Cell. Signal. [JOURNAL]
Sun
200 papers
RARG promotes gastric cancer progression by activating PMEPA1 transcription and Wnt/β-catenin signalling.
Qin L, Wen F, Guo S … +7 more , Zhang W, Cai W, Ma R, Liu C, Ren W, Ye H, Jiao Z
Cell Signal · 2026 Aug · PMID 42025891 · Publisher ↗
OBJECTIVE: Gastric cancer (GC) has a complex pathogenesis driven by infection, genetic mutations, epigenetic reprogramming, and tumor microenvironment (TME) remodelling, all of which contribute to tumorigenesis, metastas...
OBJECTIVE: Gastric cancer (GC) has a complex pathogenesis driven by infection, genetic mutations, epigenetic reprogramming, and tumor microenvironment (TME) remodelling, all of which contribute to tumorigenesis, metastasis, and immune evasion. Retinoic acid receptor gamma (RARG) is implicated in many cancers, but its role in GC remains unclear. This study investigates the function of RARG in GC and explores its underlying regulatory mechanisms. METHODS: Transcription factor prediction and CUT&Tag sequencing were used to identify upstream regulators of PMEPA1. RARG expression in GC was assessed by western blotting and immunohistochemistry (IHC). The impact of RARG on GC via PMEPA1 was evaluated through functional assays. The mechanism of RARG in GC was further analysed using single-cell RNA sequencing (scRNA-seq) and validated in vitro and in vivo. RESULTS: We identify RARG as a transcriptional regulator of PMEPA1 and show that RARG abundance is elevated in GC epithelial cells and associated with poorer overall survival. RARG depletion suppressed GC cell proliferation, invasion, and migration, whereas PMEPA1 re-expression partially rescued these phenotypes. Additionally, RARG directly binds β-catenin to promote its nuclear accumulation, consistent with enhanced Wnt/β-catenin signalling. CONCLUSION: RARG overexpression promotes GC progression by transcriptionally activating PMEPA1 via a genomic mechanism and, in parallel, directly binding β-catenin to enhance Wnt/β-catenin signalling.
ST7 binds YBX1 to suppress MMP14 expression and inhibit metastasis in non-small cell lung cancer.
Qin Y, Chen Y, Cao Q … +2 more , Zhang B, Wan Y
Cell Signal · 2026 Aug · PMID 42025890 · Publisher ↗
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and a major contributor to cancer-related deaths globally. The mechanisms of NSCLC metastasis, largely driven by epithelial-mesenchymal transition...
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and a major contributor to cancer-related deaths globally. The mechanisms of NSCLC metastasis, largely driven by epithelial-mesenchymal transition (EMT), remain incompletely understood. The Cancer Genome Atlas - Lung Adenocarcinoma (TCGA-LUAD) dataset analysis revealed that suppression of tumorigenicity 7 (ST7) may play a role in preventing the EMT process and metastasis in NSCLC. In this study, we revealed that ST7 suppressed the expression of Matrix metalloproteinase 14 (MMP14) by binding Y-box binding protein 1 (YBX1) and blocking its nuclear translocation. Consequently, ST7 silencing enhanced both EMT and metastatic progression in NSCLC experimental models, including A549 and H1299 cell lines in vitro and a tail-vein lung metastasis model in BALB/c nude mice in vivo. Collectively, our results revealed a novel ST7/YBX1/MMP14 signaling axis that might be targeted in NSCLC metastasis.
NSUN2 restrains renal fibrosis via m5C-stabilized GPX4 and ferroptosis inhibition.
Zan Y, Chen L, Ma L … +7 more , Meng P, Ma S, Liu H, Tian Y, He X, Wang Z, Ding Y
Cell Signal · 2026 Aug · PMID 42025889 · Publisher ↗
BACKGROUND: Renal fibrosis (RFib) is a final common pathway in chronic kidney disease (CKD) progression. Although 5-methylcytosine (m5C) RNA modification can regulate mRNA fate, its role in RFib and redox-regulated cell...
BACKGROUND: Renal fibrosis (RFib) is a final common pathway in chronic kidney disease (CKD) progression. Although 5-methylcytosine (m5C) RNA modification can regulate mRNA fate, its role in RFib and redox-regulated cell death remains incompletely defined. METHODS: Public GEO cohorts were analyzed to identify dysregulated m5C regulators and enriched pathways in RFib. RFib was modeled in vivo using unilateral ureteral obstruction (UUO) and in vitro using TGF-β1-treated HK-2 cells. Gene set enrichment analysis (GSEA) and a ferroptosis-focused qPCR array were used to prioritize downstream programs. NSUN2 knockdown/overexpression experiments, dot blot assays, and m5C RNA immunoprecipitation followed by qPCR (MeRIP-qPCR) were performed to evaluate m5C-associated regulation of GPX4. Network pharmacology and in silico docking/dynamics were used to nominate candidate NSUN2-binding compounds. RESULTS: NSUN2 was consistently downregulated in fibrotic kidneys and TGF-β1-stimulated HK-2 cells, accompanied by ferroptosis activation. NSUN2 increased GPX4 protein abundance primarily by enhancing GPX4 mRNA stability, which correlated with increased m5C enrichment on GPX4 mRNA. Computational screening suggested that ginsenosides, particularly Rh2, may bind the NSUN2 catalytic pocket with favorable predicted affinity and complex stability. CONCLUSIONS: NSUN2 attenuates renal fibrogenesis by sustaining GPX4 expression through m5C-associated post-transcriptional regulation and thereby limiting ferroptosis. The identified ginsenosides provide testable leads for targeting the NSUN2-GPX4 axis, although further experimental validation is required.
