Pub Date : 2025-12-19DOI: 10.1016/j.cellsig.2025.112333
Mengning Sun , Li Li , Rongrong Fu, Qinglan Yang, Wenjuan Chen, Yi Sun, Hui Gao, Hang Gao, Na Dong
Glycolysis inhibitor 2-Deoxy-D-glucose (2DG) has been extensively studied as a potential therapeutic agent because tumors depend more on aerobic glycolysis than normal cells for their energy supply. However, the precise mechanism underlying 2DG's toxicity remains not so clear. In this study, we confirmed that 2DG induces apoptosis primarily by disrupting glycosylation rather than glycolysis. We observed that glucose depletion or 2DG treatment leads to a significant reduction of MCL-1 protein levels. Further analysis revealed that 2DG toxicity required MCL-1 degradation. Moreover, BAD was identified as the only BH3-only protein whose single knockout can block 2DG-induced apoptosis. The downregulation of MCL-1, combined with the dephosphorylation of BAD at Serine 155, contribute to the simultaneous inactivation of the anti-apoptotic functions of both MCL-1 and BCL-xL, which is sufficient to induce 2DG toxicity. Additionally, our experiments showed that Endoplasmic Reticulum (ER) stress induced PERK-eIF2α pathway mediated translational inhibition of MCL-1 contributes to 2DG toxicity. Based on these findings, the combined use of 2DG with BAD BH3 mimetic have proven effective against various types of cancer cells. In conclusion, this study provides a theoretical basis and rationale for the combined use of 2DG and BH3 mimetics as a promising therapeutic strategy for cancers.
{"title":"PERK-eIF2alpha-mediated translational inhibition of MCL-1 contributes to potential 2-deoxy-D-glucose and BAD mimetic combinatorial cancer therapy","authors":"Mengning Sun , Li Li , Rongrong Fu, Qinglan Yang, Wenjuan Chen, Yi Sun, Hui Gao, Hang Gao, Na Dong","doi":"10.1016/j.cellsig.2025.112333","DOIUrl":"10.1016/j.cellsig.2025.112333","url":null,"abstract":"<div><div>Glycolysis inhibitor 2-Deoxy-D-glucose (2DG) has been extensively studied as a potential therapeutic agent because tumors depend more on aerobic glycolysis than normal cells for their energy supply. However, the precise mechanism underlying 2DG's toxicity remains not so clear. In this study, we confirmed that 2DG induces apoptosis primarily by disrupting glycosylation rather than glycolysis. We observed that glucose depletion or 2DG treatment leads to a significant reduction of MCL-1 protein levels. Further analysis revealed that 2DG toxicity required MCL-1 degradation. Moreover, BAD was identified as the only BH3-only protein whose single knockout can block 2DG-induced apoptosis. The downregulation of MCL-1, combined with the dephosphorylation of BAD at Serine 155, contribute to the simultaneous inactivation of the anti-apoptotic functions of both MCL-1 and BCL-xL, which is sufficient to induce 2DG toxicity. Additionally, our experiments showed that Endoplasmic Reticulum (ER) stress induced PERK-eIF2α pathway mediated translational inhibition of MCL-1 contributes to 2DG toxicity. Based on these findings, the combined use of 2DG with BAD BH3 mimetic have proven effective against various types of cancer cells. In conclusion, this study provides a theoretical basis and rationale for the combined use of 2DG and BH3 mimetics as a promising therapeutic strategy for cancers.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"139 ","pages":"Article 112333"},"PeriodicalIF":3.7,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145803297","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}
Pub Date : 2025-12-19DOI: 10.1016/j.cellsig.2025.112337
Junfei Liu , Mengnan Guo , Mingze Geng , Wenqian Lv , Yixin Liang , Yibo Zhang , Xuhao Meng , Jingxin Li , Xia Wang , Xiuli Zuo
The intestinal mucosa undergoes a tightly regulated process of proliferation and differentiation, essential for maintaining gut homeostasis. We have previously demonstrated that oxytocin (OXT), a novel gastrointestinal (GI) hormone, plays a crucial role in regulating intestinal injury. However, its functional significance in intestinal epithelial cells (IECs) remains largely uncharacterized. In this study, we demonstrate that the OXT/OXTR signaling axis enhanced proliferation and differentiation of IECs in mouse small intestinal organoids. Pharmacological inhibition or genetic knockout (KO) of OXTR in IECs leads to impaired intestinal stem cell self-renewal, reduced Paneth cell abundance, and exacerbated 5-fluorouracil (5-FU)-induced mucositis. Mechanistically, OXT stimulates prostaglandin E2 (PGE2) production via upregulation of prostaglandin-endoperoxide synthases (COX-1/COX-2), and activates the PGE2 receptor EP4. Notably, the OXT-driven effects are abrogated by COX or EP4 inhibition. Furthermore, OXT signaling enhances YAP activation through a PGE2/EP4-dependent mechanism, linking the OXT/PGE2/EP4 axis to modulation of the Hippo pathway. Our findings establish that OXT orchestrates intestinal epithelial regeneration by promoting stem cell self-renewal via the PGE2/EP4/Hippo/YAP signaling cascade. These results highlight the therapeutic potential of OXT in mitigating chemotherapy-induced intestinal injury.
