Pub Date : 2026-01-03DOI: 10.1016/j.cellsig.2025.112351
Meng Wang , Meiling Zhang , Jian Chen , Yan Wang , Junming Zhang , Yuwen Dai , Chenfei Zhao , Yukun Gan , Limin Liu , Zhichao Li
Hypoxic pulmonary hypertension (HPH) is a complex vascular disease that is difficult to reverse in its advanced stages and has a poor prognosis. Senescent pulmonary artery smooth muscle cells (PASMCs) had been shown to secrete senescence-associated secretory phenotype (SASP) mediators in HPH, including the pro-inflammatory factors IL-6 and IL-8, which up-regulate the inflammatory response, but the upstream regulatory mechanisms linking hypoxia to senescence remain elusive. SIRT6 regulates retrotransposon silencing, and LINE1 activation triggers cGAS-STING-mediated inflammation, yet their crosstalk in HPH is unreported. Our results show that hypoxia reduced nuclear SIRT6 abundance in PASMCs, which was associated with increased LINE1 activity, cGAS-STING pathway activation, and increased senescence markers (P16INK4A, β-galactosidase). SIRT6 activation (UBCS039) suppressed LINE1-cGAS-STING signaling and alleviated senescence, while SIRT6 inhibition (OSS-128167) recapitulated the hypoxic phenotype. Similar changes were observed in MCT-induced PH models. In addition, clearing the accumulation of LINE1 cDNA in the cytoplasm can inhibit the senescence of PASMCs, thereby reducing the inflammatory response and proliferation of PASMCs. Our findings identify the nuclear SIRT6-LINE1-cGAS-STING axis as a novel regulator of PASMCs senescence in HPH, providing a potential therapeutic target.
{"title":"Nuclear SIRT6 depletion activates LINE1-cGAS-STING pathway to induce PASMCs senescence in hypoxic pulmonary hypertension","authors":"Meng Wang , Meiling Zhang , Jian Chen , Yan Wang , Junming Zhang , Yuwen Dai , Chenfei Zhao , Yukun Gan , Limin Liu , Zhichao Li","doi":"10.1016/j.cellsig.2025.112351","DOIUrl":"10.1016/j.cellsig.2025.112351","url":null,"abstract":"<div><div>Hypoxic pulmonary hypertension (HPH) is a complex vascular disease that is difficult to reverse in its advanced stages and has a poor prognosis. Senescent pulmonary artery smooth muscle cells (PASMCs) had been shown to secrete senescence-associated secretory phenotype (SASP) mediators in HPH, including the pro-inflammatory factors IL-6 and IL-8, which up-regulate the inflammatory response, but the upstream regulatory mechanisms linking hypoxia to senescence remain elusive. SIRT6 regulates retrotransposon silencing, and LINE1 activation triggers cGAS-STING-mediated inflammation, yet their crosstalk in HPH is unreported. Our results show that hypoxia reduced nuclear SIRT6 abundance in PASMCs, which was associated with increased LINE1 activity, cGAS-STING pathway activation, and increased senescence markers (P16<sup>INK4A</sup>, β-galactosidase). SIRT6 activation (UBCS039) suppressed LINE1-cGAS-STING signaling and alleviated senescence, while SIRT6 inhibition (OSS-128167) recapitulated the hypoxic phenotype. Similar changes were observed in MCT-induced PH models. In addition, clearing the accumulation of LINE1 cDNA in the cytoplasm can inhibit the senescence of PASMCs, thereby reducing the inflammatory response and proliferation of PASMCs. Our findings identify the nuclear SIRT6-LINE1-cGAS-STING axis as a novel regulator of PASMCs senescence in HPH, providing a potential therapeutic target.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"139 ","pages":"Article 112351"},"PeriodicalIF":3.7,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145905765","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 : 2025-12-31DOI: 10.1016/j.cellsig.2025.112349
Xiaofei Duan , Zhipin Yan , Jie Gao , Zhihui Wang , Bowen Hu , An Zhao , Lei Liu , Minghao Li , Jihua Shi , Wenzhi Guo , Shuijun Zhang
Thioredoxin-related transmembrane protein 1 (TMX1), a member of the thioredoxin-like family, upregulated in certain human malignancies and is implicated in tumorigenesis and progression. However, its biological functions in hepatocellular carcinoma (HCC) remain largely unexplored. Through bioinformatic analysis and validation with clinical samples, it was determined that TMX1 expression is elevated in HCC patients and is associated with poor survival outcomes. Knocking down TMX1 resulted in a marked reduction in cell proliferation both in vivo and in vitro, whereas overexpressing TMX1 increased cell proliferation. Mechanistically, TMX1 binds to Fatty Acid-Binding Protein 5 (FABP5), thereby competitively blocking the interaction between FABP5 and the E3 ubiquitin ligase neuronally expressed developmentally downregulated 4 (NEDD4), and preventing K48-associated ubiquitination degradation of FABP5, thereby enhances the inhibition of FABP5-mediated ferroptosis signaling pathways. Furthermore, in TMX1-overexpressing HuH-7 cells, FABP5 knockdown negated the effects of TMX1 overexpression, suggesting that FABP5 mediates TMX1's regulation of HCC cell proliferation. Consequently, this study elucidates the mechanisms by which TMX1 contributes to HCC development, suggesting that TMX1 may serve as a potential biomarker and therapeutic target in the context of HCC.