SRY-box transcription factor 7 functions as a tumor suppressor regulating Wnt signaling and cancer stemness with its promoter methylation as a potential biomarker.
Xie L, Zhou J, Xie J … +5 more , Chai X, Luo B, Zeng X, Tao Q, Li L
Cell Signal · 2026 Aug · PMID 42025888 · Publisher ↗
BACKGROUND: Wnt signaling, critical for development, is often dysregulated in cancer via genetic or/and epigenetic changes. SOX7, a high mobility group protein, is downregulated in cancers, but its alterations and underl...
BACKGROUND: Wnt signaling, critical for development, is often dysregulated in cancer via genetic or/and epigenetic changes. SOX7, a high mobility group protein, is downregulated in cancers, but its alterations and underlying mechanism in gastric cancer (GsCa) pathogenesis remain to be clearly defined. METHODS: SOX7 mRNA expression and promoter methylation were analyzed in GsCa. Functional impacts were assessed through assays for colony formation, proliferation (CCK-8), cell cycle/apoptosis (flow cytometry), migration/invasion (wound healing, Transwell), and ferroptosis. Mechanistic studies involving Western blot, immunofluorescence, dual-luciferase reporter assays, chromatin immunoprecipitation (ChIP)-qPCR, and bidirectional rescue experiments focused on the Wnt/β-catenin signaling and cancer stemness markers. RESULTS: SOX7 was widely expressed in normal tissues, including stomach, but was frequently downregulated in GsCa due to promoter CpG methylation, which correlated with worse overall patient survival. Functionally, SOX7 restoration inhibited GsCa cell growth by inducing G0/G1 arrest, ferroptosis, and apoptosis. It also suppressed migration and invasion by inhibiting epithelial-mesenchymal transition (EMT) and cancer stemness. Mechanistically, SOX7 is localized to nuclear speckles and antagonized Wnt/β-catenin signaling through sequestering active β-catenin in the cytoplasm, directly binding to Wnt target gene promoters (e.g., c-MYC), and competitively β-catenin displacement. Bidirectional rescue experiments confirmed its tumor-suppressive functions dependent on inactivation of β-catenin. CONCLUSIONS: SOX7 is a tumor suppressor in GsCa frequently inactivated by promoter methylation. It suppresses tumorigenesis by direct antagonizing Wnt signaling, thereby inhibiting EMT and stemness. SOX7 promoter methylation is a potential biomarker for GsCa prognosis and detection.
CCL17 drives the expression of MMP9 and MMP13 expression via ERK1/2 and NF-κB signaling pathways in rheumatoid arthritis.
Balendran T, Hourani T, Ganeshalingam S … +7 more , Hatch K, Fletcher S, Hor C, Lee KMC, Hamilton JA, Lim K, Achuthan AA
Cell Signal · 2026 Aug · PMID 42019646 · Publisher ↗
Chemokine (CC motif) ligand 17 (CCL17), an inflammatory chemokine, has been shown to mediate pain and inflammation in animal models of arthritis. However, the specific molecular mechanisms by which CCL17 mediates its inf...
Chemokine (CC motif) ligand 17 (CCL17), an inflammatory chemokine, has been shown to mediate pain and inflammation in animal models of arthritis. However, the specific molecular mechanisms by which CCL17 mediates its inflammatory functions remain largely unknown. Matrix metalloproteinases (MMPs), particularly MMP9 and MMP13, are cartilage degrading enzymes that are known to contribute to joint pain and inflammation in arthritis. These MMPs, produced in significant quantities by macrophages, facilitate the breakdown of the extracellular matrix and are regulated by various signaling pathways, including extracellular signal-related kinase (ERK1/2) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). However, how CCL17 regulates downstream mediators in arthritis has not yet been elucidated. This study investigates the regulatory role of CCL17 on MMP expression in peripheral blood mononuclear cells (PBMCs) and plasma from rheumatoid arthritis (RA) patients, as well as in monocyte-derived macrophages (MDMs) from healthy donors. Analysis of RA patient samples revealed a positive correlation between CCL17 levels and MMP9/MMP13 expression. Furthermore, CCL17 treatment of MDMs resulted in an upregulation of MMP9 and MMP13 expression, correlating with increased activity of ERK1/2 and NF-κB. Markedly, pre-treatment with pharmacological inhibitors, U0126 (an ERK1/2 inhibitor) and NF-κB Activation Inhibitor IV (NF-κB inhibitor), in both MDMs and RA PBMCs, demonstrated that CCL17-driven MMP9 and MMP13 expression was critically dependent on ERK1/2 and NF-κB activation. Our findings provide new insights into possible mechanisms driving joint destruction in RA, highlighting potential benefits of targeting CCL17 and/or its downstream mediators as potential therapeutic strategies for treating inflammation.
UFL1 deficiency impairs skeletal muscle development by activating PERK/eIF2α/ATF4/CHOP pathway-dependent apoptosis.
