Cell Communication and Signaling最新文献

{"title":"CELF family of RNA-binding proteins: roles in disease biology and potential for therapeutic intervention.","authors":"Yukang Ma, Chi Ma, Aobo Yang, Yiming Chen, Jiajun Gao, Qunshu Wang, Zhixi Wei, Meiling Gao, Xiangling Xing, Wancheng Liu","doi":"10.1186/s12964-026-02924-x","DOIUrl":"https://doi.org/10.1186/s12964-026-02924-x","url":null,"abstract":"<p><p>The CUG-BP and Elav-like (CELF) family of RNA-binding proteins are key regulators of post-transcriptional gene expression, coordinating alternative splicing, mRNA stability, and translation. Although individual members, particularly CELF1 and CELF2, have been extensively characterized, a systematic, paralog-resolved integration of structural determinants, regulatory mechanisms, and disease relevance across all six CELF proteins remains limited. Here, we establish an integrative framework linking conserved RNA recognition motifs and divergent linker domains to context-dependent regulatory outputs, mediated by phosphorylation, nucleocytoplasmic dynamics, and RNA network interactions. We further highlight the neuron-enriched CELF3-CELF6 subfamily, consolidating emerging evidence that extends their roles beyond neural splicing into cancer-associated regulatory programs. Notably, we delineate functional divergence within the family, with CELF1 frequently acting as an oncogenic driver in contrast to the tumor-suppressive role of CELF2, while positioning less-characterized paralogs within this regulatory spectrum. Together, this work defines a unified structure-function-disease axis for CELF proteins and provides a conceptual framework for their prognostic and therapeutic exploitation. However, current CELF-targeted strategies remain largely preclinical and face key translational challenges, including paralog selectivity, off-target effects, and delivery barriers such as limited blood-brain barrier penetration. Accordingly, the most immediate clinical utility of CELF biology is likely to lie in biomarker development and patient stratification, rather than direct therapeutic intervention.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147857658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acrodysostosis type 1: mechanisms explaining PRKAR1A mutation mediated dysregulation of cAMP-PKA signalling.","authors":"Harry Moxom, Susan J Kimber","doi":"10.1186/s12964-026-02890-4","DOIUrl":"https://doi.org/10.1186/s12964-026-02890-4","url":null,"abstract":"<p><p>Acrodysostosis type 1 (ACRDYS1) is a rare multisystem developmental disorder affecting skeletal growth, endocrine function, neurodevelopment, metabolism, and tooth formation. It is caused by heterozygous mutations in PRKAR1A, which encodes the type Iα regulatory subunit (RIα) of protein kinase A (PKA), a central mediator of cyclic AMP (cAMP)-dependent signalling. Although ACRDYS1 belongs to the broader family of Gsα-cAMP-PKA-related disorders, its underlying mechanism is distinct. Disease-associated PRKAR1A mutations cluster within regions of RIα that bind cAMP and undergo conformational rearrangements required for PKA activation. These variants impair cAMP binding and disrupt the structural transitions needed to disinhibit catalytic subunits. Importantly, mutant RIα is expressed at near-normal levels and assembles efficiently into PKA holoenzymes, but these complexes respond weakly and sluggishly to physiological cAMP signals. Drawing on structural, biochemical, cellular, and in vivo studies, we define a dual pathogenic mechanism underlying ACRDYS1. First, defective cAMP-driven conformational changes reduce the sensitivity and amplitude of type I PKA activation, producing a hypomorphic signalling state despite intact upstream receptor coupling and cAMP production. Second, activation-resistant RIα holoenzymes impose a dominant-negative constraint by retaining catalytic subunits, further limiting the pool available for productive signalling in heterozygous cells. We relate this core defect in signal responsiveness to tissue-specific vulnerability. Impaired RIα-dependent decoding of cAMP signals disrupts the Ihh-PTHrP feedback loop in the growth plate, blunts hormone-responsive transcriptional programmes in endocrine epithelia, and alters spatially restricted PKA signalling domains in neurons and metabolically active tissues. Despite the diversity of affected organs, the unifying defect is an inability to generate appropriately timed and scaled PKA responses. This framework establishes ACRDYS1 as a disorder of signal decoding rather than signal generation, clarifies its mechanistic distinction from PRKAR1A-related Carney Complex, and highlights therapeutic strategies aimed at restoring local cAMP-PKA signalling dynamics rather than globally amplifying pathway activity.