{"title":"TMX1 promotes the progression of hepatocellular carcinoma by inhibiting ferroptosis via stabilizing FABP5","authors":"Xiaofei Duan , Zhipin Yan , Jie Gao , Zhihui Wang , Bowen Hu , An Zhao , Lei Liu , Minghao Li , Jihua Shi , Wenzhi Guo , Shuijun Zhang","doi":"10.1016/j.cellsig.2025.112349","DOIUrl":"10.1016/j.cellsig.2025.112349","url":null,"abstract":"<div><div>Thioredoxin-related transmembrane protein 1 (TMX1), a member of the thioredoxin-like family, upregulated in certain human malignancies and is implicated in tumorigenesis and progression. However, its biological functions in hepatocellular carcinoma (HCC) remain largely unexplored. Through bioinformatic analysis and validation with clinical samples, it was determined that TMX1 expression is elevated in HCC patients and is associated with poor survival outcomes. Knocking down TMX1 resulted in a marked reduction in cell proliferation both in vivo and in vitro, whereas overexpressing TMX1 increased cell proliferation. Mechanistically, TMX1 binds to Fatty Acid-Binding Protein 5 (FABP5), thereby competitively blocking the interaction between FABP5 and the E3 ubiquitin ligase neuronally expressed developmentally downregulated 4 (NEDD4), and preventing K48-associated ubiquitination degradation of FABP5, thereby enhances the inhibition of FABP5-mediated ferroptosis signaling pathways. Furthermore, in TMX1-overexpressing HuH-7 cells, FABP5 knockdown negated the effects of TMX1 overexpression, suggesting that FABP5 mediates TMX1's regulation of HCC cell proliferation. Consequently, this study elucidates the mechanisms by which TMX1 contributes to HCC development, suggesting that TMX1 may serve as a potential biomarker and therapeutic target in the context of HCC.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"140 ","pages":"Article 112349"},"PeriodicalIF":3.7,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892206","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 : 2025-12-31DOI: 10.1016/j.cellsig.2025.112350
Kangyu Wang , Changhong Xu , Hao Wang , Yalong Zhang , Zijian Zhang , Rui Yan , Li Wang , Jianwei Yang , Jiangwei Man , Li Yang
Background
Renal ischemia–reperfusion injury (RIRI) is a major cause of perioperative acute kidney injury and a driver of chronic kidney disease, in which mitochondrial dysfunction and inflammatory activation create a vicious cycle of oxidative stress, inflammation, and tubular cell death. Puerarin, a natural isoflavone with established cardio- and neuroprotective effects, has not been fully evaluated as a modulator of the mitochondrial–immune axis in RIRI.
Methods
Network pharmacology and RNA sequencing of mouse kidneys with bilateral RIRI were integrated to identify shared puerarin–RIRI targets and enriched pathways. Molecular docking and 100-ns molecular dynamics simulations were performed to assess puerarin–PI3K binding. In vivo, C57BL/6 mice underwent 45-min bilateral renal ischemia and 24-h reperfusion with or without puerarin pretreatment and/or the PI3K inhibitor LY294002. In vitro, HK-2 cells were subjected to hypoxia/reoxygenation. Renal injury, apoptosis, oxidative stress, inflammatory cytokines, mitochondrial ultrastructure, membrane potential, and mitochondrial dynamics proteins (Drp1, Opa1, Mfn2) were evaluated.
Results
Network pharmacology and transcriptomics consistently pointed to the PI3K/AKT/NF-κB pathway, which was enriched in oxidative stress, apoptosis, inflammatory signaling, and mitochondrial processes. In both RIRI mice and HR-treated HK-2 cells, puerarin improved renal histology and function, reduced tubular apoptosis and IL-6/IL-1β/TNF-α levels, restored SOD and GSH-Px, lowered ROS and MDA, and preserved mitochondrial membrane potential and ultrastructure. These benefits were accompanied by activation of PI3K/AKT signaling and attenuation of NF-κB, together with normalization of mitochondrial fission–fusion (decreased Drp1, increased Opa1/Mfn2), whereas LY294002 markedly blunted puerarin-induced improvements in mitochondrial dynamics, membrane potential, and injury indices.
Conclusion
Puerarin ameliorates RIRI by activating PI3K/AKT signaling, restoring mitochondrial homeostasis, and attenuating NF-κB–linked inflammatory and apoptotic responses. These findings support puerarin as a mitochondria- and immune-targeted candidate for perioperative renal protection and justify further translational evaluation.
