Pub Date : 2025-08-15DOI: 10.1016/j.bbamcr.2025.120046
Joshua Chung , Nathan Isles , Stuart Johnston , David J. Collins , Julie R. McMullen , H. Llewelyn Roderick , Vijay Rajagopal
Cardiomyocyte hypertrophic growth contributes to the adaptative response of the heart to meet sustained increases in hemodynamic demand. While hypertrophic responses to physiological cues maintains or enhances cardiac function, when triggered by pathological cues, this response is maladaptive, associated with compromised heart function, although initially, this response maybe adaptive with preserved function. Since cues and activated pathways associated with both forms of hypertrophy overlap, the question arises as to the mechanism that determines these different outcomes. Here we evaluate the hypothesis that cardiomyocyte Ca2+ signalling – a regulator of pathological hypertrophy – also signals physiological hypertrophy. We discuss how different Ca2+ profiles, in distinct subcellular organelles/microdomains, and interacting with other signalling pathways, provide a mechanism for Ca2+ to be decoded to induce distinct hypertrophic phenotypes. We discuss how integration of computational with rich structural and functional cellular measurements can be used to decipher the role of Ca2+ in hypertrophic gene programming.
{"title":"Calcium-dependent regulation of physiological vs pathological cardiomyocyte hypertrophy","authors":"Joshua Chung , Nathan Isles , Stuart Johnston , David J. Collins , Julie R. McMullen , H. Llewelyn Roderick , Vijay Rajagopal","doi":"10.1016/j.bbamcr.2025.120046","DOIUrl":"10.1016/j.bbamcr.2025.120046","url":null,"abstract":"<div><div>Cardiomyocyte hypertrophic growth contributes to the adaptative response of the heart to meet sustained increases in hemodynamic demand. While hypertrophic responses to physiological cues maintains or enhances cardiac function, when triggered by pathological cues, this response is maladaptive, associated with compromised heart function, although initially, this response maybe adaptive with preserved function. Since cues and activated pathways associated with both forms of hypertrophy overlap, the question arises as to the mechanism that determines these different outcomes. Here we evaluate the hypothesis that cardiomyocyte Ca<sup>2+</sup> signalling – a regulator of pathological hypertrophy – also signals physiological hypertrophy. We discuss how different Ca<sup>2+</sup> profiles, in distinct subcellular organelles/microdomains, and interacting with other signalling pathways, provide a mechanism for Ca<sup>2+</sup> to be decoded to induce distinct hypertrophic phenotypes. We discuss how integration of computational with rich structural and functional cellular measurements can be used to decipher the role of Ca<sup>2+</sup> in hypertrophic gene programming.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 8","pages":"Article 120046"},"PeriodicalIF":3.7,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144871189","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 : 2025-08-14DOI: 10.1016/j.bbamcr.2025.120047
Lei Yin , Yanze Lin , Zhongdian Yuan , Rexiati Ruze , Zhen Yang , Yingmei Shao
This study aimed to characterize the oncogenic functions of Prominin 2 (PROM2), the pro-cancer and ferroptosis resistance gene, in breast cancer (BC). PROM2 expression was analyzed using single-cell RNA sequencing and the TCGA database. Its expression was confirmed in BC tissues and cell lines using qRT-PCR, immunohistochemistry, and western blot assays. The effects of PROM2 were evaluated in vivo and in vitro. RNA sequencing and GSEA were used to investigate the potential underlying molecular mechanisms of PROM2 in BC. Co-immunoprecipitation was used to determine the interaction between AKT and PROM2. PROM2 expression was elevated in clinical samples and BC cells and positively correlated with a worse prognosis. Functional experiments demonstrated that PROM2 silencing suppressed tumor growth and malignancy. Mechanistically, PROM2 interacts with AKT to activate mTOR signaling, thereby promoting glycolysis and inhibiting ferroptosis. Specifically, for glycolysis, PROM2 silencing decreased glucose uptake, extracellular acidification rate, lactate production, and glycolysis-related enzyme expression, while increasing oxygen consumption. For ferroptosis, PROM2 silencing upregulated reactive oxygen species, malondialdehyde, iron, Fe2+, and downregulated SLC7A11, GPX4, and glutathione levels. Overexpression of AKT or the AKT agonist (SC79) reversed the effects of PROM2 silencing on BC cell glycolysis and ferroptosis. Our results suggest that PROM2 is an oncogenic gene that supports BC progression by enhancing glycolysis and inhibiting ferroptosis via AKT/mTOR signaling. Therefore, PROM2 may be a potential therapeutic target for BC treatment.