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147857672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding the metabolic cipher of dormant cancer cells: molecular mechanisms and therapeutic potentials.","authors":"Yuao Qin, Junling Zhang, Yuyang Xiao, Yikai Zhang, Wenbin Liu, Xiangjian Luo","doi":"10.1186/s12964-026-02933-w","DOIUrl":"https://doi.org/10.1186/s12964-026-02933-w","url":null,"abstract":"<p><p>Dormant cancer cells (DCCs) are non-proliferative cancer cells that enter cell cycle arrest in the G0-G1 phase and are recognized as a major cause of therapeutic resistance and cancer recurrence. In response to various intracellular and extracellular signals, DCCs undergo cellular reprogramming that confers drug resistance and enables them to evade immune surveillance. Once reactivated, these cells can resume proliferation, ultimately leading to tumor relapse. Metabolic reprogramming allows DCCs to adapt to the nutrient-deprived tumor microenvironment (TME), reduce energy consumption, and maintain redox homeostasis. Targeting these metabolic vulnerabilities provides promising opportunities to control recurrence and improve therapeutic outcomes. However, the metabolic reprogramming of DCCs is highly heterogeneous, which poses a major challenge for their complete eradication. In this review, we summarize the metabolic features of DCCs, describe the molecular mechanisms underlying metabolic reprogramming across distinct DCC subtypes, elucidate the interactive networks among distinct metabolic pathways, and discuss therapeutic strategies targeting metabolism of DCCs, with the goal of providing new insights into improving treatment efficacy and preventing recurrence.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147846532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Defective branched-chain amino acid catabolism promotes pulmonary fibrosis by inducing apoptosis resistance of myofibroblasts in mice.","authors":"Da-Yan Xiong, Chen-Yu Zhang, Yan-Feng Zhang, Qian Zeng, Wei Liu, Nan-Shi-Yu Yang, Si-Yuan Tang, Jia-Hui Zheng, Yong Zhou, Xiao-Ting Huang","doi":"10.1186/s12964-026-02921-0","DOIUrl":"https://doi.org/10.1186/s12964-026-02921-0","url":null,"abstract":"<p><strong>Background: </strong>Pulmonary fibrosis (PF) is a life-threatening disease characterized by progressive dyspnea and worsening pulmonary function. Branched-chain amino acids (BCAAs) are a group of essential amino acids consisting of valine, leucine, and isoleucine. BCAAs can be converted into intermediate products, branched-chain α-keto acids (BCKAs), which undergo irreversible decarboxylation and dehydrogenation reactions under the action of the branched-chain α-keto acid dehydrogenase complex (BCKDH). Although evidence suggests that the deficiency of BCAA catabolism contributes to tumor and heart failure, the contribution of BCAA metabolism regulation to PF remains largely elusive.</p><p><strong>Methods: </strong>Mouse PF models were induced by bleomycin (BLM). We first evaluated the changes in BCAA metabolism in the lungs of PF mice. Subsequently, BCAA metabolic regulation was achieved through exogenous BCAA supplementation, BCKDK inhibitor BT2, or adenovirus-mediated overexpression of PP2Cm (Ad-PP2Cm). We evaluated whether BCAA metabolic defects induce apoptosis resistance in myofibroblasts through the mTORC1/p70S6K/BAD axis, thereby promoting the progression of pulmonary fibrosis via histopathological, biochemical, and molecular biological assessments.</p><p><strong>Results: </strong>We found that, in the lungs of BLM-induced PF mice, the expression and activity of BCAA metabolic enzymes are inhibited, accompanied by the accumulation of BCAAs and BCKAs in the lungs. Supplementation of BCAA promoted the development of PF. Conversely, enhancing BCAA catabolism by inhibiting BCKDK or overexpressing PP2Cm to activate BCKDH suppressed PF progression in mice. Mechanistically, the deficiency of BCAA catabolism facilitated myofibroblast accumulation by conferring resistance to apoptosis. Furthermore, mTORC1/p70S6K/BAD was found to be the key upstream regulator of BCAA catabolism defect-induced apoptosis resistance in myofibroblasts.</p><p><strong>Conclusions: </strong>Our study reveals that defective BCAA catabolism significantly promotes the progression of PF by inducing apoptosis resistance in myofibroblasts. Therefore, targeting this pathway may be a promising therapeutic strategy for PF.