{"title":"Puerarin protects against renal ischemia-reperfusion injury by restoring mitochondrial function and modulating the PI3K/AKT/NF-k B pathway and suppressing inflammatory responses","authors":"Kangyu Wang , Changhong Xu , Hao Wang , Yalong Zhang , Zijian Zhang , Rui Yan , Li Wang , Jianwei Yang , Jiangwei Man , Li Yang","doi":"10.1016/j.cellsig.2025.112350","DOIUrl":"10.1016/j.cellsig.2025.112350","url":null,"abstract":"<div><h3>Background</h3><div>Renal ischemia–reperfusion injury (RIRI) is a major cause of perioperative acute kidney injury and a driver of chronic kidney disease, in which mitochondrial dysfunction and inflammatory activation create a vicious cycle of oxidative stress, inflammation, and tubular cell death. Puerarin, a natural isoflavone with established cardio- and neuroprotective effects, has not been fully evaluated as a modulator of the mitochondrial–immune axis in RIRI.</div></div><div><h3>Methods</h3><div>Network pharmacology and RNA sequencing of mouse kidneys with bilateral RIRI were integrated to identify shared puerarin–RIRI targets and enriched pathways. Molecular docking and 100-ns molecular dynamics simulations were performed to assess puerarin–PI3K binding. In vivo, C57BL/6 mice underwent 45-min bilateral renal ischemia and 24-h reperfusion with or without puerarin pretreatment and/or the PI3K inhibitor LY294002. In vitro, HK-2 cells were subjected to hypoxia/reoxygenation. Renal injury, apoptosis, oxidative stress, inflammatory cytokines, mitochondrial ultrastructure, membrane potential, and mitochondrial dynamics proteins (Drp1, Opa1, Mfn2) were evaluated.</div></div><div><h3>Results</h3><div>Network pharmacology and transcriptomics consistently pointed to the PI3K/AKT/NF-κB pathway, which was enriched in oxidative stress, apoptosis, inflammatory signaling, and mitochondrial processes. In both RIRI mice and HR-treated HK-2 cells, puerarin improved renal histology and function, reduced tubular apoptosis and IL-6/IL-1β/TNF-α levels, restored SOD and GSH-Px, lowered ROS and MDA, and preserved mitochondrial membrane potential and ultrastructure. These benefits were accompanied by activation of PI3K/AKT signaling and attenuation of NF-κB, together with normalization of mitochondrial fission–fusion (decreased Drp1, increased Opa1/Mfn2), whereas LY294002 markedly blunted puerarin-induced improvements in mitochondrial dynamics, membrane potential, and injury indices.</div></div><div><h3>Conclusion</h3><div>Puerarin ameliorates RIRI by activating PI3K/AKT signaling, restoring mitochondrial homeostasis, and attenuating NF-κB–linked inflammatory and apoptotic responses. These findings support puerarin as a mitochondria- and immune-targeted candidate for perioperative renal protection and justify further translational evaluation.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"139 ","pages":"Article 112350"},"PeriodicalIF":3.7,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145881113","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 : 2025-12-29DOI: 10.1016/j.cellsig.2025.112341
Xiaoke Wu , Yao Zhang , Guang Rong , Zixiao Zhang , Jieyu Jin , Junchao Feng , Haiyang Wu , Yin Wang
Glioma is a highly aggressive central nervous system malignancy with poor prognosis and limited therapeutic options. Selenoprotein P (SeP) plays key roles in the nervous system, but its function in glioma remains unclear. Analysis of TCGA and CGGA datasets revealed that SeP is highly expressed in glioma tissues and correlates with poor patient survival. In vitro, SeP knockdown inhibited glioma cell proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT), induced mitochondrial-dependent apoptosis, and reduced nuclear β-catenin and downstream targets Cyclin D1 and c-Myc, whereas SeP overexpression produced opposite effects. Mechanistically, SeP directly binds to low-density lipoprotein receptor-related protein 8 (LRP8) to activate Wnt/β-catenin signaling. Rescue experiments showed that LRP8 overexpression or Wnt agonist treatment reversed the inhibitory effects of SeP knockdown, while LRP8 knockdown or Wnt inhibition blocked SeP-induced malignancy. In subcutaneous xenograft models, SeP silencing suppressed tumor growth, decreased Ki-67 proliferation, and increased Caspase-3–mediated apoptosis, whereas LRP8 overexpression restored tumor growth and Wnt/β-catenin activity. Collectively, these results demonstrate that SeP promotes glioma malignancy via an LRP8-dependent activation of Wnt/β-catenin signaling and suggest the SeP–LRP8–Wnt/β-catenin axis as a potential therapeutic target.