{"title":"Oxytocin regulation of intestinal stem cell self-renewal and differentiation","authors":"Junfei Liu , Mengnan Guo , Mingze Geng , Wenqian Lv , Yixin Liang , Yibo Zhang , Xuhao Meng , Jingxin Li , Xia Wang , Xiuli Zuo","doi":"10.1016/j.cellsig.2025.112337","DOIUrl":"10.1016/j.cellsig.2025.112337","url":null,"abstract":"<div><div>The intestinal mucosa undergoes a tightly regulated process of proliferation and differentiation, essential for maintaining gut homeostasis. We have previously demonstrated that oxytocin (OXT), a novel gastrointestinal (GI) hormone, plays a crucial role in regulating intestinal injury. However, its functional significance in intestinal epithelial cells (IECs) remains largely uncharacterized. In this study, we demonstrate that the OXT/OXTR signaling axis enhanced proliferation and differentiation of IECs in mouse small intestinal organoids. Pharmacological inhibition or genetic knockout (KO) of OXTR in IECs leads to impaired intestinal stem cell self-renewal, reduced Paneth cell abundance, and exacerbated 5-fluorouracil (5-FU)-induced mucositis. Mechanistically, OXT stimulates prostaglandin E2 (PGE2) production via upregulation of prostaglandin-endoperoxide synthases (COX-1/COX-2), and activates the PGE2 receptor EP4. Notably, the OXT-driven effects are abrogated by COX or EP4 inhibition. Furthermore, OXT signaling enhances YAP activation through a PGE2/EP4-dependent mechanism, linking the OXT/PGE2/EP4 axis to modulation of the Hippo pathway. Our findings establish that OXT orchestrates intestinal epithelial regeneration by promoting stem cell self-renewal via the PGE2/EP4/Hippo/YAP signaling cascade. These results highlight the therapeutic potential of OXT in mitigating chemotherapy-induced intestinal injury.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"139 ","pages":"Article 112337"},"PeriodicalIF":3.7,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145803253","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}
Pub Date : 2025-12-19DOI: 10.1016/j.cellsig.2025.112335
Kun Jiao , Liou Jin , Ye Zheng , Yuan Zhang , Zhi Cui
Oral squamous cell carcinoma (OSCC) is the eighth most common malignancy worldwide and the predominant type of head and neck cancer. N-α-acetyltransferase 40 (NAA40), a histone acetyltransferase specifically modifying histones H4 and H2A, has been implicated in oncogenic processes across multiple tumor types. However, its role in OSCC remains unexplored. This study aimed to investigate the functional significance of NAA40 in OSCC and delineate its underlying molecular mechanisms. Bioinformatics analyses were performed to evaluate NAA40 expression and its prognostic value in OSCC tissues. Quantitative real-time PCR, western blot, chromatin immunoprecipitation, CD8+ T cell isolation, co-culture, flow cytometry, and humanized immune-reconstituted subcutaneous xenograft/syngeneic transplantation models were used to clarify its function, mechanism, and therapeutic efficacy. Results showed that NAA40 was upregulated in OSCC tissues, and this upregulation was associated with worse overall survival in patients. In vitro experiments revealed that NAA40 overexpression inhibited T cell activation and their cytotoxic capacity against OSCC cells by upregulating programmed death-ligand 1 (PD-L1) expression, whereas NAA40 knockdown yielded the opposite effect. In vivo studies further suggested that downregulation of NAA40 effectively inhibited tumor growth in immunocompetent mice. Mechanistically, NAA40 promotes histone H4 lysine acetylation enrichment at the lap endonuclease-1 (FEN1) promoter and its transcriptional activation through an indirect mechanism, which is mediated by its regulation of H4 N-terminal acetylation at the first serine residue. This cascade ultimately upregulates PD-L1 expression. Knockdown of FEN1 reversed the suppression of CD8+ T cell activation and antitumor immunity caused by NAA40 overexpression. This study demonstrates NAA40 promotes OSCC progression via enhancing FEN1 transcription and suppressing CD8+ T cell function, suggesting that NAA40 may serve as a novel prognostic marker and therapeutic target for OSCC.