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147846516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tuberous sclerosis complex 2 association with RelA/p65 is critical for NF-κB activation and endothelial cell inflammation.","authors":"Imran Tahir, Rauf A Najar, Arshad Rahman","doi":"10.1186/s12964-026-02922-z","DOIUrl":"https://doi.org/10.1186/s12964-026-02922-z","url":null,"abstract":"<p><strong>Background: </strong>Endothelial cell (EC) inflammation is a key component of many inflammatory conditions including sepsis and acute lung injury (ALI). However, the role of Tuberous Sclerosis Complex 2 (TSC2) in activating NF-κB and inflammatory response in EC has not been addressed.</p><p><strong>Methods: </strong>Human pulmonary artery endothelial cells (HPAEC) or human lung microvascular endothelial cells (HLMVEC) were transfected with siRNA targeting TSC2 and then challenged with thrombin, a procoagulant and proinflammatory mediator whose concentration is elevated in patients with ALI and sepsis, to address the role of TSC2 in activating NF-κB subunit RelA/p65 to cause inflammatory response in EC. In some experiments, lipopolysaccharide (LPS), a robust inducer of EC inflammation, was used to determine if TSC2 is common mediator of this response. The cells were evaluated for IκBα phosphorylation/degradation, RelA/p65 phosphorylation and nuclear accumulation by immunoblotting. DNA binding of nuclear RelA/p65 was determined using an ELISA-based assay kit. RelA/p65 transcriptional activity was determined by measuring NF-κB-luciferase reporter activity. TSC2 association with RelA/p65 was assessed by immunoprecipitation followed by immunoblotting.</p><p><strong>Results: </strong>We found that RelA/p65 is constitutively associated with TSC2 (in addition to IκBα), and this association is reduced in thrombin-stimulated cells, suggesting a role of TSC2 in regulating RelA/p65 activation and EC inflammatory response. We examined this possibility by silencing TSC2 to disrupt its association with RelA/p65-IκBα complex. TSC2 silencing resulted in reduced IκBα phosphorylation/degradation, and subsequently, RelA/p65 nuclear translocation and DNA binding activity in response to thrombin. TSC2-silenced cells also showed reduced Ser⁵³⁶ phosphorylation of RelA/p65, a key modification required for its transcriptional function. Consistent with this, TSC2 silencing impaired NF-κB-dependent reporter activity and expression of proinflammatory mediators such as ICAM-1, VCAM-1 and IL-6 induced by thrombin. Similarly, TSC2 silencing was also effective in decreasing LPS-induced activation of RelA/p65 and expression of proinflammatory mediators, indicating that TSC2 is a common mediator of these responses. Notably, the proinflammatory action of TSC2 in EC appears to be independent of its ability to inhibit MTORC1.</p><p><strong>Conclusions: </strong>Together, these results identify TSC2 as a critical component of RelA/p65-IκBα complex that aids in facilitating the activation of RelA/p65 to cause EC inflammatory response. Thus, the targeting of TSC2 may be a useful strategy for mitigating EC inflammation associated with intravascular coagulation and sepsis.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147846474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The dynamic expression pattern of signaling pathways involved in early embryo development.","authors":"Zifan Song, Shi Song, Nan Wang, Xiaomeng Wang, Liying Yan, Jie Qiao, Peng Yuan","doi":"10.1186/s12964-026-02909-w","DOIUrl":"https://doi.org/10.1186/s12964-026-02909-w","url":null,"abstract":"<p><p>Early embryonic development in mammals involves extensive intercellular communication and interaction. The rapidly changing signaling pathways, governed by signaling pathway-related genes (SPGs), underlie these intricate communication networks and mediate a series of developmental events, including blastulation and gastrulation. However, the detailed expression patterns of SPGs remain to be clearly illustrated. In this study, we used mouse and human transcriptomic and epigenomic data to systematically depict the dynamics of signaling pathway networks during early embryonic development. Our results indicate that zygotic genome activation (ZGA) triggers considerable remodeling of SPGs transcriptional patterns, which coincides with noticeably elevated promoter accessibility after ZGA in both humans and mice. In addition, most SPGs are maternally inherited and are more conserved between humans and mice compared to those activated by the zygotic genome. Interestingly, we found that various extracellular matrix (ECM)-related signaling pathways were highly enriched during early embryogenesis. Two enriched and conserved receptors in several ECM-related pathways, SDC1 and SDC4, were expressed on the cell membrane from oocyte to blastocyst stage both in humans and mice. Knockdown of Sdc1 and Sdc4 in mice resulted in an impaired developmental rate from the 8-cell stage via different mechanisms. Collectively, our study provides new insights into understanding the underlying mechanisms of early embryo development.