{"title":"Selenoprotein P drives glioma malignancy via LRP8-dependent activation of Wnt/β-catenin signaling","authors":"Xiaoke Wu , Yao Zhang , Guang Rong , Zixiao Zhang , Jieyu Jin , Junchao Feng , Haiyang Wu , Yin Wang","doi":"10.1016/j.cellsig.2025.112341","DOIUrl":"10.1016/j.cellsig.2025.112341","url":null,"abstract":"<div><div>Glioma is a highly aggressive central nervous system malignancy with poor prognosis and limited therapeutic options. Selenoprotein P (SeP) plays key roles in the nervous system, but its function in glioma remains unclear. Analysis of TCGA and CGGA datasets revealed that SeP is highly expressed in glioma tissues and correlates with poor patient survival. In vitro, SeP knockdown inhibited glioma cell proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT), induced mitochondrial-dependent apoptosis, and reduced nuclear β-catenin and downstream targets Cyclin D1 and c-Myc, whereas SeP overexpression produced opposite effects. Mechanistically, SeP directly binds to low-density lipoprotein receptor-related protein 8 (LRP8) to activate Wnt/β-catenin signaling. Rescue experiments showed that LRP8 overexpression or Wnt agonist treatment reversed the inhibitory effects of SeP knockdown, while LRP8 knockdown or Wnt inhibition blocked SeP-induced malignancy. In subcutaneous xenograft models, SeP silencing suppressed tumor growth, decreased Ki-67 proliferation, and increased Caspase-3–mediated apoptosis, whereas LRP8 overexpression restored tumor growth and Wnt/β-catenin activity. Collectively, these results demonstrate that SeP promotes glioma malignancy via an LRP8-dependent activation of Wnt/β-catenin signaling and suggest the SeP–LRP8–Wnt/β-catenin axis as a potential therapeutic target.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"139 ","pages":"Article 112341"},"PeriodicalIF":3.7,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145877853","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 : 2025-12-29DOI: 10.1016/j.cellsig.2025.112347
Oygul Mirzalieva, Ryan E. Reed, Arthur L. Haas, Meredith A. Juncker , Patrick Logarbo, Jennifer M. Klein, David Worthylake, Shyamal D. Desai
Dysregulation of endoplasmic reticulum and mitochondrial (ER:Mit) contacts and mitochondrial calcium (mitCa2+) homeostasis are found in several neurodegenerative disorders, including Ataxia Telangiectasia (A-T). However, the cellular basis of these defects remains unclear. Previously, we demonstrated that the aberrantly elevated Interferon-Stimulated Gene 15 (ISG15) pathway inhibits protein polyubiquitylation, its dependent protein turnover, and mitophagy pathways in A-T. Literature indicates that silencing of mitochondrial ubiquitin ligase 1 (MUL1) stabilizes mitofusin2 (MFN2) and attenuates mitCa2+ uptake from ER to Mit (mitCa2+influx) in primary neurons. We have replicated these findings in apparently healthy fibroblasts. We hypothesized that elevated ISG15 may inhibit ubiquitin-dependent MUL1-mediated degradation of MFN2 and dysregulate ER:Mit contacts and mitCa2+ homeostasis in A-T fibroblasts. Concurrently, MFN2 is stabilized in A-T, MUL1-silenced A-T, MUL1/ISG15-silenced A-T vs ISG15-silenced A-T fibroblasts. Moreover, the number of ER:Mit contacts is increased in A-T vs ISG15-silenced A-T fibroblasts. Notably, mitCa2+efflux is significantly attenuated in A-T vs ISG15-silenced A-T fibroblasts in which mitCa2+efflux is restored to levels comparable to those observed in normal fibroblasts. The mitCa2+efflux remains attenuated in MUL1 and MUL1/ISG15-silenced A-T fibroblasts. We conclude that ISG15 impairs MUL1/MFN2-mediated regulation of ER:Mit contacts and attenuates mitCa2+efflux, which may, in turn, cause Ca2+ overload-mediated mitochondrial damage in A-T. These findings suggest that ISG15 silencers may correct mitochondrial abnormalities and improve mitochondrial health in A-T patients and in those with other neurodegenerative disorders in which ISG15 is elevated, such as ALS.
{"title":"ISG15 dysregulates endoplasmic reticulum-mitochondrial contacts and calcium homeostasis in Ataxia telangiectasia","authors":"Oygul Mirzalieva, Ryan E. Reed, Arthur L. Haas, Meredith A. Juncker , Patrick Logarbo, Jennifer M. Klein, David Worthylake, Shyamal D. Desai","doi":"10.1016/j.cellsig.2025.112347","DOIUrl":"10.1016/j.cellsig.2025.112347","url":null,"abstract":"<div><div>Dysregulation of endoplasmic reticulum and mitochondrial (ER:Mit) contacts and mitochondrial calcium (mitCa<sup>2+</sup>) homeostasis are found in several neurodegenerative disorders, including Ataxia Telangiectasia (A-T). However, the cellular basis of these defects remains unclear. Previously, we demonstrated that the aberrantly elevated Interferon-Stimulated Gene 15 (ISG15) pathway inhibits protein polyubiquitylation, its dependent protein turnover, and mitophagy pathways in A-T. Literature indicates that silencing of mitochondrial ubiquitin ligase 1 (MUL1) stabilizes mitofusin2 (MFN2) and attenuates mitCa<sup>2+</sup> uptake from ER to Mit (mitCa<sup>2+</sup><sub>influx</sub>) in primary neurons. We have replicated these findings in apparently healthy fibroblasts. We hypothesized that elevated ISG15 may inhibit ubiquitin-dependent MUL1-mediated degradation of MFN2 and dysregulate ER:Mit contacts and mitCa<sup>2+</sup> homeostasis in A-T fibroblasts. Concurrently, MFN2 is stabilized in