Xu J, Guo M, Li P … +4 more , Li F, Zhou K, Chen F, Cai Y
Cell Signal · 2026 Aug · PMID 42019645 · Publisher ↗
Ubiquitin-like modifier 1 ligating enzyme 1 (UFL1), the essential E3 ligase in the UFMylation system, plays a crucial yet undefined role in skeletal muscle development. In this study, our primary objective was to elucida...
Ubiquitin-like modifier 1 ligating enzyme 1 (UFL1), the essential E3 ligase in the UFMylation system, plays a crucial yet undefined role in skeletal muscle development. In this study, our primary objective was to elucidate the function and molecular mechanism of UFL1 in myoblast survival and myofiber development. UFL1 deficiency in mice exacerbated ultra structural damage in myofibers and significantly increased myoblast apoptosis both in vivo and in vitro, as evidenced by upregulation of Cleaved Poly (ADP-ribose) polymerase (cleaved PARP), Cleaved Cysteinyl aspartate specific proteinase 3 (cleaved Caspase-3), and BCL2-associated X protein (BAX), alongside downregulation of B-cell lymphoma 2 (BCL2). Mechanistically, UFL1 knockout robustly activated the ER stress response, characterized by a significant increase in mRNA levels of Glucose-regulated protein 78 (GRP78), Activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP), as well as specific activation of the Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK)/Eukaryotic translation initiation factor 2 subunit alpha (eIF2α)/ATF4/CHOP signaling axis. Conversely, UFL1 overexpression effectively suppressed this pathway and reduced apoptosis. Notably, treatment with the PERK inhibitor GSK2606414 successfully reversed the UFL1 deficiency-induced upregulation of p-PERK, p-eIF2α, ATF4, and CHOP and rescued the apoptotic phenotype. Our study demonstrates for the first time that UFL1 is a critical regulator for maintaining myoblast survival and normal myofiber development, acting partly through suppressing the PERK-mediated ER sress. These findings provide novel insights into the pathogenesis of muscle developmental disorders and suggest UFL1 as a potential therapeutic target.
NUPR1 alleviates renal ischemia reperfusion injury by inhibiting ferroptosis involving the ATF4-CHAC1 pathway.
Luo Y, Han J, Huang G
Cell Signal · 2026 Aug · PMID 42019644 · Publisher ↗
As a major cause of acute kidney injury (AKI), renal ischemia reperfusion injury (IRI) poses a considerable clinical challenge worldwide. Currently, effective therapeutic strategies for renal IRI remain limited. Although...
As a major cause of acute kidney injury (AKI), renal ischemia reperfusion injury (IRI) poses a considerable clinical challenge worldwide. Currently, effective therapeutic strategies for renal IRI remain limited. Although ferroptosis has been identified as a pivotal factor in the pathogenesis of renal IRI, the molecular mechanisms underlying the regulation of ferroptosis in renal IRI require further elucidation. To investigate the regulatory role of nuclear protein 1 (NUPR1) in ferroptosis during renal IRI, we established a murine model of renal IRI and an in vitro hypoxia-reoxygenation model using HK2 cells based on bioinformatics analysis. We found that the expression of NUPR1 was markedly upregulated in renal IRI. The overexpression of NUPR1 was found to alleviate renal IRI, whereas injury was exacerbated by an inhibition of NUPR1. Correspondingly, the overexpression of NUPR1 suppressed ferroptosis in renal IRI and HK2 cells exposed to hypoxia-reoxygenation, whereas inhibition or knockdown of NUPR1 enhanced ferroptosis. Furthermore, we detected a significant upregulation of transcription factor 4 (ATF4) in renal IRI and HK2 cells exposed to hypoxia-reoxygenation, and immunoprecipitation revealed an interaction between NUPR1 and ATF4 in HK2 cells. Mechanistically, NUPR1 suppressed ferroptosis by inhibiting the ATF4-CHAC1 pathway. On the basis of our findings in this study, we propose that NUPR1 regulates ferroptosis in renal IRI by modulating the ATF4-CHAC1 pathway, and thus NUPR1 and the ATF4-CHAC1 pathway could serve as promising targets for the treatment of renal IRI.
Fosb promotes ferroptosis in vascular smooth muscle cells via the NF-κB pathway to exacerbate abdominal aortic aneurysm progression.
Li X, Wang Q, Zhang J … +2 more , Zhao W, Zheng X
Cell Signal · 2026 Aug · PMID 42013987 · Publisher ↗
BACKGROUND: Abdominal aortic aneurysm (AAA) is a fatal disease characterized by vascular wall inflammation and matrix remodeling. The inflammatory phenotypic transformation of smooth muscle cells (SMCs) holds a pivotal r...