{"title":"Loss of Prominin 2 expression inhibits AKT/mTOR signaling to limit glycolysis and drive ferroptosis in breast cancer cells","authors":"Lei Yin , Yanze Lin , Zhongdian Yuan , Rexiati Ruze , Zhen Yang , Yingmei Shao","doi":"10.1016/j.bbamcr.2025.120047","DOIUrl":"10.1016/j.bbamcr.2025.120047","url":null,"abstract":"<div><div>This study aimed to characterize the oncogenic functions of Prominin 2 (<em>PROM2</em>), the pro-cancer and ferroptosis resistance gene, in breast cancer (BC). <em>PROM2</em> expression was analyzed using single-cell RNA sequencing and the TCGA database. Its expression was confirmed in BC tissues and cell lines using qRT-PCR, immunohistochemistry, and western blot assays. The effects of <em>PROM2</em> were evaluated <em>in vivo</em> and <em>in vitro</em>. RNA sequencing and GSEA were used to investigate the potential underlying molecular mechanisms of <em>PROM2</em> in BC. Co-immunoprecipitation was used to determine the interaction between AKT and PROM2. <em>PROM2</em> expression was elevated in clinical samples and BC cells and positively correlated with a worse prognosis. Functional experiments demonstrated that <em>PROM2</em> silencing suppressed tumor growth and malignancy. Mechanistically, PROM2 interacts with AKT to activate mTOR signaling, thereby promoting glycolysis and inhibiting ferroptosis. Specifically, for glycolysis, <em>PROM2</em> silencing decreased glucose uptake, extracellular acidification rate, lactate production, and glycolysis-related enzyme expression, while increasing oxygen consumption. For ferroptosis, <em>PROM2</em> silencing upregulated reactive oxygen species, malondialdehyde, iron, Fe<sup>2+</sup>, and downregulated SLC7A11, GPX4, and glutathione levels. Overexpression of AKT or the AKT agonist (SC79) reversed the effects of <em>PROM2</em> silencing on BC cell glycolysis and ferroptosis. Our results suggest that <em>PROM2</em> is an oncogenic gene that supports BC progression by enhancing glycolysis and inhibiting ferroptosis <em>via</em> AKT/mTOR signaling. Therefore, <em>PROM2</em> may be a potential therapeutic target for BC treatment.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 8","pages":"Article 120047"},"PeriodicalIF":3.7,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862092","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 : 2025-08-10DOI: 10.1016/j.bbamcr.2025.120043
Pingchuan Li , Lineng Wei , Meng Li , Huawei Yang
Breast cancer remains a major global health threat to women, underscoring the urgent need for novel therapeutic targets. While ESCO2, an essential cell cycle regulator, has been implicated in cancer progression, its precise role and molecular mechanisms in breast cancer remain poorly understood. In this study, we first demonstrated significant upregulation of ESCO2 in breast cancer through analysis of TCGA and GEO datasets, which was further validated in clinical specimens and cell lines, with its expression correlating with advanced T-stage, aggressive molecular subtypes and poor prognosis. Functional studies in MDA-MB-231 and MDA-MB-468 cells revealed that ESCO2 overexpression promoted cell proliferation, migration and invasion, while its knockdown exerted opposite effects. Mechanistic investigations uncovered that ESCO2 depletion reduced phosphorylation of PI3K/AKT/mTOR pathway components, and co-immunoprecipitation assays confirmed direct interaction between ESCO2 and PI3K. Importantly, the tumor-suppressive effects of ESCO2 knockdown could be rescued by SC79-mediated AKT activation. In vivo experiments using xenograft mouse models consistently showed that ESCO2 silencing significantly inhibited tumor growth, increased apoptosis and necrosis, and reduced metastasis. Collectively, our findings establish ESCO2 as a novel oncogene driving breast cancer progression through PI3K/AKT/mTOR pathway activation, highlighting its potential as a promising therapeutic target for breast cancer intervention.