A-T, MUL1-silenced A-T, MUL1/ISG15-silenced A-T <em>vs</em> ISG15-silenced A-T fibroblasts. Moreover, the number of ER:Mit contacts is increased in A-T <em>vs</em> ISG15-silenced A-T fibroblasts. Notably, mitCa<sup>2+</sup><sub>efflux</sub> is significantly attenuated in A-T <em>vs</em> ISG15-silenced A-T fibroblasts in which mitCa<sup>2+</sup><sub>efflux</sub> is restored to levels comparable to those observed in normal fibroblasts. The mitCa<sup>2+</sup><sub>efflux</sub> remains attenuated in MUL1 and MUL1/ISG15-silenced A-T fibroblasts. We conclude that ISG15 impairs MUL1/MFN2-mediated regulation of ER:Mit contacts and attenuates mitCa<sup>2+</sup><sub>efflux</sub>, which may, in turn, cause Ca<sup>2+</sup> overload-mediated mitochondrial damage in A-T. These findings suggest that ISG15 silencers may correct mitochondrial abnormalities and improve mitochondrial health in A-T patients and in those with other neurodegenerative disorders in which ISG15 is elevated, such as ALS.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"139 ","pages":"Article 112347"},"PeriodicalIF":3.7,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145877867","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 : 2025-12-26DOI: 10.1016/j.cellsig.2025.112344
Ying Ren , Yunfang Yang , Xiaodan Zhu , Lingyi Li , Yaoyao Pan , Hong Sun , Qian Fang , Hui Xiong , Dong Guo , Yongzhan Sun , Hailong Li , Junqi Wang
Clear cell renal cell carcinoma (ccRCC), the most common type of kidney cancer, remains challenging to treat due to the lack of effective targeted therapies. Although c-Myc is frequently overexpressed in ccRCC, the mechanisms governing its stability are not well understood. Here, we identify the deubiquitinating enzyme USP28 as a key regulator of c-Myc protein stability in ccRCC. USP28 interacts with c-Myc, removes K48-linked polyubiquitin chains, and thereby prevents its proteasomal degradation, leading to c-Myc stabilization in ccRCC cells. Genetic or pharmacological inhibition of USP28 significantly reduces c-Myc expression, impairs ccRCC cell proliferation in vitro, and suppresses tumor growth in vivo. Tumors with high c-Myc expression exhibit heightened sensitivity to USP28 inhibition, underscoring the therapeutic potential of targeting this axis. Collectively, our findings position USP28 as a promising therapeutic target for ccRCC.
{"title":"Targeting USP28 inhibits clear cell renal cell carcinoma growth","authors":"Ying Ren , Yunfang Yang , Xiaodan Zhu , Lingyi Li , Yaoyao Pan , Hong Sun , Qian Fang , Hui Xiong , Dong Guo , Yongzhan Sun , Hailong Li , Junqi Wang","doi":"10.1016/j.cellsig.2025.112344","DOIUrl":"10.1016/j.cellsig.2025.112344","url":null,"abstract":"<div><div>Clear cell renal cell carcinoma (ccRCC), the most common type of kidney cancer, remains challenging to treat due to the lack of effective targeted therapies. Although c-Myc is frequently overexpressed in ccRCC, the mechanisms governing its stability are not well understood. Here, we identify the deubiquitinating enzyme USP28 as a key regulator of c-Myc protein stability in ccRCC. USP28 interacts with c-Myc, removes K48-linked polyubiquitin chains, and thereby prevents its proteasomal degradation, leading to c-Myc stabilization in ccRCC cells. Genetic or pharmacological inhibition of USP28 significantly reduces c-Myc expression, impairs ccRCC cell proliferation <em>in vitro</em>, and suppresses tumor growth <em>in vivo</em>. Tumors with high c-Myc expression exhibit heightened sensitivity to USP28 inhibition, underscoring the therapeutic potential of targeting this axis. Collectively, our findings position USP28 as a promising therapeutic target for ccRCC.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"139 ","pages":"Article 112344"},"PeriodicalIF":3.7,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145849033","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 : 2025-12-26DOI: 10.1016/j.cellsig.2025.112345
Yuxuan Shi , Guoqiang Xu , Shuang Liu , Xin Liu , Wendi Chen , Guolong Wang , Yongzhi Cao , Yunna Ning , Yanfei Jia , Yueran Zhao
Diabetic cardiomyopathy (DCM) is a significant cardiovascular consequence of diabetes, marked by increasing myocardial dysfunction that culminates in heart failure. Current treatments prioritize glucose control but frequently neglect the fundamental metabolic dysfunction and excessive cardiomyocyte death that propel disease progression. Recent data indicates that β-hydroxybutyrate dehydrogenase 1 (BDH1), the rate-limiting enzyme in ketolysis may serve a protective function by supplying alternative energy substrates and regulating apoptosis. This study demonstrates that BDH1 overexpression in H9c2 and AC16 cardiomyocytes treated with high glucose and palmitate dramatically decreases apoptosis. In a streptozotocin-induced diabetic mouse model, cardiac-specific BDH1 overexpression via AAV9 delivery maintained cardiac structure and function by inhibiting apoptosis through two primary mechanisms: (1) interaction with KIF1Bβ to modulate mitochondrial dynamics, and (2) suppression of ROS-mediated apoptosome formation (Cytc/Apaf-1 complex). These findings designate BDH1 as an innovative therapeutic target for DCM by illustrating its dual function in metabolic regulation and apoptosis inhibition, while recognizing ROS and KIF1Bβ as pivotal mediators of DCM pathogenesis.