BACKGROUND: Abdominal aortic aneurysm (AAA) is a fatal disease characterized by vascular wall inflammation and matrix remodeling. The inflammatory phenotypic transformation of smooth muscle cells (SMCs) holds a pivotal role in AAA pathogenesis. As an inflammatory regulator, whether FBJ osteosarcoma oncogene B (Fosb) participates in AAA progression by driving SMC phenotypic switching remains unclear. METHODS: Using the scRNA-seq data from AAA patients, we identified Fosb as a key driver of SMC phenotypic switching through cell clustering annotation, differential gene screening, functional enrichment, and pseudo-time trajectory analysis. An in vitro AAA cell model was established using Ang-II-stimulated T/G HA-VSMC cells. Fosb expression was assessed by qRT-PCR and western blot (WB). AAA cell models with Fosb knockdown or overexpression were constructed to investigate the effects of Fosb on T/G HA-VSMC cell proliferation, apoptosis, migration, invasion, contractile marker protein expression, and inflammatory cytokine secretion via WB, CCK8, Transwell, flow cytometry, and ELISA. Furthermore, WB was applied in detecting ferroptosis and NF-κB signaling pathway protein expression. Kits were employed for the determination of MDA, GSH, and Fe levels, and flow cytometry was for ROS levels. Finally, an Ang-II-induced ApoE/ mouse AAA model was constructed, and histological staining, WB, IHC, and ELISA were carried out to validate that Fosb boosted AAA ferroptosis and inflammation via the NF-κB pathway in vivo. RESULTS: Fosb inflammatory SMCs were significantly increased in AAA and were key drivers of the transition from a contractile to an inflammatory phenotype. Cellular experiments confirmed that Fosb knockdown reversed Ang-II-induced downregulation of SMC contractile markers and repressed cell migration, invasion, apoptosis, and inflammatory cytokine secretion. Mechanistically, through activation of the NF-κB pathway, Fosb triggered ferroptosis, thus boosting AAA ferroptosis and inflammatory responses. Animal experiments demonstrated that in vivo Fosb knockout ameliorated Ang-II-induced AAA progression in mice. CONCLUSION: Fosb drives SMC ferroptosis and inflammatory phenotypic switching, via NF-κB pathway activation, thereby reinforcing AAA progression. Targeting Fosb or the ferroptosis pathway may provide new therapeutic strategies for AAA treatment.
IL-6 as a key regulator of ferroptosis in diabetic nephropathy: From molecular mechanisms to therapeutic implications.
Zhang W, Xu S, Cao Z … +5 more , Jin W, Deng S, Zhou Q, Xia X, Wang X
Cell Signal · 2026 Aug · PMID 42013986 · Publisher ↗
Diabetic nephropathy (DN) is a microvascular disease resulting from diabetes mellitus and is the leading cause of end-stage renal disease worldwide. Recently, ferroptosis, a form of regulated iron-dependent cell death ca...
Diabetic nephropathy (DN) is a microvascular disease resulting from diabetes mellitus and is the leading cause of end-stage renal disease worldwide. Recently, ferroptosis, a form of regulated iron-dependent cell death caused by lipid peroxide accumulation, has been suggested to be a major cause of renal tubular injury in diabetics. Concurrently, interleukin-6 (IL-6), a pleiotropic pro-inflammatory cytokine abundantly expressed in the diabetic kidney, has been progressively acknowledged as a key orchestrator of renal pathology. However, the molecular mechanisms by which IL-6 intersects with ferroptotic pathways to drive DN progression remain incompletely defined. In this review, we systematically delineate the molecular circuitry through which IL-6 operates as a key regulator of ferroptosis in the DN. We demonstrate that sustained activation of the the interleukin-6 (IL-6)/Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling axis suppresses critical antioxidant defenses by transcriptionally downregulating glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), thereby rendering renal cells vulnerable to ferroptotic death. Furthermore, we provide, for the first time, an integrative analysis establishing the causal relationship between IL-6-mediated iron metabolic imbalance and lipid peroxidation in the pathogenesis of DN, revealing how metabolic reprogramming under chronic hyperglycemia amplifies ferroptotic susceptibility through perturbed iron homeostasis. Based on these results, we propose that sustained IL-6 elevation provides a feed-forward loop linking diabetic metabolic stress with ferroptosis injury. We also propose a combination therapy targeting the IL-6-ferroptosis axis with JAK/STAT inhibitors and ferroptosis suppressors, multitarget approaches to overcome single-pathway blockade limitations, and may guide the development of therapies simultaneously targeting inflammation and ferroptosis in DN.
B4GALT1 drives osteoarthritis progression by stabilizing IL-1R1 through N-linked glycosylation.
Ma W, OuYang D, Xu Z … +6 more , Luo W, Tian G, Jiang N, Liu C, Zhang R, Yu Q
Cell Signal · 2026 Aug · PMID 42002123 · Publisher ↗
BACKGROUND: Osteoarthritis (OA) is a prevalent degenerative joint disease with an unclear molecular pathogenesis. B4GALT1 has been implicated in various pathological processes, but its role and mechanism in OA remain lar...
