue browning,which can be a characteristic early-onset manifestation,occurs prior to the loss of body weight and skeletal muscle wasting.By analysing the proteins differentially expressed in extracellular vesicles derived from cachexia-inducing tumours,we identified a molecular chaperone,Glucose-regulated protein 75(GRP75),as a critical mediator of adipocyte browning.Mechanistically,GRP75 binds adenine nucleotide translocase 2(ANT2)to form a GRP75-ANT2 complex.Strikingly,stabilized ANT2 enhances its interaction with uncoupling protein 1,leading to elevated expression of the latter,which,in turn,promotes adipocyte browning.Treatment with withanone,a GRP75 inhibitor,can reverse this browning and alleviate cachectic phenotypes in vivo.Overall,our findings reveal a novel mechanism by which tumour-derived GRP75 regulates white adipose tissue browning during cachexia development and suggest a potential white adipose tissue-centred targeting approach for early cachexia intervention.
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    Palmitoylation regulates myelination by modulating the ZDHHC3-Cadm4 axis in the central nervous system

    Yanli ChangJiangli ZhuXiaopeng LiYi Deng...
    4683-4699页
    查看更多>>摘要：The downregulation of Cadm4(Cell adhesion molecular 4)is a prominent feature in demyelination diseases,yet,the underlying molecular mechanism remains elusive.Here,we reveal that Cadm4 undergoes specific palmitoylation at cysteine-347(C347),which is crucial for its stable localization on the plasma membrane(PM).Mutation of C347 to alanine(C347A),blocking palmitoylation,causes Cadm4 internalization from the PM and subsequent degradation.In vivo experiments introducing the C347A mutation(Cadm4-KI)lead to severe myelin abnormalities in the central nervous system(CNS),characterized by loss,demyelination,and hypermyelination.We further identify ZDHHC3(Zinc finger DHHC-type palmitoyltransferase 3)as the enzyme responsible for catalyzing Cadm4 palmitoylation.Depletion of ZDHHC3 reduces Cadm4 palmitoylation and diminishes its PM localization.Remarkably,genetic deletion of ZDHHC3 results in decreased Cadm4 palmitoylation and defects in CNS myelination,phenocopying the Cadm4-KI mouse model.Consequently,altered Cadm4 palmitoylation impairs neuronal transmission and cognitive behaviors in both Cadm4-KI and ZDHHC3 knockout mice.Importantly,attenuated ZDHHC3-Cadm4 signaling significantly influences neuroinflammation in diverse demyelination diseases.Mechanistically,we demonstrate the predominant expression of Cadm4 in the oligodendrocyte lineage and its potential role in modulating cell differentiation via the WNT-β-Catenin pathway.Together,our findings propose that dysregulated ZDHHC3-Cadm4 signaling contributes to myelin abnormalities,suggesting a common pathological mechanism underlying demyelination diseases associated with neuroinflammation.
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    Surufatinib plus toripalimab combined with etoposide and cisplatin as first-line treatment in advanced small-cell lung cancer patients:a phase Ⅰb/Ⅱ trial

    Yaxiong ZhangYan HuangYunpeng YangYuanyuan Zhao...
    4700-4707页
    查看更多>>摘要：There is still room for improvement in first-line treatment of advanced small cell lung cancer(SCLC).This trial firstly investigated efficacy and safety of antiangiogenic therapy(surufatinib)(200 mg,qd,po)plus anti-PD-1 treatment(toripalimab)(240 mg,d1,ivdrip)combined with etoposide(100 mg/m2,d1-d3,iv,drip)and cisplatin(25 mg/m2,d1-d3,ivdrip)for advanced SCLC as first-line treatment,which has been registered on ClinicalTrials.gov under the identifier NCT04996771.The four-drug regimen was conducted q3w for 4 cycles with maintenance therapy of surufatinib and toripalimab.The primary endpoint was progression-free survival(PFS).The secondary end points included objective response rate(ORR),disease control rate(DCR),overall survival(OS)and safety.All of the 38 patients were enrolled for safety analysis,while only 35 patients were enrolled for efficacy analysis since loss of efficacy evaluation in 3 cases after treatment.After a median follow-up of 21.3 months,the ORR was 97.1％(34/35),and the DCR and the tumor shrinkage rate were both 100％(35/35).The median PFS was 6.9 months(95％CI:4.6 m-9.2 m)and the median OS was 21.1 months(95％CI:12.1 m-30.1 m).The 12-month,18-month,and 24-month OS rates were 66.94％,51.39％and 38.54％.The occurrence rate of grade ≥3 treatment-emergent adverse events(TEAEs)was 63.2％(24/38),including neutrophil count decreased(31.6％,12/38),white blood cell count decreased(23.7％,9/38)and platelet count decreased(10.5％,4/38).No unexpected adverse events occurred.This novel four-drug regimen(surufatinib,toripalimab,etoposide plus cisplatin)revealed impressive therapeutic efficacy and tolerable toxicities.
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    Epigenetic reader ZMYND11 noncanonical function restricts HNRNPA1-mediated stress granule formation and oncogenic activity