{"title":"BDH1 regulates cardiomyocyte apoptosis and diabetic cardiomyopathy by modulating mitochondrial dynamics and attenuating oxidative stress","authors":"Yuxuan Shi , Guoqiang Xu , Shuang Liu , Xin Liu , Wendi Chen , Guolong Wang , Yongzhi Cao , Yunna Ning , Yanfei Jia , Yueran Zhao","doi":"10.1016/j.cellsig.2025.112345","DOIUrl":"10.1016/j.cellsig.2025.112345","url":null,"abstract":"<div><div>Diabetic cardiomyopathy (DCM) is a significant cardiovascular consequence of diabetes, marked by increasing myocardial dysfunction that culminates in heart failure. Current treatments prioritize glucose control but frequently neglect the fundamental metabolic dysfunction and excessive cardiomyocyte death that propel disease progression. Recent data indicates that β-hydroxybutyrate dehydrogenase 1 (BDH1), the rate-limiting enzyme in ketolysis may serve a protective function by supplying alternative energy substrates and regulating apoptosis. This study demonstrates that BDH1 overexpression in H9c2 and AC16 cardiomyocytes treated with high glucose and palmitate dramatically decreases apoptosis. In a streptozotocin-induced diabetic mouse model, cardiac-specific BDH1 overexpression via AAV9 delivery maintained cardiac structure and function by inhibiting apoptosis through two primary mechanisms: (1) interaction with KIF1Bβ to modulate mitochondrial dynamics, and (2) suppression of ROS-mediated apoptosome formation (Cytc/Apaf-1 complex). These findings designate BDH1 as an innovative therapeutic target for DCM by illustrating its dual function in metabolic regulation and apoptosis inhibition, while recognizing ROS and KIF1Bβ as pivotal mediators of DCM pathogenesis.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"139 ","pages":"Article 112345"},"PeriodicalIF":3.7,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145849017","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 : 2025-12-26DOI: 10.1016/j.cellsig.2025.112346
Ke Chen , Yujie Lin , Liudan Chen, Jianjun Li, Aizhen Pan
Objective
Cardiac ischemia/reperfusion (I/R) injury is characterized by excessive inflammation and aberrant activation of intracellular signaling pathways, including JAK/STAT. Cornus officinalis total glycosides (COTG) possess anti-inflammatory properties, but their role in myocardial I/R injury remains incompletely defined. This study aimed to investigate the cardioprotective effects of COTG against I/R -induced injury and clarify its pathway-dependent mechanism involving JAK1/STAT3 signaling.
Methods
A myocardial I/R injury model was established in male Sprague–Dawley rats, which were randomly divided into Sham control, I/R control, and COTG-treated groups (200, 400, and 600 mg/kg). Cardiac function was evaluated by echocardiography, and myocardial histopathology was assessed by hematoxylin and eosin staining. Serum myocardial injury markers were measured by ELISA. Inflammatory cytokine expression and macrophage polarization were analyzed using qRT-PCR and immunofluorescence, respectively. JAK1/2 and STAT3 phosphorylation was detected by Western blotting. An in vitro hypoxia/reoxygenation (H/R) model combined with a pharmacological JAK inhibitor was further employed to verify pathway dependency.
Results
COTG treatment significantly improved cardiac function, as evidenced by increased left ventricular ejection fraction and fractional shortening and reduced ventricular dilation. Histological damage and serum levels of cardiac troponin I, cardiac troponin T, and creatine kinase-MB were markedly attenuated. COTG suppressed pro-inflammatory markers (iNOS, IL-1β, IL-6) while enhancing anti-inflammatory mediators (Arg-1, IL-10). Mechanistically, COTG dose-dependently inhibited JAK1, JAK2, and STAT3 phosphorylation without altering total protein levels. Pharmacological inhibition experiments confirmed that JAK/STAT suppression by COTG was pathway-dependent. Moreover, COTG reduced myocardial apoptosis by increasing Bcl-2 and decreasing Bax and cleaved caspase-3 expression.
Conclusion
COTG protects against myocardial I/R injury by pathway-dependent inhibition of JAK/STAT signaling, modulation of inflammatory responses, and attenuation of cardiomyocyte apoptosis, highlighting its therapeutic potential for ischemic heart disease.