{"title":"N-α-Acetyltransferase 40 promotes oral squamous cell carcinoma progression by enhancing FEN1 transcription and suppressing CD8+ T cell antitumor immunity","authors":"Kun Jiao , Liou Jin , Ye Zheng , Yuan Zhang , Zhi Cui","doi":"10.1016/j.cellsig.2025.112335","DOIUrl":"10.1016/j.cellsig.2025.112335","url":null,"abstract":"<div><div>Oral squamous cell carcinoma (OSCC) is the eighth most common malignancy worldwide and the predominant type of head and neck cancer. N-α-acetyltransferase 40 (NAA40), a histone acetyltransferase specifically modifying histones H4 and H2A, has been implicated in oncogenic processes across multiple tumor types. However, its role in OSCC remains unexplored. This study aimed to investigate the functional significance of NAA40 in OSCC and delineate its underlying molecular mechanisms. Bioinformatics analyses were performed to evaluate NAA40 expression and its prognostic value in OSCC tissues. Quantitative real-time PCR, western blot, chromatin immunoprecipitation, CD8<sup>+</sup> T cell isolation, co-culture, flow cytometry, and humanized immune-reconstituted subcutaneous xenograft/syngeneic transplantation models were used to clarify its function, mechanism, and therapeutic efficacy. Results showed that NAA40 was upregulated in OSCC tissues, and this upregulation was associated with worse overall survival in patients. In vitro experiments revealed that NAA40 overexpression inhibited T cell activation and their cytotoxic capacity against OSCC cells by upregulating programmed death-ligand 1 (PD-L1) expression, whereas NAA40 knockdown yielded the opposite effect. In vivo studies further suggested that downregulation of NAA40 effectively inhibited tumor growth in immunocompetent mice. Mechanistically, NAA40 promotes histone H4 lysine acetylation enrichment at the lap endonuclease-1 (FEN1) promoter and its transcriptional activation through an indirect mechanism, which is mediated by its regulation of H4 N-terminal acetylation at the first serine residue. This cascade ultimately upregulates PD-L1 expression. Knockdown of FEN1 reversed the suppression of CD8<sup>+</sup> T cell activation and antitumor immunity caused by NAA40 overexpression. This study demonstrates NAA40 promotes OSCC progression via enhancing FEN1 transcription and suppressing CD8<sup>+</sup> T cell function, suggesting that NAA40 may serve as a novel prognostic marker and therapeutic target for OSCC.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"139 ","pages":"Article 112335"},"PeriodicalIF":3.7,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145803241","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}
Pub Date : 2025-12-18DOI: 10.1016/j.cellsig.2025.112334
Jiaojiao Yang , Ning Wang , Siyao Tong , Piwen Zhao
Premature ovarian insufficiency (POI) affects up to 1 % of the female population worldwide. Icariin (ICA) has shown promising potential for the alleviation of POI. However, the molecular mechanisms underlying the protective effects of ICA warrant further exploration. In this study, we aimed to elucidate the mechanisms by which ICA improves ovarian function via antioxidant effects mediated by the ERβ/SIRT3 pathway. Cisplatin-induced murine models of POI were used to systematically investigate the cytoprotective efficacy of ICA by comprehensive ovarian histopathological analysis, follicular quantification, estrous cycle monitoring, serum hormonal profiling, and the evaluation of biomarkers of ovarian oxidative stress and apoptosis. Then, an integrated methodological approach encompassing molecular docking, dual-luciferase reporter gene assay, and chromatin immunoprecipitation, was implemented to analyze the mechanism of the ERβ/SIRT3 pathway in conferring antioxidant protection in vitro against ICA. In cisplatin-induced murine models of POI, the administration of ICA significantly elevated follicle counts, restored normal estrous cyclicity, and normalized serum hormone levels (p < 0.01). Furthermore, ICA activated the ERβ/SIRT3 pathway, thus ameliorating cisplatin-induced ovarian oxidative damage. In vitro, ICA conferred protection against H2O2-induced injury in KGN cells. Mechanistically, ICA enhanced the binding of ERβ to the promoter of the SIRT3 gene, thereby promoting the activation of SIRT3. Critically, the protective effects of ICA were abolished following the pharmacological inhibition of ERβ or SIRT3. ICA ameliorated cisplatin-induced ovarian oxidative damage by activating the ERβ/SIRT3 pathway, providing scientific evidence for its potential as a therapeutic agent for POI. This finding facilitates further optimization of drug design and could enhance the quality-of-life for patients with POI.