    Cheng LianChunyi ZhangPan TianQilong Tan...
    4708-4729页
    查看更多>>摘要：Epigenetic readers frequently affect gene regulation,correlate with disease prognosis,and hold significant potential as therapeutic targets for cancer.Zinc finger MYND-type containing 11(ZMYND11)is notably recognized for reading the epigenetic marker H3.3K36me3;however,its broader functions and mechanisms of action in cancer remain underexplored.Here,we report that ZMYND11 downregulation is prevalent across various cancers and profoundly correlates with poorer outcomes in prostate cancer patients.Depletion of ZMYND11 promotes tumor cell growth,migration,and invasion in vitro,as well as tumor formation and metastasis in vivo.Mechanistically,we discover that ZMYND11 exhibits tumor suppressive roles by recognizing arginine-194-methylated HNRNPA1 dependent on its MYND domain,thereby retaining HNRNPA1 in the nucleus and preventing the formation of stress granules in the cytoplasm.Furthermore,ZMYND11 counteracts the HNRNPA1-driven increase in the PKM2/PKM1 ratio,thus mitigating the aggressive tumor phenotype promoted by PKM2.Remarkably,ZMYND11 recognition of HNRNPA1 can be disrupted by pharmaceutical inhibition of the arginine methyltransferase PRMT5.Tumors with low ZMYND11 expression show sensitivity to PRMT5 inhibitors.Taken together,our findings uncover a previously unexplored noncanonical role of ZMYND11 as a nonhistone methylation reader and underscore the critical importance of arginine methylation in the ZMYND11-HNRNPA1 interaction for restraining tumor progression,thereby proposing novel therapeutic targets and potential biomarkers for cancer treatment.
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    Histone deacetylase inhibition enhances extracellular vesicles from muscle to promote osteogenesis via miR-873-3p

    Ming ChenYi LiMingming ZhangSiliang Ge...
    4730-4748页
    查看更多>>摘要：Regular physical activity is widely recognized for reducing the risk of various disorders,with skeletal muscles playing a key role by releasing biomolecules that benefit multiple organs and tissues.However,many individuals,particularly the elderly and those with clinical conditions,are unable to engage in physical exercise,necessitating alternative strategies to stimulate muscle cells to secrete beneficial biomolecules.Histone acetylation and deacetylation significantly influence exercise-induced gene expression,suggesting that targeting histone deacetylases(HDACs)could mimic some exercise responses.In this study,we explored the effects of the HDAC inhibitor Trichostatin A(TSA)on human skeletal muscle myoblasts(HSMMs).Our findings showed that TSA-induced hyperacetylation enhanced myotube fusion and increased the secretion of extracellular vesicles(EVs)enriched with miR-873-3p.These TSA-EVs promoted osteogenic differentiation in human bone marrow mesenchymal stem cells(hBMSCs)by targeting H2 calponin(CNN2).In vivo,systemic administration of TSA-EVs to osteoporosis mice resulted in significant improvements in bone mass.Moreover,TSA-EVs mimicked the osteogenic benefits of exercise-induced EVs,suggesting that HDAC inhibition can replicate exercise-induced bone health benefits.These results demonstrate the potential of TSA-induced muscle-derived EVs as a therapeutic strategy to enhance bone formation and prevent osteoporosis,particularly for individuals unable to exercise.Given the FDA-approved status of various HDAC inhibitors,this approach holds significant promise for rapid clinical translation in osteoporosis treatment.
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