{"title":"Cornus officinalis total glycosides modulate inflammatory response and inhibit the JAK1/STAT3 pathway within a preclinical rat model of cardiac ischemia/reperfusion-induced injury","authors":"Ke Chen , Yujie Lin , Liudan Chen, Jianjun Li, Aizhen Pan","doi":"10.1016/j.cellsig.2025.112346","DOIUrl":"10.1016/j.cellsig.2025.112346","url":null,"abstract":"<div><h3>Objective</h3><div>Cardiac ischemia/reperfusion (I/R) injury is characterized by excessive inflammation and aberrant activation of intracellular signaling pathways, including JAK/STAT. <em>Cornus officinalis</em> total glycosides (COTG) possess anti-inflammatory properties, but their role in myocardial I/R injury remains incompletely defined. This study aimed to investigate the cardioprotective effects of COTG against I/R -induced injury and clarify its pathway-dependent mechanism involving JAK1/STAT3 signaling.</div></div><div><h3>Methods</h3><div>A myocardial I/R injury model was established in male Sprague–Dawley rats, which were randomly divided into Sham control, I/R control, and COTG-treated groups (200, 400, and 600 mg/kg). Cardiac function was evaluated by echocardiography, and myocardial histopathology was assessed by hematoxylin and eosin staining. Serum myocardial injury markers were measured by ELISA. Inflammatory cytokine expression and macrophage polarization were analyzed using qRT-PCR and immunofluorescence, respectively. JAK1/2 and STAT3 phosphorylation was detected by Western blotting. An in vitro hypoxia/reoxygenation (H/R) model combined with a pharmacological JAK inhibitor was further employed to verify pathway dependency.</div></div><div><h3>Results</h3><div>COTG treatment significantly improved cardiac function, as evidenced by increased left ventricular ejection fraction and fractional shortening and reduced ventricular dilation. Histological damage and serum levels of cardiac troponin I, cardiac troponin T, and creatine kinase-MB were markedly attenuated. COTG suppressed pro-inflammatory markers (iNOS, IL-1β, IL-6) while enhancing anti-inflammatory mediators (Arg-1, IL-10). Mechanistically, COTG dose-dependently inhibited JAK1, JAK2, and STAT3 phosphorylation without altering total protein levels. Pharmacological inhibition experiments confirmed that JAK/STAT suppression by COTG was pathway-dependent. Moreover, COTG reduced myocardial apoptosis by increasing Bcl-2 and decreasing Bax and cleaved caspase-3 expression.</div></div><div><h3>Conclusion</h3><div>COTG protects against myocardial I/R injury by pathway-dependent inhibition of JAK/STAT signaling, modulation of inflammatory responses, and attenuation of cardiomyocyte apoptosis, highlighting its therapeutic potential for ischemic heart disease.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"139 ","pages":"Article 112346"},"PeriodicalIF":3.7,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145848951","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}
The mechanisms underlying ubiquitination-mediated degradation of bestrophinopathy-causing mutants and their in vivo effects on retinal pigment epithelium (RPE) localization and retinal structure remain poorly understood. Furthermore, the upstream signaling cascade that induces degradation of these mutants and the detailed ubiquitination mechanism are unknown. Here, we report a c.1037C > A (p.P346H) mutation and a c.698C > T (p.P233L) mutation that co-segregate with the phenotypes of pedigrees affected by RP50 and Best vitelliform macular dystrophy (BVMD), respectively. The BEST1 mutants p.P233L and p.P346H reduced chloride channel activity and induced mislocalization of bestrophin-1 in polarized MDCK II cells, significantly affecting the channel activity of wild-type bestrophin-1. Lys149 was identified as the site responsible for ubiquitination of p.P346H- and p.P233L-bestrophin-1, mediated by Hsp70 and the C-terminal Hsp70-interacting protein (CHIP). Mutant bestrophin-1 proteins p.P346H and p.P233L undergo ubiquitination and degradation, preventing their localization to the cell membrane of MDCK II cells and the RPE of zebrafish, thereby reducing chloride channel activity. Mislocalization of mutant bestrophin-1 to the RPE impaired the multicellular layered structure of the retina. Our study reveals a ubiquitination signaling pathway mediated by Hsp70 and CHIP that depends on Lys149 of bestrophin-1. Aberrant activation of this pathway leads to loss of function in the p.P233L and p.P346H mutants and triggers retinopathy.
泛素化介导的白视病突变体降解的机制及其对视网膜色素上皮（RPE）定位和视网膜结构的体内影响尚不清楚。此外，诱导这些突变体降解的上游信号级联和详细的泛素化机制尚不清楚。在这里，我们报道了一个c.1037C > a （p.P346H）突变和一个c.698C > T （p.P233L）突变，它们分别与受RP50和BVMD影响的家系表型共分离。BEST1突变体p.P233L和p.P346H降低了MDCK II细胞中氯离子通道的活性，诱导了bestrophin-1的错定位，显著影响了野生型bestrophin-1的通道活性。Lys149被鉴定为由Hsp70和c端Hsp70相互作用蛋白（CHIP）介导的p.P346H-和p.p 233l - strophin-1泛素化的位点。突变的bestrophin-1蛋白p.P346H和p.P233L发生泛素化和降解，阻止其定位于MDCK II细胞的细胞膜和斑马鱼的RPE，从而降低氯离子通道活性。突变的strophin-1在RPE上的错误定位损害了视网膜的多细胞分层结构。我们的研究揭示了一个由Hsp70和CHIP介导的泛素化信号通路，它依赖于bestrophin-1的Lys149。该通路的异常激活导致p.P233L和p.P346H突变体功能丧失，并引发视网膜病变。