{"title":"ESCO2 drives breast cancer proliferation and metastasis through PI3K/AKT/mTOR phosphorylation: A potential therapeutic target","authors":"Pingchuan Li , Lineng Wei , Meng Li , Huawei Yang","doi":"10.1016/j.bbamcr.2025.120043","DOIUrl":"10.1016/j.bbamcr.2025.120043","url":null,"abstract":"<div><div>Breast cancer remains a major global health threat to women, underscoring the urgent need for novel therapeutic targets. While ESCO2, an essential cell cycle regulator, has been implicated in cancer progression, its precise role and molecular mechanisms in breast cancer remain poorly understood. In this study, we first demonstrated significant upregulation of ESCO2 in breast cancer through analysis of TCGA and GEO datasets, which was further validated in clinical specimens and cell lines, with its expression correlating with advanced T-stage, aggressive molecular subtypes and poor prognosis. Functional studies in MDA-MB-231 and MDA-MB-468 cells revealed that ESCO2 overexpression promoted cell proliferation, migration and invasion, while its knockdown exerted opposite effects. Mechanistic investigations uncovered that ESCO2 depletion reduced phosphorylation of PI3K/AKT/mTOR pathway components, and co-immunoprecipitation assays confirmed direct interaction between ESCO2 and PI3K. Importantly, the tumor-suppressive effects of ESCO2 knockdown could be rescued by SC79-mediated AKT activation. In vivo experiments using xenograft mouse models consistently showed that ESCO2 silencing significantly inhibited tumor growth, increased apoptosis and necrosis, and reduced metastasis. Collectively, our findings establish ESCO2 as a novel oncogene driving breast cancer progression through PI3K/AKT/mTOR pathway activation, highlighting its potential as a promising therapeutic target for breast cancer intervention.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 8","pages":"Article 120043"},"PeriodicalIF":3.7,"publicationDate":"2025-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144833875","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}
Breast cancer is the most common tumor in women, and approximately 70 % of cases are diagnosed to be estrogen receptor α (ERα)-positive. Estradiol (E2)-ERα signaling is undoubtedly involved in the development of breast cancer, and the upregulation of this pathway is linked to tamoxifen resistance. However, ERα regulation is complex, and the underlying mechanisms have not been comprehensively elucidated.
Pin4 is a prolyl isomerase that promotes cis-trans isomerization of proline residues. Although its role remains unclear, an analysis of public databases reveals that Pin4 expression in breast cancer tissues is higher than that in normal tissues.
Here, we reveal that Pin4 regulates ERα transcriptional activity and is essential for the proliferation of ERα-positive breast cancer cells. In MCF7 and T47D cells, Pin4 knockdown drastically decreased cell proliferation by inducing cell cycle arrest. In addition, the silencing of Pin4 impaired the expression of E2-induced genes, including E2F1. We also found that Pin4 interacted with ERα and affected its transcriptional activity by promoting phosphorylation at Ser167, which was involved in the recruitment of steroid receptor coactivator-3 (SRC-3) into ERα. Importantly, the silence of Pin4 gene in T47D cells attenuated the interaction between SRC-3 and ERα.
Collectively, the study findings show that Pin4 is a critical factor in the development of ERα-positive breast cancers and the identification of Pin4 inhibitors could be a promising therapeutic strategy.