BACKGROUND: Osteoarthritis (OA) is a prevalent degenerative joint disease with an unclear molecular pathogenesis. B4GALT1 has been implicated in various pathological processes, but its role and mechanism in OA remain largely unexplored. METHODS: The expression of B4GALT1 was examined in OA clinical samples and experimental OA models. In vivo OA models were established by destabilization of the medial meniscus (DMM) in mice, while in vitro OA models were generated by lipopolysaccharide (LPS) stimulation of human chondrocytes. CCK-8, flow cytometry, qRT-PCR, and Western blot were employed to investigate the role of B4GALT1 in chondrocyte viability, apoptosis, and inflammatory response. The B4GALT1-IL-1R1 protein interaction was analyzed by Co-IP, and N-glycosylation was assessed using PNGase F treatment and site-directed mutagenesis. OA progression was further evaluated by SO/FG staining, H&E, and X-ray following intra-articular AAV-mediated B4GALT1 knockdown in DMM mice. RESULTS: B4GALT1 was upregulated in OA samples. Functionally, B4GALT1 overexpression exacerbated LPS-induced chondrocyte apoptosis, decline in cell viability, and inflammatory cytokine imbalance (increased TNF-α and IL-1β, decreased IL-13), while its knockdown reversed these effects. Mechanistically, B4GALT1 directly interacted with IL-1R1 and promoted its N-linked glycosylation, specifically at the N193 site, thereby enhancing IL-1R1 protein stability. In vivo, AAV-mediated knockdown of B4GALT1 attenuated DMM-induced cartilage degeneration, joint space narrowing, and inflammatory responses, concomitant with reduced IL-1R1 protein levels. CONCLUSION: B4GALT1 is upregulated in OA and promotes disease progression by stabilizing IL-1R1 via N-glycosylation at the N193 site. Targeting B4GALT1 may represent a promising therapeutic strategy for the treatment of OA.
RBMS3 synergistically suppresses ovarian cancer progression at the post-transcriptional level by destabilizing ELAVL1 mRNA and inhibiting UPF1 methylation.
Wang Y, Sun H, Hou X … +4 more , Xing W, Xu Z, Zhang Q, Yang B
Cell Signal · 2026 Aug · PMID 42002122 · Publisher ↗
Tumor metastasis is a major cause of poor prognosis in ovarian cancer, and angiogenesis plays an important role in metastatic progression. RBMS3 has been shown to possess tumor-suppressive functions in several cancers, b...
Tumor metastasis is a major cause of poor prognosis in ovarian cancer, and angiogenesis plays an important role in metastatic progression. RBMS3 has been shown to possess tumor-suppressive functions in several cancers, but its specific molecular mechanisms in ovarian cancer remain unclear. In this study, we investigated the molecular mechanisms and functions of RBMS3 in ovarian cancer using in vitro assays (including angiogenesis and migration assays), in vivo nude mouse tumor models, immunoprecipitation, western blotting, immunofluorescence, mRNA stability assays, and methylation assays. We found that RBMS3 forms a protein complex with ELAVL1 and UPF1. Mechanistically, RBMS3 reduces the stability of ELAVL1 mRNA at the post-transcriptional level, leading to downregulation of downstream oncogenic targets, including VEGF-A and IL-6. In addition, RBMS3 was found to inhibit UPF1 methylation, although the functional consequences of this modification remain to be further characterized. In vivo experiments showed that RBMS3 overexpression significantly inhibited ovarian tumor growth and reduces tumor vascular density. Functionally, overexpression of RBMS3 suppressed angiogenesis and invasion of ovarian cancer cells and reduced STAT3 phosphorylation levels. Restoring ELAVL1 expression reversed the inhibitory effects of RBMS3 on these malignant phenotypes and STAT3 phosphorylation. Our study reveals for the first time that RBMS3 coordinates a dual regulatory mechanism by bringing ELAVL1 and UPF1 together into a functional complex. This complex synergistically suppresses ovarian cancer at the post-transcriptional level by reducing ELAVL1 mRNA stability and inhibiting UPF1 methylation. These findings suggest that RBMS3 serves as a key regulator of dual mechanisms and provide a basis for targeting the RBMS3-ELAVL1-UPF1 axis in ovarian cancer therapy.
Retraction notice to "Low expression of PDK1 inhibits renal cell carcinoma cell proliferation, migration, invasion and epithelial mesenchymal transition through inhibition of the PI3K-PDK1-Akt pathway" [Cellular Signalling 56 (2019) 1-14].
Zhou WM, Wu GL, Huang J … +6 more , Li JG, Hao C, He QM, Chen XD, Wang GX, Tu XH
Cell Signal · 2026 Aug · PMID 42000237 · Publisher ↗
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Rhotekin contributes to osteoblast differentiation and bone homeostasis by interacting with Chibby 1.
Wang Y, Shi L, Yang Y … +5 more , Wang S, Chen M, Xie Y, Li X, Wang B
Cell Signal · 2026 Aug · PMID 42000008 · Publisher ↗
Rhotekin, an effector protein for Rho proteins, is implicated in tumorigenesis, yet its function in other biological processes remains largely unexplored. In the current study, we investigate the function of Rhotekin in...
Rhotekin, an effector protein for Rho proteins, is implicated in tumorigenesis, yet its function in other biological processes remains largely unexplored. In the current study, we investigate the function of Rhotekin in osteoblast differentiation and bone homeostasis. Our data show that Rhotekin is expressed in bone and adipose tissue, with its levels increasing as mesenchymal progenitor cells differentiate toward both osteoblasts and adipocytes. When Rhotekin is overexpressed in progenitor cells, it facilitates osteogenic differentiation while inhibiting adipogenic differentiation, whereas knockdown of Rhotekin leads to opposite effects. Moreover, in vivo silencing of Rhotekin in bone marrow results in an increase in adipocytes and a decrease in osteoblasts, ultimately leading to a reduction in cancellous bone mass in mice. Further mechanistic investigations unveil that Rhotekin interacts with Chibby 1 (CBY1), an antagonistic regulator of β-catenin, and competes with β-catenin for binding to CBY1, thereby activating the canonical Wnt/β-catenin pathway. CBY1 is found to suppress osteoblast differentiation, an effect that is counteracted by overexpression of Rhotekin. Moreover, Rhotekin activates the focal adhesion kinase (FAK)/AKT signaling. Collectively, this study provides compelling evidence that Rhotekin interacts with CBY1, relieves its antagonistic effect on β-catenin, and thereby activates canonical Wnt/β-catenin signaling. Together with the concomitant activation of the FAK/AKT pathway, these events contribute to osteoblast differentiation and maintenance of bone homeostasis. Rhotekin may represent a promising therapeutic target for metabolic bone disorders such as osteoporosis.