{"title":"Hsp70/CHIP E3 ligase complex triggers K149-linked ubiquitination and degradation of BEST1 mutants p.P233L and p.P346H, impairing chloride channel function and retinal integrity","authors":"Zhongxue Zhou , Hongxia Tian , Ning Ma , Wen Fang , Qingxia Lu , Huiyang , HaiyingTian , Yu Tang , Ling Tian , Xu Jia , Yuanju Zhang , Yuqian Li , Xiaoyan Zhu , Qiao Yu , Ding'an Zhou","doi":"10.1016/j.cellsig.2025.112343","DOIUrl":"10.1016/j.cellsig.2025.112343","url":null,"abstract":"<div><div>The mechanisms underlying ubiquitination-mediated degradation of bestrophinopathy-causing mutants and their in vivo effects on retinal pigment epithelium (RPE) localization and retinal structure remain poorly understood. Furthermore, the upstream signaling cascade that induces degradation of these mutants and the detailed ubiquitination mechanism are unknown. Here, we report a c.1037C > A (p.P346H) mutation and a c.698C > T (p.P233L) mutation that co-segregate with the phenotypes of pedigrees affected by RP50 and Best vitelliform macular dystrophy (BVMD), respectively. The <em>BEST1</em> mutants p.P233L and p.P346H reduced chloride channel activity and induced mislocalization of bestrophin-1 in polarized MDCK II cells, significantly affecting the channel activity of wild-type bestrophin-1. Lys149 was identified as the site responsible for ubiquitination of p.P346H- and p.P233L-bestrophin-1, mediated by Hsp70 and the C-terminal Hsp70-interacting protein (CHIP). Mutant bestrophin-1 proteins p.P346H and p.P233L undergo ubiquitination and degradation, preventing their localization to the cell membrane of MDCK II cells and the RPE of zebrafish, thereby reducing chloride channel activity. Mislocalization of mutant bestrophin-1 to the RPE impaired the multicellular layered structure of the retina. Our study reveals a ubiquitination signaling pathway mediated by Hsp70 and CHIP that depends on Lys149 of bestrophin-1. Aberrant activation of this pathway leads to loss of function in the p.P233L and p.P346H mutants and triggers retinopathy.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"139 ","pages":"Article 112343"},"PeriodicalIF":3.7,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145848988","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 : 2025-12-23DOI: 10.1016/j.cellsig.2025.112342
Kaili Mao , Wensi Zhu , Huayu Sun , Hongliang Zheng , Zhenling Fu
Senescence of vascular endothelial cells (ECs) and smooth muscle cells is pivotal in vascular aging. While the long non-coding RNA JPX has been shown to induce smooth muscle cell senescence, its role in EC senescence remains unknown. Senolytics (dasatinib + quercetin, D + Q) can eliminate senescent cells and attenuate the senescence-associated secretory phenotype (SASP), but their mechanisms in ECs are unclear. Here, we investigated the interplay between Senolytics and JPX in human umbilical vein endothelial cells (HUVECs). Using a lipopolysaccharide (LPS)-induced senescence model, we found that Senolytics alleviated endothelial senescence while suppressing the upregulation of JPX observed in senescent HUVECs. Functional assays showed that JPX knockdown inhibited, whereas JPX overexpression aggravated, EC senescence. Mechanistically, JPX interacted with bromodomain-containing protein 4 (BRD4) and transcription factor p65 to form a JPX-BRD4-p65 complex that promoted SASP expression. In vivo, Senolytics disrupted this complex and effectively mitigated endothelial senescence. Collectively, our study identifies JPX as a key regulator of vascular endothelial senescence and reveals that Senolytics exert anti-senescent effects by antagonizing the JPX-BRD4-p65 complex, providing novel mechanistic insights and potential therapeutic targets for vascular aging–related diseases.
{"title":"The anti-aging drug Senolytics alleviates vascular endothelial cell senescence by antagonizing the JPX-BRD4-p65 complex","authors":"Kaili Mao , Wensi Zhu , Huayu Sun , Hongliang Zheng , Zhenling Fu","doi":"10.1016/j.cellsig.2025.112342","DOIUrl":"10.1016/j.cellsig.2025.112342","url":null,"abstract":"<div><div>Senescence of vascular endothelial cells (ECs) and smooth muscle cells is pivotal in vascular aging. While the long non-coding RNA JPX has been shown to induce smooth muscle cell senescence, its role in EC senescence remains unknown. Senolytics (dasatinib + quercetin, D + Q) can eliminate senescent cells and attenuate the senescence-associated secretory phenotype (SASP), but their mechanisms in ECs are unclear. Here, we investigated the interplay between Senolytics and JPX in human umbilical vein endothelial cells (HUVECs). Using a lipopolysaccharide (LPS)-induced senescence model, we found that Senolytics alleviated endothelial senescence while suppressing the upregulation of JPX observed in senescent HUVECs. Functional assays showed that JPX knockdown inhibited, whereas JPX overexpression aggravated, EC senescence. Mechanistically, JPX interacted with bromodomain-containing protein 4 (BRD4) and transcription factor p65 to form a JPX-BRD4-p65 complex that promoted SASP expression. In vivo, Senolytics disrupted this complex and effectively mitigated endothelial senescence. Collectively, our study identifies JPX as a key regulator of vascular endothelial senescence and reveals that Senolytics exert anti-senescent effects by antagonizing the JPX-BRD4-p65 complex, providing novel mechanistic insights and potential therapeutic targets for vascular aging–related diseases.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"139 ","pages":"Article 112342"},"PeriodicalIF":3.7,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145833221","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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