{"title":"Prolyl isomerase Pin4 impacts estrogen receptor transactivation by enhancing phosphorylation and consequently promotes the proliferation of breast cancer cells","authors":"Masa-Ki Inoue , Rena Ueda , Mikako Nakanishi , Machi Kanna , Yasuka Matsunaga , Tomoichiro Asano , Yusuke Nakatsu","doi":"10.1016/j.bbamcr.2025.120044","DOIUrl":"10.1016/j.bbamcr.2025.120044","url":null,"abstract":"<div><div>Breast cancer is the most common tumor in women, and approximately 70 % of cases are diagnosed to be estrogen receptor α (ERα)-positive. Estradiol (E2)-ERα signaling is undoubtedly involved in the development of breast cancer, and the upregulation of this pathway is linked to tamoxifen resistance. However, ERα regulation is complex, and the underlying mechanisms have not been comprehensively elucidated.</div><div>Pin4 is a prolyl isomerase that promotes cis-trans isomerization of proline residues. Although its role remains unclear, an analysis of public databases reveals that Pin4 expression in breast cancer tissues is higher than that in normal tissues.</div><div>Here, we reveal that Pin4 regulates ERα transcriptional activity and is essential for the proliferation of ERα-positive breast cancer cells. In MCF7 and T47D cells, Pin4 knockdown drastically decreased cell proliferation by inducing cell cycle arrest. In addition, the silencing of Pin4 impaired the expression of E2-induced genes, including E2F1. We also found that Pin4 interacted with ERα and affected its transcriptional activity by promoting phosphorylation at Ser167, which was involved in the recruitment of steroid receptor coactivator-3 (SRC-3) into ERα. Importantly, the silence of Pin4 gene in T47D cells attenuated the interaction between SRC-3 and ERα.</div><div>Collectively, the study findings show that Pin4 is a critical factor in the development of ERα-positive breast cancers and the identification of Pin4 inhibitors could be a promising therapeutic strategy.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 8","pages":"Article 120044"},"PeriodicalIF":3.7,"publicationDate":"2025-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144833887","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 : 2025-08-07DOI: 10.1016/j.bbamcr.2025.120041
Stephanie Probst , Nadiya Romanova , Robin Herbrechter , Teresa Kern , Marie Bergmeier , Wing-Kee Lee , Frank Thévenod
The collecting duct (CD) is the final segment of the renal nephron and is involved in the fine regulation of osmotic and ionic homeostasis. Its medullary segment is continuously exposed to a wide spectrum of osmotic gradients and resultant osmotic stress. Strikingly, the expression of the mechanically activated non-selective cationic and Ca2+-permeable transduction ion channel PIEZO1 is most prominent in inner medullary CD (IMCD) cells, yet its functions there are still not well understood. We hypothesized increased PIEZO1 expression in the IMCD could be linked to its hyperosmotic stress environment. Using the mouse mIMCD3 cell line, which has been used to characterize hyperosmotic stress-induced cell death, we demonstrate twice as much PIEZO1 expression compared to proximal tubule (WKPT-0293 Cl.2) or cortical CD (mCCD(cl.1)) cell lines. Hyperosmolarity/−tonicity by addition of NaCl ± urea to the culture medium (+ 100–300 mosmol/l) or PIEZO1 agonist Yoda1 (20 μmol/l) decreased mIMCD3 cell viability assayed by MTT, which were antagonized by PIEZO1 inhibitors GsMTx4 (2.5 μmol/l) and salvianolic acid (SalB, 10 μmol/l). PIEZO1 activation by hyperosmolarity and agonists (Yoda1, Jedi1) increased Ca2+ influx, downstream reactive oxygen species (ROS), in particular mitochondrial superoxide (O2•-) formation, and subsequent adaptive ROS-decomposing catalase expression and activity that were sensitive to PIEZO1 antagonists (GsMTx4, SalB). Hence, the data demonstrate hyperosmolarity/−tonicity of the kidney elicits PIEZO1 activation, mitochondrial ROS formation and cell death that are partially countered by catalase-mediated stress adaptation.
{"title":"Hyperosmolarity-induced activation of PIEZO1 engages detrimental calcium/oxidative stress signaling and adaptive catalase response in renal inner medullary collecting duct (mIMCD3) cells","authors":"Stephanie Probst , Nadiya Romanova , Robin Herbrechter , Teresa Kern , Marie Bergmeier , Wing-Kee Lee , Frank Thévenod","doi":"10.1016/j.bbamcr.2025.120041","DOIUrl":"10.1016/j.bbamcr.2025.120041","url":null,"abstract":"<div><div>The collecting duct (CD) is the final segment of the renal nephron and is involved in the fine regulation of osmotic and ionic homeostasis. Its medullary segment is continuously exposed to a wide spectrum of osmotic gradients and resultant osmotic stress. Strikingly, the expression of the