TP53 links mitochondria-endoplasmic reticulum crosstalk and ferroptosis in septic cardiomyopathy: Protective modulation by nicorandil.
Lu J, Tao Y, Li J … +3 more , Wubuliaila M, Wang J, Li N
Cell Signal · 2026 Aug · PMID 41997516 · Publisher ↗
BACKGROUND: Septic cardiomyopathy (SCM) is a major contributor to sepsis-related mortality, with limited targeted therapies. Ferroptosis and mitochondria-associated endoplasmic reticulum membranes (MAMs) have emerged as...
BACKGROUND: Septic cardiomyopathy (SCM) is a major contributor to sepsis-related mortality, with limited targeted therapies. Ferroptosis and mitochondria-associated endoplasmic reticulum membranes (MAMs) have emerged as important regulators of cardiac injury. TP53 can influence ferroptosis and MAM function, but its role in SCM remains unclear. This study investigated the involvement of TP53 in MAM-associated ferroptosis and the potential protective effects of nicorandil (Nic). METHODS: Bioinformatics analyses were performed to identify key SCM-related genes. Functional validation was conducted in LPS-induced H9C2 cells and a rat SCM model using pharmacological and genetic interventions, including Nic, GSK2656157, TP53 overexpression, and TP53 knockdown. Mitochondrial function, oxidative stress, calcium homeostasis, ferroptosis, and ER-mitochondria interactions were assessed. RESULTS: TP53 was identified as a hub gene associated with ferroptosis and mitochondrial-related pathways. LPS stimulation increased TP53 expression and transcriptional activity, accompanied by enhanced ER-mitochondria proximity, calcium dysregulation, oxidative stress, and ferroptosis-related changes. Nic significantly attenuated myocardial injury, reduced lipid peroxidation and iron accumulation, and restored GPX4 and SLC7A11 expression (P < 0.01). TP53 overexpression weakened these protective effects, whereas TP53 knockdown alleviated LPS-induced injury and ferroptosis-related changes. In addition, the ferroptosis inhibitor ferrostatin-1 partially recapitulated the protective effects of Nic. Combined treatment with GSK further improved ER stress-related alterations and calcium homeostasis. CONCLUSION: These findings suggest that TP53 is functionally involved in SCM and is associated with MAM-related alterations, calcium dysregulation, and ferroptosis. Nic confers cardioprotective effects in vitro and in vivo, at least in part through modulation of TP53-associated stress signaling and ferroptosis. Targeting TP53-related subcellular stress pathways may represent a potential therapeutic strategy for septic cardiomyopathy.
Sildenafil suppresses osteoporosis-related bone marrow adiposity by inhibiting Adipogenic differentiation of mesenchymal stem cells.
Wu L, Hu M, Wei E … +8 more , Pan X, Zhu Q, Wu T, Xiuyun X, Lv L, Dong X, Liu H, Liu Y
Cell Signal · 2026 Aug · PMID 41985733 · Publisher ↗
BACKGROUND: Within the bone marrow niche, maintaining equilibrium between mesenchymal stem cell (MSC) commitment toward osteoblasts and adipocytes is essential for preserving tissue homeostasis. Excessive adipogenic diff...
BACKGROUND: Within the bone marrow niche, maintaining equilibrium between mesenchymal stem cell (MSC) commitment toward osteoblasts and adipocytes is essential for preserving tissue homeostasis. Excessive adipogenic differentiation of MSCs contributes to disorders such as osteoporosis. Targeting marrow adiposity, alongside promoting osteogenesis, may offer a promising therapeutic approach. Sildenafil, a U.S. Food and Drug Administration-approved drug, has been suggested to influence cellular differentiation; however, its potential role in regulating adipogenic differentiation of MSCs remains unclear. Here, we investigated its regulatory effects on MSC adipogenic conversion and bone marrow fat accumulation under osteoporotic conditions, as well as its underlying mechanisms. METHODS: Adipogenic differentiation of human MSCs (hMSCs)-specifically human adipose-derived MSCs (hASCs) and human bone marrow-derived MSCs (hBMSCs)-was assessed by Oil Red O staining, quantitative reverse transcription polymerase chain reaction, and immunofluorescence. In vivo effects were evaluated using an ectopic adipogenesis model in nude mice and two osteoporotic mouse models (ovariectomized and tail-suspension models). RNA sequencing was performed for mechanistic analysis, followed by experimental validation. RESULTS: Sildenafil significantly inhibited adipogenic differentiation of hMSCs in vitro, suppressed adipogenesis of hBMSCs in vivo, and reduced bone marrow adiposity in osteoporotic mice. The results demonstrated that 10 mg/L exerted the most pronounced inhibitory effect on lipid accumulation. Mechanistically, these effects may occur through suppression of the PI3K-AKT signaling pathway. CONCLUSIONS: Sildenafil inhibited adipogenic differentiation of hMSCs and reduced osteoporosis-related bone marrow adiposity, highlighting its therapeutic potential for marrow adiposity associated with osteoporosis and other conditions characterized by excessive MSC adipogenesis.