{"title":"Icariin attenuates premature ovarian insufficiency via a phytoestrogenic mechanism mediated by the ERβ/SIRT3 pathway","authors":"Jiaojiao Yang , Ning Wang , Siyao Tong , Piwen Zhao","doi":"10.1016/j.cellsig.2025.112334","DOIUrl":"10.1016/j.cellsig.2025.112334","url":null,"abstract":"<div><div>Premature ovarian insufficiency (POI) affects up to 1 % of the female population worldwide. Icariin (ICA) has shown promising potential for the alleviation of POI. However, the molecular mechanisms underlying the protective effects of ICA warrant further exploration. In this study, we aimed to elucidate the mechanisms by which ICA improves ovarian function <em>via</em> antioxidant effects mediated by the ERβ/SIRT3 pathway. Cisplatin-induced murine models of POI were used to systematically investigate the cytoprotective efficacy of ICA by comprehensive ovarian histopathological analysis, follicular quantification, estrous cycle monitoring, serum hormonal profiling, and the evaluation of biomarkers of ovarian oxidative stress and apoptosis. Then, an integrated methodological approach encompassing molecular docking, dual-luciferase reporter gene assay, and chromatin immunoprecipitation, was implemented to analyze the mechanism of the ERβ/SIRT3 pathway in conferring antioxidant protection <em>in vitro</em> against ICA. In cisplatin-induced murine models of POI, the administration of ICA significantly elevated follicle counts, restored normal estrous cyclicity, and normalized serum hormone levels (<em>p < 0.01</em>). Furthermore, ICA activated the ERβ/SIRT3 pathway, thus <em>ameliorating</em> cisplatin-induced ovarian oxidative damage. <em>In vitro</em>, ICA conferred protection against H<sub>2</sub>O<sub>2</sub>-induced injury in KGN cells. Mechanistically, ICA enhanced the binding of ERβ to the promoter of the <em>SIRT3</em> gene, thereby promoting the activation of SIRT3. Critically, the protective effects of ICA were abolished following the pharmacological inhibition of ERβ or SIRT3. ICA ameliorated cisplatin-induced ovarian oxidative damage by activating the ERβ/SIRT3 pathway, providing scientific evidence for its potential as a therapeutic agent for POI. This finding facilitates further optimization of drug design and could enhance the quality-of-life for patients with POI.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"139 ","pages":"Article 112334"},"PeriodicalIF":3.7,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800512","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}
Pub Date : 2025-12-18DOI: 10.1016/j.cellsig.2025.112336
Hua Wang , Xiaohui Li , Ziyu Liu , Ruirui Lu , Xiaopeng Li , Xiaoguang Zhang
Background
Annexin A1 (ANXA1) can be activated by ischemia/reperfusion (I/R) events or inflammatory processes, but its specific regulatory mechanisms need further investigation.
Methods
ANXA1 in BV-2 cells was knocked down or overexpressed, and OGD/R induced injury, while 740YP and LY294002 were used for intervention. Microglia polarization phenotype and marker levels were assessed through flow cytometry, RT-qPCR and western blot. Autophagic flux and lysosomal function were evaluated by mCherry-GFP-LC3B, acridine orange (AO) staining and LysoTracker staining. ANXA1 and PI3K/Akt/mTOR proteins were detected by western blot. The tMCAO/R mouse model was established. Longa score, behavioral test and pathological staining to assess the extent of nerve injury, and microglia polarization and autophagy indicators were detected.
Results
ANXA1 expression was decreased in OGD/R-treated microglia. ANXA1 overexpression facilitated the transformation of microglia phenotype from M1-like phenotype to M2-like phenotype, increased CD206 and IL-10 expression, reduced the GFP/mCherry ratio and LysoTracker positive cells, and increased the red fluorescence of AO staining. ANXA1 overexpression also significantly reduced PI3K, Akt and mTOR phosphorylation. Moreover, ANXA1 overexpression markedly decreased Longa score, brain water content and infarct size, improved motor and neurological impairment in tMCAO/R mice, elevated Nissl bodies and Iba-1+CD206+ positive area, and reduced necrotic neuron numbers, inflammatory factor content and autophagy protein levels. In addition, 740YP significantly inhibited the improvement of ANXA1 overexpression, and LY294002 significantly enhanced the improvement of ANXA1 overexpression.
Conclusion
Overexpression of ANXA1 regulated microglia polarization and autophagic flux via regulating PI3K/Akt/mTOR pathway, and improved cerebral I/R inflammatory injury.
{"title":"ANXA1 regulates microglia polarization and autophagy via PI3K/Akt/mTOR pathway to reduce inflammatory injury after cerebral ischemia-reperfusion","authors":"Hua Wang , Xiaohui Li , Ziyu Liu , Ruirui Lu , Xiaopeng Li , Xiaoguang Zhang","doi":"10.1016/j.cellsig.2025.112336","DOIUrl":"10.1016/j.cellsig.2025.112336","url":null,"abstract":"<div><h3>Background</h3><div>Annexin A1 (ANXA1) can be activated by ischemia/reperfusion (I/R) events or inflammatory processes, but its specific regulatory mechanisms need further investigation.</div></div><div><h3>Methods</h3><div>ANXA1 in BV-2 cells was knocked down or overexpressed, and OGD/R induced injury, while 740Y<img>P and LY294002 were used for intervention. Microglia polarization phenotype and marker levels were assessed through flow cytometry, RT-qPCR and western blot. Autophagic flux and lysosomal function were evaluated by mCherry-GFP-LC3B, acridine orange (AO) staining and LysoTracker staining. ANXA1 and PI3K/Akt/mTOR proteins were detected by western blot. The tMCAO/R mouse model was established. Longa score, behavioral test and pathological staining to assess the extent of nerve injury, and microglia polarization and autophagy indicators were detected.</div></div><div><h3>Results</h3><div>ANXA1 expression was decreased in OGD/R-treated microglia. ANXA1 overexpression facilitated the transformation of microglia phenotype from M1-like phenotype to M2-like phenotype, increased CD206 and IL-10 expression, reduced the GFP/mCherry ratio and LysoTracker positive cells, and increased the red fluorescence of AO staining. ANXA1 overexpression also significantly reduced PI3K, Akt and mTOR phosphorylation. Moreover, ANXA1 overexpression markedly decreased Longa score, brain water content and infarct size, improved motor and neurological impairment in tMCAO/R mice, elevated Nissl bodies and Iba-1<sup>+</sup>CD206<sup>+</sup> positive area, and reduced necrotic neuron numbers, inflammatory factor content and autophagy protein levels. In addition, 740Y<img>P significantly inhibited the improvement of ANXA1 overexpression, and LY294002 significantly enhanced the improvement of ANXA1 overexpression.</div></div><div><h3>Conclusion</h3><div>Overexpression of ANXA1 regulated microglia polarization and autophagic flux via regulating PI3K/Akt/mTOR pathway, and improved cerebral I/R inflammatory injury.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"139 ","pages":"Article 112336"},"PeriodicalIF":3.7,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145788231","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}