mechanically activated non-selective cationic and Ca<sup>2+</sup>-permeable transduction ion channel PIEZO1 is most prominent in inner medullary CD (IMCD) cells, yet its functions there are still not well understood. We hypothesized increased PIEZO1 expression in the IMCD could be linked to its hyperosmotic stress environment. Using the mouse mIMCD<sub>3</sub> cell line, which has been used to characterize hyperosmotic stress-induced cell death, we demonstrate twice as much PIEZO1 expression compared to proximal tubule (WKPT-0293 Cl.2) or cortical CD (mCCD(cl.1)) cell lines. Hyperosmolarity/−tonicity by addition of NaCl ± urea to the culture medium (+ 100–300 mosmol/l) or PIEZO1 agonist Yoda1 (20 μmol/l) decreased mIMCD<sub>3</sub> cell viability assayed by MTT, which were antagonized by PIEZO1 inhibitors GsMTx4 (2.5 μmol/l) and salvianolic acid (SalB, 10 μmol/l). PIEZO1 activation by hyperosmolarity and agonists (Yoda1, Jedi1) increased Ca<sup>2+</sup> influx, downstream reactive oxygen species (ROS), in particular mitochondrial superoxide (O<sub>2</sub><sup>•-</sup>) formation, and subsequent adaptive ROS-decomposing catalase expression and activity that were sensitive to PIEZO1 antagonists (GsMTx4, SalB). Hence, the data demonstrate hyperosmolarity/−tonicity of the kidney elicits PIEZO1 activation, mitochondrial ROS formation and cell death that are partially countered by catalase-mediated stress adaptation.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 8","pages":"Article 120041"},"PeriodicalIF":3.7,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144803337","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 : 2025-08-05DOI: 10.1016/j.bbamcr.2025.120030
Ezequiel Rías , Camila Carignano , Valeria C. Castagna , Leonardo Dionisio , Jimena A. Ballestero , Giuliana Paolillo , Ingrid Ouwerkerk , María Eugenia Gomez-Casati , Guillermo Spitzmaul
Hearing loss (HL) is the most common sensory disorder, caused by genetic mutations and acquired factors like presbycusis and noise exposure. A critical factor in HL development is the dysfunction of potassium (K+) channels, essential for sensory cell function in the organ of Corti (OC). Inner and outer hair cells (IHCs and OHCs) convert sound into electrical signals, while supporting cells (SCs) maintain ionic and structural balance. KCNQ4 channels, located in the basal membrane of OHCs, regulate K+ efflux. Mutations in KCNQ4 are linked to progressive HL (DFNA2), noise-induced hearing loss, and presbycusis, leading to K+ accumulation, cellular stress, and OHC death. Gene editing or pharmacological activation of KCNQ4 has shown potential in partially preventing HL in mouse models. In this study, we demonstrate KCNQ4 deletion disrupts the localization of key proteins like prestin and BK channels, alters OHC organization, and induces apoptosis in sensory and SC. Spiral ganglion neurons (SGNs) also degenerate over time. Despite these structural changes, noise exposure does not exacerbate OHC damage in our KCNQ4-deficient model. This highlights KCNQ4's role in maintaining ion homeostasis and cochlear function, as its absence triggers widespread dysfunction in the OC. The present study demonstrates that disruptions in a single cell type can have a cascade effect on overall cochlear health. Understanding the molecular and cellular consequences of KCNQ4 mutations is crucial for developing targeted therapies to mitigate progressive HL caused by genetic and environmental factors.
{"title":"Insights into early cochlear damage induced by potassium channel deficiency","authors":"Ezequiel Rías , Camila Carignano , Valeria C. Castagna , Leonardo Dionisio , Jimena A. Ballestero , Giuliana Paolillo , Ingrid Ouwerkerk , María Eugenia Gomez-Casati , Guillermo Spitzmaul","doi":"10.1016/j.bbamcr.2025.120030","DOIUrl":"10.1016/j.bbamcr.2025.120030","url":null,"abstract":"<div><div>Hearing loss (HL) is the most common sensory disorder, caused by genetic mutations and acquired factors like presbycusis and noise exposure. A critical factor in HL development is the dysfunction of potassium (K<sup>+</sup>) channels, essential for sensory cell function in the organ of Corti (OC). Inner and outer hair cells (IHCs and OHCs) convert sound into electrical signals, while supporting cells (SCs) maintain ionic and structural balance. KCNQ4 channels, located in the basal membrane of OHCs, regulate K<sup>+</sup> efflux. Mutations in KCNQ4 are linked to progressive HL (DFNA2), noise-induced hearing loss, and presbycusis, leading to K<sup>+</sup> accumulation, cellular stress, and OHC death. Gene editing or pharmacological activation of KCNQ4 has shown potential in partially preventing HL in mouse models. In this study, we demonstrate KCNQ4 deletion disrupts