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147846515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent advances in TMEM16F: structural plasticity, functional versatility, and implications for human diseases.","authors":"Li Chen, Zhigang Qian","doi":"10.1186/s12964-026-02929-6","DOIUrl":"https://doi.org/10.1186/s12964-026-02929-6","url":null,"abstract":"<p><p>TMEM16F is a calcium-activated membrane protein that functions as both a non-selective ion channel and a phospholipid scramblase, linking intracellular Ca²⁺ signaling to dynamic regulation of plasma membrane lipid asymmetry. Recent studies have substantially advanced our understanding of TMEM16F structure and regulation, revealing pronounced conformational heterogeneity and allosteric mechanisms through which Ca²⁺, pH and membrane context coordinate its dual functions. Cell- and tissue-specific analyses indicate that TMEM16F-mediated membrane remodeling contributes to diverse physiological processes, including blood coagulation, cell-cell fusion, regulated cell death, immune responses, and neurodevelopment. Dysregulation of TMEM16F activity has been associated with a broad spectrum of pathological conditions, ranging from bleeding disorders and thromboinflammation to neurodegeneration, infection-associated tissue damage, and cancer. This review integrates recent structural, cellular and pathological insights to provide a comprehensive overview of TMEM16F biology, highlighting mechanisms underlying its dual functions and summarizing emerging evidence for its roles in health and disease.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147846529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Paternal Sertoli cell-derived extracellular vesicles transfer mtDNA and microRNA cargo to trigger germ cell oxidative stress and induce metabolic risks in offspring.","authors":"Jingxian Deng, Lu Li, Zhuoying Huang, Xi Wei, Xiaorui Zhang, Sutong Hua, Jiawei Hao, Yanze Zhang, Yuwei Fu, Xuanzhe Cao, Yan Yang, Yadong Huang","doi":"10.1186/s12964-026-02889-x","DOIUrl":"https://doi.org/10.1186/s12964-026-02889-x","url":null,"abstract":"<p><p>While obesity causes male infertility through testicular lipid stress, the mechanisms by which this stress alters Sertoli cell-derived extracellular vesicles (EVs) to induce paternal reproductive defects and offspring metabolic dysfunction remain unclear. Here, we report that lipid-overloaded Sertoli cells release modified EVs that impair paternal reproductive health and predispose offspring to metabolic disorders. Specifically, we found that palmitic acid treatment alters the lipid composition of Sertoli-derived EVs, resulting in an elevated phosphatidylethanolamine (PE)/phosphatidylcholine (PC) ratio that facilitates their uptake by spermatogonia. Omics sequencing revealed that lipid-overloaded Sertoli cells secreted mitochondrial-rich EVs containing mitochondrial DNA (mtDNA) and miR-6240, induced oxidative stress and repressed Creb1/Crem in recipient germ cells. In vivo, injection these PA-EVs impaired spermatogenesis, resulting in a 21.87% reduction in sperm density. Notably, paternal exposure to these modified EVs induced adverse outcomes in F1 offspring. F1 male offspring exhibited developmental retardation and increased susceptibility to metabolic syndrome, characterized by severe hepatic steatosis under a high-fat diet challenge. Mechanistically, this inherited predisposition was driven by a reprogramming of hepatic lipid metabolism, as multi-omics analysis revealed a significant upregulation of genes critical for fatty acid uptake and metabolism. Collectively, our findings demonstrate that Sertoli cell-derived EVs serve as mediators of paternal effects on offspring metabolic health, highlighting a potential therapeutic target to mitigate obesity-related infertility and prevent metabolic dysfunction in offspring.