Small nucleolar RNAs (snoRNAs) have emerged as critical regulators in cancer progression, yet their mechanistic roles in gastric cancer (GC) remain poorly understood. Here, we identify SNORA21 as an oncogenic snoRNA that drives GC pathogenesis through P53 pathway inactivation. We demonstrated significant SNORA21 upregulation in GC tissues and cell lines compared to normal controls. Functional studies revealed that SNORA21 knockdown inhibited tumor growth, while its overexpression promoted malignant phenotypes, establishing its crucial role in determining GC cell fate. Transcriptomic profiling and mechanistic investigations uncovered that SNORA21 represses P53 tumor suppressor activity through a novel CHK1-dependent mechanism. Specifically, SNORA21 attenuated DNA damage responses by inhibiting CHK1 phosphorylation, thereby preventing P53 activation. Remarkably, SNORA21 depletion triggered PERP induction – a P53 effector – which formed a positive feedback loop by suppressing MDM2-mediated P53 degradation. This dual regulatory mechanism (CHK1 inhibition and PERP-MDM2 feedback) explains how SNORA21 sustains P53 inactivation in GC cells. In vivo xenograft models confirmed that SNORA21 silencing suppressed tumor growth while enhancing P53 signaling activity. Our work not only elucidates SNORA21 as a master regulator of the P53 pathway in GC but also reveals its therapeutic potential. The discovery of the SNORA21-CHK1-PERP-MDM2 axis provides a conceptual framework for targeting snoRNA-mediated P53 regulation in GC treatment. These findings position SNORA21 as both a prognostic biomarker and a candidate for RNA-based therapeutics in P53-wildtype gastric cancers.
{"title":"The snoRNA SNORA21 promotes gastric tumorigenesis by attenuating P53 activity through CHK1 phosphorylation inhibition and PERP-dependent feedback loops","authors":"Fanqi Wu , Wangyue Wu , Xueni Ma , Huimei Xu , Dekui Zhang","doi":"10.1016/j.cellsig.2025.112326","DOIUrl":"10.1016/j.cellsig.2025.112326","url":null,"abstract":"<div><div>Small nucleolar RNAs (snoRNAs) have emerged as critical regulators in cancer progression, yet their mechanistic roles in gastric cancer (GC) remain poorly understood. Here, we identify SNORA21 as an oncogenic snoRNA that drives GC pathogenesis through P53 pathway inactivation. We demonstrated significant SNORA21 upregulation in GC tissues and cell lines compared to normal controls. Functional studies revealed that SNORA21 knockdown inhibited tumor growth, while its overexpression promoted malignant phenotypes, establishing its crucial role in determining GC cell fate. Transcriptomic profiling and mechanistic investigations uncovered that SNORA21 represses P53 tumor suppressor activity through a novel CHK1-dependent mechanism. Specifically, SNORA21 attenuated DNA damage responses by inhibiting CHK1 phosphorylation, thereby preventing P53 activation. Remarkably, SNORA21 depletion triggered PERP induction – a P53 effector – which formed a positive feedback loop by suppressing MDM2-mediated P53 degradation. This dual regulatory mechanism (CHK1 inhibition and PERP-MDM2 feedback) explains how SNORA21 sustains P53 inactivation in GC cells. In vivo xenograft models confirmed that SNORA21 silencing suppressed tumor growth while enhancing P53 signaling activity. Our work not only elucidates SNORA21 as a master regulator of the P53 pathway in GC but also reveals its therapeutic potential. The discovery of the SNORA21-CHK1-PERP-MDM2 axis provides a conceptual framework for targeting snoRNA-mediated P53 regulation in GC treatment. These findings position SNORA21 as both a prognostic biomarker and a candidate for RNA-based therapeutics in P53-wildtype gastric cancers.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"139 ","pages":"Article 112326"},"PeriodicalIF":3.7,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145788264","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}
Pub Date : 2025-12-17DOI: 10.1016/j.cellsig.2025.112318
M. Cristina Castañeda-Patlán , Juan Carlos Martínez- Morales , Marco Antonio Morquecho-León , Paola Briseño-Díaz , K. Helivier Solís , M. Teresa Romero-Ávila , J. Adolfo García-Sáinz , Martha Robles-Flores
Colorectal cancer is the third leading cause of cancer-related deaths worldwide. Aberrant canonical Wnt signaling is a hallmark of this cancer type. It has been reported that LPA is a bioactive lipid that plays different roles in colon cancer by activating its G-protein-coupled receptors, promoting cell proliferation, migration, survival, and angiogenesis. Although it has been reported that LPA activates canonical Wnt signaling, the mechanisms underlying their interaction remain unclear; this study aims to investigate them. As previously reported, LPA receptor expression changes under malignant conditions: while LPA1 is expressed at high levels and LPA2 is low in non-malignant 112CoN cells, the opposite occurs in malignant cells, with colon cancer cells showing low LPA1 levels and high LPA2 levels. We also observed that both LPA and Wnt-3a induce strong ERK activation in all colon cell lines; these effects are not additive. Additionally, LPA and Wnt-3a stimulate β-catenin transcriptional activity and its phosphorylation at residues S552 and S675, again in a non-additive manner. We further found that LPA2 and the Wnt effectors Dvl2 and Dvl3 co-precipitate in colon cancer cells, and that the PDZ-interacting motif in the carboxyl terminus of the LPA2 receptor is critical for their direct interaction. Moreover, expressing a mutated LPA2−PDZminus receptor inhibited cell migration while increasing proliferation. Remarkably, the LPA2−PDZminus receptor negatively affected its ability to activate canonical Wnt signaling and unexpectedly, it also impaired the Wnt-3a ligand-induced activation of canonical Wnt signaling in colon cancer cells.