the localization of key proteins like prestin and BK channels, alters OHC organization, and induces apoptosis in sensory and SC. Spiral ganglion neurons (SGNs) also degenerate over time. Despite these structural changes, noise exposure does not exacerbate OHC damage in our KCNQ4-deficient model. This highlights KCNQ4's role in maintaining ion homeostasis and cochlear function, as its absence triggers widespread dysfunction in the OC. The present study demonstrates that disruptions in a single cell type can have a cascade effect on overall cochlear health. Understanding the molecular and cellular consequences of KCNQ4 mutations is crucial for developing targeted therapies to mitigate progressive HL caused by genetic and environmental factors.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 8","pages":"Article 120030"},"PeriodicalIF":3.7,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144768259","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}
Androgenetic alopecia (AGA), the most prevalent form of patterned hair loss, manifests through androgen sensitivity, age-dependent progression, and genetic predisposition. Emerging evidence highlights microRNAs as critical post-transcriptional regulators in hair follicle pathophysiology. This study used human hair follicle stem cells (HFSCs), hair follicle samples of AGA patients and AGA mouse model to explore the role of miR-22-3p/CLIC4 signaling in AGA. A significant rise in miR-22-3p expression was observed in balding hair follicles of grade 5 AGA patients. Then we identify chloride intracellular channel 4 (CLIC4) as a novel target of miR-22-3p and CLIC4 is markedly low expressed in balding hair follicle of AGA patients. Functional studies demonstrated that knockdown CLIC4 (shCLIC4) impaired HFSCs proliferative capacity and disrupted sonic hedgehog (SHH) pathway activation, evidenced by decreased Gli1 and Gli2 transcriptional activity. These findings establish the miR-22-3p/CLIC4 axis as a novel regulator of hair follicular miniaturization, proposing CLIC4-mediated SHH modulation as a potential therapeutic target for AGA intervention.
{"title":"MicroRNA-22-3p suppresses hair regrowth in androgenetic alopecia by targeting chloride intracellular channel 4","authors":"Haijing Fu , Chenxi Wu , Tianyi Xu , Wumei Zhao , Leiwei Jiang , Shijun Shan","doi":"10.1016/j.bbamcr.2025.120033","DOIUrl":"10.1016/j.bbamcr.2025.120033","url":null,"abstract":"<div><div>Androgenetic alopecia (AGA), the most prevalent form of patterned hair loss, manifests through androgen sensitivity, age-dependent progression, and genetic predisposition. Emerging evidence highlights microRNAs as critical post-transcriptional regulators in hair follicle pathophysiology. This study used human hair follicle stem cells (HFSCs), hair follicle samples of AGA patients and AGA mouse model to explore the role of miR-22-3p/CLIC4 signaling in AGA. A significant rise in miR-22-3p expression was observed in balding hair follicles of grade 5 AGA patients. Then we identify chloride intracellular channel 4 (CLIC4) as a novel target of miR-22-3p and CLIC4 is markedly low expressed in balding hair follicle of AGA patients. Functional studies demonstrated that knockdown CLIC4 (shCLIC4) impaired HFSCs proliferative capacity and disrupted sonic hedgehog (SHH) pathway activation, evidenced by decreased Gli1 and Gli2 transcriptional activity. These findings establish the miR-22-3p/CLIC4 axis as a novel regulator of hair follicular miniaturization, proposing CLIC4-mediated SHH modulation as a potential therapeutic target for AGA intervention.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 8","pages":"Article 120033"},"PeriodicalIF":3.7,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144766740","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 : 2025-07-30DOI: 10.1016/j.bbamcr.2025.120031
Johannes Lehmann , Alberto Catanese
Synaptotagmin-13 (SYT13) is a non-canonical member of the of synaptotagmin family that, canonical synaptotagmins, doesn't contain Ca2+ binding sites, but still appears to play a key role in the control of different cellular processes such as vesicle transport, cell migration, signaling and cell development. The recent findings associate SYT13 with neuronal survival and development, metabolic homeostasis (especially insulin secretion) and both oncogenic and tumor suppressive function in multiple cancers. And yet all this data is scattered in fields, with no systematic review covering SYT13's detailed biology. A comprehensive literature review is therefore needed to explain SYT13's multifaceted roles, uncover informational gaps and direct future studies to exploit SYT13 as a target for neurodegeneration, metabolic disease and cancer therapy.