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147846521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional relationships linking C99/APP-βCTF dimerization, proteostasis disruption, and organelle dysfunction.","authors":"Céline Badot, Anaïs Bini, Eric Duplan, Frédéric Checler, Inger Lauritzen","doi":"10.1186/s12964-026-02928-7","DOIUrl":"https://doi.org/10.1186/s12964-026-02928-7","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;The amyloid β (Aβ) precursor C99 (or APP-βCTF) accumulates in Alzheimer's disease and has been proposed to display Aβ-independent toxicity, notably by affecting the endosomal-lysosomal-autophagic (ELA) network. Our previous findings suggested that some ELA-associated C99 could correspond to dimeric and oligomeric species, but the intracellular sites of C99 dimerization, as well as the toxicity linked to it, remains unknown.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We here developed a bimolecular fluorescence complementation (BiFC) probe to visualize de novo C99 dimerization and dimer trafficking, as well as to identify possible cellular responses specifically linked to C99 dimerization. Moreover, to confirm dimer localizations and toxicities, the localization and cellular effects of the dimerization mutant C99&lt;sup&gt;G29L/G33L&lt;/sup&gt; was compared to that of wildtype C99. The C99 constructs were transfected into HeLa cells and dimer localizations, expression levels and intracellular toxicities were evaluated by Western blot and immunocytochemistry.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;BiFC-C99 dimers were first detected within the TGN, in which monomers initially accumulate. The proteasomal inhibitor MG-132 led to increased dimer formation, indicating that the proteasomal activity status is a key determinant of C99 dimerization. Conversely, TGN-associated C99 dimerization had a negative impact on both the ubiquitin-proteasome system (UPS) and the TGN, as highlighted by the appearance of p62/SQSTM1-positive aggresomes and fragmented Golgi, then suggesting a two-way relationship between UPS function and C99 dimerization. Dimerization also led to lysosome repositioning and to the accumulation of LC3B-positive autophagy vesicles, agreeing with the well-known interplay between autophagy and proteasome in protein turnover. P62/SQSTM1 and LC3B accumulation could similarly be observed in cells expressing C99&lt;sup&gt;G29L/G33L&lt;/sup&gt;, a mutant favoring dimerization, while this was not the case in wildtype C99 expressing cells, confirming the dimerization-specific effect. While proteasomal inhibition caused TGN-associated dimer formation, repression of γ-secretase-mediated C99 proteolysis instead led to a redistribution of monomers to EEA1-positive endosomes, whereas already existing C99 dimers remained unaffected by this treatment. These new endosome-associated monomers were found also to dimerize, resulting in dimers destined for either secretion via small extracellular vesicles or autophagy-lysosomal degradation.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Taken together, our findings indicate that the cellular status of UPS, autophagy and γ-secretase activities are all determinant for C99 expression levels, and are thus crucial for both the level of C99 dimerization and for the fate of the dimers. Moreover, our data show that C99 dimerization itself negatively affects these activities thereby indicating a two-way relationship between C99 dimerization, ","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147846514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthetic lethality in cancer: mechanism exploration and therapeutic applications.","authors":"Pusong Zhao, Peng Wang, Tianqi Xu, Ligang Chen, Qingge Jia, Mingyang Li","doi":"10.1186/s12964-026-02932-x","DOIUrl":"https://doi.org/10.1186/s12964-026-02932-x","url":null,"abstract":"<p><p>Synthetic lethality (SL) is a genetic interaction phenomenon in which a cell can survive when either of two genes is individually mutated, but simultaneous disruption of both genes leads to cell death. This phenomenon reveals the redundancy and complementarity among gene functions and provides a theoretical basis for precision cancer therapies targeting specific genetic defects. The SL approach achieves the selective elimination of cancer cells by targeting the synergistic survival pathways on which tumor-specific genetic defects rely. This review highlights the core molecular mechanisms of SL in DNA damage repair, cell cycle checkpoint regulation, metabolic reprogramming, and epigenetic regulation; summarizes target discovery strategies based on high-throughput functional genomics and computational biology; and discusses successful clinical translation cases exemplified by poly(ADP-ribose) polymerase (PARP) inhibitors, along with current challenges and future directions.</p>","PeriodicalId":55268,"journal":{"name":"Cell Communication and Signaling","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147846519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}