{"title":"The LPA2 receptor PDZ domain affects canonical Wnt signaling in colon cancer cells","authors":"M. Cristina Castañeda-Patlán , Juan Carlos Martínez- Morales , Marco Antonio Morquecho-León , Paola Briseño-Díaz , K. Helivier Solís , M. Teresa Romero-Ávila , J. Adolfo García-Sáinz , Martha Robles-Flores","doi":"10.1016/j.cellsig.2025.112318","DOIUrl":"10.1016/j.cellsig.2025.112318","url":null,"abstract":"<div><div>Colorectal cancer is the third leading cause of cancer-related deaths worldwide. Aberrant canonical Wnt signaling is a hallmark of this cancer type. It has been reported that LPA is a bioactive lipid that plays different roles in colon cancer by activating its G-protein-coupled receptors, promoting cell proliferation, migration, survival, and angiogenesis. Although it has been reported that LPA activates canonical Wnt signaling, the mechanisms underlying their interaction remain unclear; this study aims to investigate them. As previously reported, LPA receptor expression changes under malignant conditions: while LPA<sub>1</sub> is expressed at high levels and LPA<sub>2</sub> is low in non-malignant 112CoN cells, the opposite occurs in malignant cells, with colon cancer cells showing low LPA<sub>1</sub> levels and high LPA<sub>2</sub> levels. We also observed that both LPA and Wnt-3a induce strong ERK activation in all colon cell lines; these effects are not additive. Additionally, LPA and Wnt-3a stimulate β-catenin transcriptional activity and its phosphorylation at residues S552 and S675, again in a non-additive manner. We further found that LPA<sub>2</sub> and the Wnt effectors Dvl2 and Dvl3 co-precipitate in colon cancer cells, and that the PDZ-interacting motif in the carboxyl terminus of the LPA<sub>2</sub> receptor is critical for their direct interaction. Moreover, expressing a mutated LPA<sub>2</sub><sub>−</sub>PDZminus receptor inhibited cell migration while increasing proliferation. Remarkably, the LPA<sub>2</sub><sub>−</sub>PDZminus receptor negatively affected its ability to activate canonical Wnt signaling and unexpectedly, it also impaired the Wnt-3a ligand-induced activation of canonical Wnt signaling in colon cancer cells.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"139 ","pages":"Article 112318"},"PeriodicalIF":3.7,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145788187","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}
Pub Date : 2025-12-16DOI: 10.1016/j.cellsig.2025.112328
Jiahong Tan , Wei Dong , Daoqi Wang , Aiqing Tu , Zuheng Wang , Xiaodie Wu , Fen Zhang , Yun Zhu , Li Ren , Ying Ai , Yun Feng , Jie Zhang
Despite multimodality treatment efforts, resistance to platinum and PARP inhibitors represents a primary impediment to improve prognosis of ovarian cancer. Here, we found that ovarian cancer tissues had higher C/EBPβ expression compared with normal tissues and high C/EBPβ expression predicted unfavorable survival outcomes. Elevated C/EBPβ expression enhanced cisplatin resistance and olaparib resistance. C/EBPβ could affect DDR signals of ovarian cancer. CDK12, serving as a C/EBPβ-regulated DDR-related gene, was directly targeted by and bound with C/EBPβ. C/EBPβ could promote CDK12 expression and confer drug tolerance via CDK12. Manipulation of CDK12 could reverse the effects of C/EBPβ. Using CDK12 inhibitor THZ531 could rescue C/EBPβ-mediated cisplatin resistance and olaparib resistance. Our findings indicated that C/EBPβ is a potent DDR regulator of ovarian cancer, which directly targets CDK12 and upregulates its expression. High C/EBPβ expression mediates platinum resistance and PARP inhibitor resistance via CDK12. Targeting C/EBPβ via CDK12 inhibition could rescue drug responsiveness of ovarian cancer, thereby counteracting platinum and PARP inhibitor resistance. C/EBPβ could thus be exploited as a candidate prognostic biomarker in ovarian cancer.