{"title":"SYT13: An underestimated synaptotagmin","authors":"Johannes Lehmann , Alberto Catanese","doi":"10.1016/j.bbamcr.2025.120031","DOIUrl":"10.1016/j.bbamcr.2025.120031","url":null,"abstract":"<div><div>Synaptotagmin-13 (SYT13) is a non-canonical member of the of synaptotagmin family that, canonical synaptotagmins, doesn't contain Ca<sup>2+</sup> binding sites, but still appears to play a key role in the control of different cellular processes such as vesicle transport, cell migration, signaling and cell development. The recent findings associate SYT13 with neuronal survival and development, metabolic homeostasis (especially insulin secretion) and both oncogenic and tumor suppressive function in multiple cancers. And yet all this data is scattered in fields, with no systematic review covering SYT13's detailed biology. A comprehensive literature review is therefore needed to explain SYT13's multifaceted roles, uncover informational gaps and direct future studies to exploit SYT13 as a target for neurodegeneration, metabolic disease and cancer therapy.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 8","pages":"Article 120031"},"PeriodicalIF":3.7,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144749493","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 : 2025-07-30DOI: 10.1016/j.bbamcr.2025.120032
Mengjia Jing , Yixing Luo , Lumiao Zhang , Yu Fu , Wei Yan
In the intricate process leading to liver fibrosis, which frequently correlates with inflammation, the activation of hepatic stellate cells (HSCs) is critical. High mobility group box 1(HMGB1), as endogenous danger signal in the extracellular environment, governs the activation of caspase-1 and hepatic stellate cell. Constructing a liver fibrosis model via intraperitoneal thioacetamide (TAA) administration unveiled excessive HMGB1 expression and serum release during the TAA-induced fibrosis progression. Intraperitoneal injection of ethyl pyruvate (EP, which inhibits the release of HMGB1) or AAV-shHMGB1 can significantly reverse the progression of liver fibrosis induced by TAA. Recombinant HMGB1 (rHMGB1) and Z-YVAD-FMK (Caspase-1 inhibitor) were used to treat HSCs. It was found that HMGB1 could activate caspase-1, while Z-YVAD-FMK could prevent HMGB1-induced activation of HSCs. Through immunofluorescence, immunoblotting, lentiviral transfection, luciferase reporter assay and chromatin immunoprecipitation assay, it was found that HMGB1 activated caspase-1 through GABPA-regulated ASC transcription, which not only participates in the activation of caspase-1, but also promotes the process of liver fibrosis. Taken together, HMGB1 significantly drives HSC activation. It boosts ASC transcriptional activity via GABPA leading to caspase-1 activation and fostering liver fibrosis development.
{"title":"HMGB1 activates caspase-1 and induces hepatic stellate cell activation via GABPA-ASC","authors":"Mengjia Jing , Yixing Luo , Lumiao Zhang , Yu Fu , Wei Yan","doi":"10.1016/j.bbamcr.2025.120032","DOIUrl":"10.1016/j.bbamcr.2025.120032","url":null,"abstract":"<div><div>In the intricate process leading to liver fibrosis, which frequently correlates with inflammation, the activation of hepatic stellate cells (HSCs) is critical. High mobility group box 1(HMGB1), as endogenous danger signal in the extracellular environment, governs the activation of caspase-1 and hepatic stellate cell. Constructing a liver fibrosis model via intraperitoneal thioacetamide (TAA) administration unveiled excessive HMGB1 expression and serum release during the TAA-induced fibrosis progression. Intraperitoneal injection of ethyl pyruvate (EP, which inhibits the release of HMGB1) or AAV-shHMGB1 can significantly reverse the progression of liver fibrosis induced by TAA. Recombinant HMGB1 (rHMGB1) and <em>Z</em>-YVAD-FMK (Caspase-1 inhibitor) were used to treat HSCs. It was found that HMGB1 could activate caspase-1, while Z-YVAD-FMK could prevent HMGB1-induced activation of HSCs. Through immunofluorescence, immunoblotting, lentiviral transfection, luciferase reporter assay and chromatin immunoprecipitation assay, it was found that HMGB1 activated caspase-1 through GABPA-regulated ASC transcription, which not only participates in the activation of caspase-1, but also promotes the process of liver fibrosis. Taken together, HMGB1 significantly drives HSC activation. It boosts ASC transcriptional activity via GABPA leading to caspase-1 activation and fostering liver fibrosis development.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 8","pages":"Article 120032"},"PeriodicalIF":3.7,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144757271","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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