Cell-penetrating TIPE2 peptide effectively suppresses tumor migration and progression via targeting RAC1.
Zhao M, Li Y, Jia J … +7 more , Li G, Sun Z, Jiang L, Xu M, Lu S, Zhang L, Li W
Cell Signal · 2026 Aug · PMID 41985732 · Publisher ↗
Metastasis is the leading cause of cancer-related death and a major challenge in clinical cancer therapy. Insufficient cell membrane permeability of therapeutic proteins severely hinders the clinical transformation of pr...
Metastasis is the leading cause of cancer-related death and a major challenge in clinical cancer therapy. Insufficient cell membrane permeability of therapeutic proteins severely hinders the clinical transformation of promising anti-tumor targets. As a native negative immune regulator, TIPE2 participates extensively in inflammatory immunity, cellular metabolism and tumor immunity, holding great potential for anti-tumor targeted therapy. Herein, we constructed a cell-penetrating fusion peptide 9R-TIPE2, composed of the 9R cell-penetrating sequence and the α0 domain of TIPE2 protein. 9R-TIPE2 efficiently penetrates cell membranes into the cytoplasm, with definite intracellular metabolic characteristics and no obvious cytotoxicity. It recapitulates the function of endogenous TIPE2 to promote nutrient deprivation-induced tumor cell death, and markedly inhibits the migration of HepG2 and A549 cells by suppressing RAC1-mediated F-actin polymerization and the mTOR signaling pathway. Furthermore, in vivo xenograft experiments confirmed that 9R-TIPE2 effectively inhibits the metastasis of A549 tumors in nude mice. Collectively, 9R-TIPE2 possesses favorable membrane permeability and biosafety, exerts intact biological functions to induce starvation-related tumor cell death and suppress tumor migration both in vitro and in vivo, and is a potent candidate for TIPE2-targeted therapy against hepatocellular carcinoma, lung cancer and other malignancies.
RACK1: A multifunctional scaffold protein involved in signal transduction, ribosomal regulation, and Cancer pathogenesis.
Yang JC, Du YY, Zuo WQ … +5 more , Yao JY, Ma K, Liang Y, Zhao MG, Li ZM
Cell Signal · 2026 Aug · PMID 41967623 · Publisher ↗
RACK1 (receptor for activated C kinase 1) is a highly conserved WD40 repeat family scaffold protein. As a central signaling hub, it regulates cell proliferation, migration, apoptosis, and stress responses by binding key...
RACK1 (receptor for activated C kinase 1) is a highly conserved WD40 repeat family scaffold protein. As a central signaling hub, it regulates cell proliferation, migration, apoptosis, and stress responses by binding key molecules like protein kinase C, Src kinases, and integrin β-subunits. Additionally, RACK1 acts as a ribosomal protein, associating with the 40S subunit to modulate translational stalling and ubiquitination, influencing ribosome function and protein synthesis. RACK1 shows significantly down- or up-regulated in different tumors, highlighting its complex bidirectional signaling role. These effects are mediated through regulation of oncogenic pathways, apoptosis induction, metastasis inhibition, and modulation of metabolic and immune microenvironments. Therefore, the enthusiasm for RACK1-targeted therapeutic strategy is growing and placed RACK1 under the spotlight of oncology. This manuscript, to our knowledge, is the first review to summarize the role of RACK1 in pan-cancers via analysis of comprehensive gene information, and targeted inhibitors. Specifically, we introduce the structure of RACK1 and discuss the current understanding of its mechanism as a central signaling hub that coordinates diverse pathways to regulate cell proliferation, migration, apoptosis, and stress responses. This review outlines the potential therapeutic applications for targeting RACK1 and may contribute to the development of effective RACK1 inhibitors within the strategy of structure-based drug discovery of cancer therapy.
ARID1B regulates sphingolipid metabolism and myelin development via STAG2: Mechanistic insights into ARID1B-related coffin-siris syndrome.
Yang X, Gan Z, Zhou Y … +7 more , Zhang M, Wu S, He F, Shen Z, Ma S, Su X, Xiong F
Cell Signal · 2026 Aug · PMID 41967622 · Publisher ↗
OBJECTIVES: Coffin-Siris syndrome (CSS) is predominantly attributed to variants in ARID1B gene, however, the molecular pathways connecting ARID1B to myelination and neural development are not well elucidated. METHODS: We...