{"title":"Targeting CDK12 rescues C/EBPβ-mediated platinum and PARP inhibitor resistance in ovarian cancer","authors":"Jiahong Tan , Wei Dong , Daoqi Wang , Aiqing Tu , Zuheng Wang , Xiaodie Wu , Fen Zhang , Yun Zhu , Li Ren , Ying Ai , Yun Feng , Jie Zhang","doi":"10.1016/j.cellsig.2025.112328","DOIUrl":"10.1016/j.cellsig.2025.112328","url":null,"abstract":"<div><div>Despite multimodality treatment efforts, resistance to platinum and PARP inhibitors represents a primary impediment to improve prognosis of ovarian cancer. Here, we found that ovarian cancer tissues had higher C/EBPβ expression compared with normal tissues and high C/EBPβ expression predicted unfavorable survival outcomes. Elevated C/EBPβ expression enhanced cisplatin resistance and olaparib resistance. C/EBPβ could affect DDR signals of ovarian cancer. CDK12, serving as a C/EBPβ-regulated DDR-related gene, was directly targeted by and bound with C/EBPβ. C/EBPβ could promote CDK12 expression and confer drug tolerance via CDK12. Manipulation of CDK12 could reverse the effects of C/EBPβ. Using CDK12 inhibitor THZ531 could rescue C/EBPβ-mediated cisplatin resistance and olaparib resistance. Our findings indicated that C/EBPβ is a potent DDR regulator of ovarian cancer, which directly targets CDK12 and upregulates its expression. High C/EBPβ expression mediates platinum resistance and PARP inhibitor resistance via CDK12. Targeting C/EBPβ via CDK12 inhibition could rescue drug responsiveness of ovarian cancer, thereby counteracting platinum and PARP inhibitor resistance. C/EBPβ could thus be exploited as a candidate prognostic biomarker in ovarian cancer.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"139 ","pages":"Article 112328"},"PeriodicalIF":3.7,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145780322","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}
Pub Date : 2025-12-16DOI: 10.1016/j.cellsig.2025.112330
Shijie Fan , Ying Zhao , Luyao Li , Qingqing Zhao , Ziming Fang , Diyun Xu , Jingjing Shao , Yunjie Zhao , Guang Liang , Xuelin He , Hong Zhu , Yi Wang
Hypertensive renal disease (HRD) is a significant driver of end-stage renal disease. Discovering novel therapeutic targets for HRD is essential for its prevention and treatment. Deubiquitinating enzymes (DUBs) have shown increasing significance in renal diseases. Here, we investigated the role and mechanism of the DUB, Josephin domain-containing protein 2 (JOSD2), in HRD. HRD was induced in wild-type or Josd2 knockout mice via a 4-week chronic infusion of angiotensin II (Ang II). We found that deficiency of JOSD2 aggravated renal injury, epithelial-mesenchymal transition (EMT), and fibrosis in HRD mice. Single-cell RNA-seq analysis indicated that JOSD2 is mainly expressed in tubular epithelial cells (TECs) of proximal tubules. Notably, the specific overexpression of JOSD2 in renal TECs alleviated the detrimental effects in Ang II-induced HRD mice. Mechanistically, through mass spectrometry combined with co-immunoprecipitation analysis, we considered protein kinase B (AKT) as a potential substrate of JOSD2. JOSD2 deubiquitinated the K63-linked ubiquitin chain of AKT via its active site H125 and then enhanced p62-mediated autophagic degradation of AKT. This process reduced the AKT level in TECs, thereby ultimately reducing renal EMT and fibrosis. Our study elucidates the role of the JOSD2-AKT axis in HRD and suggests that JOSD2 may serve as a promising therapeutic target for HRD.
{"title":"JOSD2 alleviates hypertensive renal disease through deubiquitinating AKT in renal tubular epithelial cells","authors":"Shijie Fan , Ying Zhao , Luyao Li , Qingqing Zhao , Ziming Fang , Diyun Xu , Jingjing Shao , Yunjie Zhao , Guang Liang , Xuelin He , Hong Zhu , Yi Wang","doi":"10.1016/j.cellsig.2025.112330","DOIUrl":"10.1016/j.cellsig.2025.112330","url":null,"abstract":"<div><div>Hypertensive renal disease (HRD) is a significant driver of end-stage renal disease. Discovering novel therapeutic targets for HRD is essential for its prevention and treatment. Deubiquitinating enzymes (DUBs) have shown increasing significance in renal diseases. Here, we investigated the role and mechanism of the DUB, Josephin domain-containing protein 2 (JOSD2), in HRD. HRD was induced in wild-type or <em>Josd2</em> knockout mice via a 4-week chronic infusion of angiotensin II (Ang II). We found that deficiency of JOSD2 aggravated renal injury, epithelial-mesenchymal transition (EMT), and fibrosis in HRD mice. Single-cell RNA-seq analysis indicated that JOSD2 is mainly expressed in tubular epithelial cells (TECs) of proximal tubules. Notably, the specific overexpression of JOSD2 in renal TECs alleviated the detrimental effects in Ang II-induced HRD mice. Mechanistically, through mass spectrometry combined with co-immunoprecipitation analysis, we considered protein kinase B (AKT) as a potential substrate of JOSD2. JOSD2 deubiquitinated the K63-linked ubiquitin chain of AKT via its active site H125 and then enhanced p62-mediated autophagic degradation of AKT. This process reduced the AKT level in TECs, thereby ultimately reducing renal EMT and fibrosis. Our study elucidates the role of the JOSD2-AKT axis in HRD and suggests that JOSD2 may serve as a promising therapeutic target for HRD.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"139 ","pages":"Article 112330"},"PeriodicalIF":3.7,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145780315","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}
Pub Date : 2025-12-16DOI: 10.1016/j.cellsig.2025.112331
Lu Hu , Chun Li , Miaomiao Chen , Qiwen Zhou , Zhilong Jiang
CD47 plays an important role in immune evasion through suppressing macrophage phagocytosis. CD47 blockade has been widely explored in immunotherapy of cancers through enhancing macrophage phagocytosis. However, the role of CD47 in lung cancer cell apoptosis and ferroptosis is not well defined. In this study, we found that CD47 was highly expressed and ferroportin (FPN) was low expressed in lung cancer cells. Over-expression of CD47 increased the expression of Nrf2 (Nuclear factor erythroid 2-related factor 2); but suppressed the expression of FPN. Knock-down and blockade of CD47 expression and activity suppressed the expression of Nrf2 and enhanced the expression of FPN, subsequently improved lung cancer cell ferroptosis, accompanied with increased expression of pro-apoptotic protein Bax, production of reactive oxygen species (ROS) and hemosiderin deposition. Suppression of Nrf2 activity by Brusatol increased FPN expression at a concentration-dependent manner; whereas over-expression of FPN increased lung cancer cell ferroptosis. More studies in mouse model showed that knockdown of CD47 effectively attenuated lung cancer cell growth after subcutaneous inoculation of shCD47-pretreated LLC cells, associated with increased infiltration of neutrophils, CD8+ T cells and Malondialdehyde (MDA) products. Meanwhile, the expressions of TNF-α, IL-6 and IL-1β were elevated in the treated tumor tissues. IL-6 and TNF-α suppressed the expression of CD47, but increased the expression of FPN, accompanied with elevated expression of Bax, Cleaved caspase-3, NCOA4 (Nuclear receptor coactivator 4). Therefore, blockade of CD47 expression attenuated lung cancer growth through suppressing Nrf2 and subsequently increasing the expression of FPN. CD47 exerts immune evasion via Nrf2/FPN axis.
{"title":"Blockade of CD47 signaling improves ferroptosis of lung cancer cells via activating Nrf2/FPN signaling","authors":"Lu Hu , Chun Li , Miaomiao Chen , Qiwen Zhou , Zhilong Jiang","doi":"10.1016/j.cellsig.2025.112331","DOIUrl":"10.1016/j.cellsig.2025.112331","url":null,"abstract":"<div><div>CD47 plays an important role in immune evasion through suppressing macrophage phagocytosis. CD47 blockade has been widely explored in immunotherapy of cancers through enhancing macrophage phagocytosis. However, the role of CD47 in lung cancer cell apoptosis and ferroptosis is not well defined. In this study, we found that CD47 was highly expressed and ferroportin (FPN) was low expressed in lung cancer cells. Over-expression of CD47 increased the expression of Nrf2 (Nuclear factor erythroid 2-related factor 2); but suppressed the expression of FPN. Knock-down and blockade of CD47 expression and activity suppressed the expression of Nrf2 and enhanced the expression of FPN, subsequently improved lung cancer cell ferroptosis, accompanied with increased expression of pro-apoptotic protein Bax, production of reactive oxygen species (ROS) and hemosiderin deposition. Suppression of Nrf2 activity by Brusatol increased FPN expression at a concentration-dependent manner; whereas over-expression of FPN increased lung cancer cell ferroptosis. More studies in mouse model showed that knockdown of CD47 effectively attenuated lung cancer cell growth after subcutaneous inoculation of shCD47-pretreated LLC cells, associated with increased infiltration of neutrophils, CD8+ T cells and Malondialdehyde (MDA) products. Meanwhile, the expressions of TNF-α, IL-6 and IL-1β were elevated in the treated tumor tissues. IL-6 and TNF-α suppressed the expression of CD47, but increased the expression of FPN, accompanied with elevated expression of Bax, Cleaved caspase-3, NCOA4 (Nuclear receptor coactivator 4). Therefore, blockade of CD47 expression attenuated lung cancer growth through suppressing Nrf2 and subsequently increasing the expression of FPN. CD47 exerts immune evasion via Nrf2/FPN axis.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"139 ","pages":"Article 112331"},"PeriodicalIF":3.7,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145780299","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}
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