OBJECTIVES: Coffin-Siris syndrome (CSS) is predominantly attributed to variants in ARID1B gene, however, the molecular pathways connecting ARID1B to myelination and neural development are not well elucidated. METHODS: We employed ARID1B knockdown in SK-N-SH cells coupled with transcriptomic analysis to identify downstream targets. We conducted quantitative Real-Time PCR, Western blotting, chromatin immunoprecipitation (ChIP) and co-immunoprecipitation (Co-IP) assays to investigate the regulatory mechanisms of ARID1B. The clinical phenotypes of three CSS patients with pathogenic ARID1B variants were examined to evaluate myelination defects. RESULTS: ARID1B knockdown resulted in a significantly reduction in expression of STAG2 and key genes involved in sphingolipid metabolism (SPTLC1, ACER3, CERS5), which was rescued by exogenous STAG2 overexpression. ChIP assays demonstrated direct binding of ARID1B to the STAG2 promoter, confirming its role in transcriptional regulation. ARID1B deficiency also led to the downregulation of the myelin gene PLP1 and the upregulation of the synaptic gene ARC, both of which were rescued upon STAG2 restoration. Clinically, all three CSS patients exhibited characteristics indicative of hypomyelination, including motor delay and delayed myelination. CONCLUSIONS: Our study reveals a novel ARID1B-STAG2-sphingolipid metabolic axis that is essential for myelin formation and neural function. These findings enhance the understanding of CSS pathogenesis and suggest potential molecular targets for therapeutic intervention in ARID1B-related neurodevelopmental disorders.
LCZ696 (Sac/Val) protects against high-fat diet-induced kidney injury in mice by targeting ROCK2 to suppress ROCK2/NF-κB signaling.
Wang W, Huang Y, Guo X … +8 more , Cao Z, Jiang H, Zheng Q, Shi S, Huang P, Zhou J, Hu F, Qian J
Cell Signal · 2026 Aug · PMID 41967621 · Publisher ↗
BACKGROUND: Obesity-related kidney disease (ORKD) is an increasingly prevalent cause of chronic kidney disease (CKD) worldwide, yet effective therapeutic strategies remain limited. LCZ696 (sacubitril/valsartan, Sac/Val),...
BACKGROUND: Obesity-related kidney disease (ORKD) is an increasingly prevalent cause of chronic kidney disease (CKD) worldwide, yet effective therapeutic strategies remain limited. LCZ696 (sacubitril/valsartan, Sac/Val), an angiotensin receptor-neprilysin inhibitor, has demonstrated cardio-renal benefits; however, its role and underlying mechanism in ORKD remain unclear. METHODS: A high-fat diet (HFD)-induced murine model and palmitate (PA)-stimulated NRK-52E cells were used to evaluate the renoprotective effects of LCZ696. Renal function, histopathology, and fibrosis were assessed by biochemical and histological analyses. Transcriptomic sequencing followed by functional enrichment, kinase analysis, molecular docking, and biochemical experiment were performed to identify key regulatory pathways. Mechanistic validation was conducted through ROCK2 overexpression. RESULTS: LCZ696 (Sac/Val) administration significantly improved renal function and alleviated interstitial fibrosis in HFD-fed mice. Transcriptomic analyses identified ROCK2/NF-κB signaling as a potential key pathway. LCZ696 suppressed PA- and HFD-induced activation of ROCK2, as evidenced by reduced MYPT1 phosphorylation, inhibition of IκBα degradation, decreased nuclear accumulation of NF-κB P65, and downregulation of pro-inflammatory cytokines. ROCK2 overexpression largely reversed these effects, supporting its functional involvement. Molecular docking predicted stable binding of Sac and Val within the ROCK2 pocket, which was further supported by CETSA, DARTS, and pull-down assays. CONCLUSIONS: LCZ696 (Sac/Val) exerts anti-inflammatory and antifibrotic effects in ORKD, at least in part, through modulation of the ROCK2/NF-κB signaling pathway. These findings identify ROCK2-dependent inflammatory signaling as a potential therapeutic target and suggest that LCZ696 may represent a promising strategy for the treatment of ORKD.
Analysis of paired primary-metastatic renal cancer lesions reveals RCN3-MMP10 axis facilitates lung metastasis.
Lin W, Wang Q, Xu K … +6 more , Ding J, Ma Z, Xing S, Xu D, He Y, Chen L
Cell Signal · 2026 Aug · PMID 41966439 · Publisher ↗
The lack of preventive measures for renal cell carcinoma (RCC) lung metastasis and effective treatments for metastatic RCC is currently an unmet clinical need that needs to be addressed. The DNA methylation profiling of...
The lack of preventive measures for renal cell carcinoma (RCC) lung metastasis and effective treatments for metastatic RCC is currently an unmet clinical need that needs to be addressed. The DNA methylation profiling of primary RCC with matched lung metastases remains unclear, which could lead to novel biomarkers and therapeutic targets that may limit the metastasis of renal cancer. In this study, extended-representation bisulfite sequencing and transcriptome sequencing were performed on primary RCC with matched lung metastases to identify metastasis-related genes associated with DNA methylation. Among these genes, reticulocalbin 3 (RCN3) was associated with RCC progression. We found that promoter hypomethylation can upregulate the expression of RCN3. The upregulation of RCN3 can promote the malignant phenotype of RCC in vitro while promoting RCC lung metastasis in vivo. We also demonstrate that RCN3 interacts with MMP10 through its EF-hand 5-6 domains, which promotes the secretion of MMP10 and activates the PI3K/Akt pathway. Finally, we identified that Carboxy-pyridostatin 2HCl may inhibit the metastasis of RCC by binding to the pocket at the binding interface between RCN3 and MMP10. Together, these findings suggest that RCN3 is hypomethylated and upregulated in RCC lung metastasis and plays an important role in RCC lung metastasis, which may serve as a potential therapeutic target.
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