Cell. Signal. [JOURNAL]
Sun
200 papers
DCN promotes dermal papilla cells proliferation by escaping chi-miR-497-5p mediated repression via circPIEZO2 sponging.
Zhang T, Zhong Z, Li X … +2 more , Du J, Wang X
Cell Signal · 2026 Aug · PMID 41966438 · Publisher ↗
The proliferation and apoptosis of dermal papilla cells (DPCs) are crucial for hair follicle morphogenesis and development. High-throughput sequencing data revealed that decorin (DCN) is significantly highly expressed du...
The proliferation and apoptosis of dermal papilla cells (DPCs) are crucial for hair follicle morphogenesis and development. High-throughput sequencing data revealed that decorin (DCN) is significantly highly expressed during the organogenesis phase of cashmere goat hair follicles, primarily within dermal lineage cells. However, its specific function and regulatory mechanisms in hair follicle morphogenesis and development remain unclear. This study focused on the role of DCN in DPCs, and functional experiments showed that DCN overexpression significantly promoted DPCs proliferation and inhibited DPCs apoptosis. Further transcriptome analysis identified a circRNA, named as circPIEZO2, which was positively expressed with DCN. Functional validation revealed that the inhibition of circPIEZO2 suppressed DPCs proliferation and induced DPCs apoptosis. Mechanistic studies revealed that circPIEZO2 was primarily localized in the cytoplasm, where it acted as a molecular sponge for chi-miR-497-5p. By sequestering chi-miR-497-5p, circPIEZO2 alleviated the inhibitory effect of chi-miR-497-5p on the binding to the 3'UTR of the DCN gene, ultimately upregulating DCN expression. Importantly, the overexpression of either DCN or circPIEZO2 activated the Wnt/β-catenin signaling pathway and upregulated its downstream proliferation-related genes Cyclin D1 and C-myc. Conversely, the overexpression of chi-miR-497-5p suppressed the activity of this pathway. In conclusion, this study elucidates the core role of the circPIEZO2/chi-miR-497-5p/DCN regulatory axis in regulating DPCs proliferation and apoptosis. These findings provide novel potential targets and a theoretical basis for cashmere goat breeding and therapeutic targets for hair loss.
RPL26 UFMylation deficiency triggers Paneth cell apoptosis associated with ER stress by impairing ATG16L1-dependent ER-phagy.
Xu J, Chen Z, Li P … +4 more , Yan J, Deng Z, Chen F, Cai Y
Cell Signal · 2026 Aug · PMID 41962728 · Publisher ↗
BACKGROUND: UFMylation plays an essential role in multiple physiological processes. Ribosomal protein L26 (RPL26), a principal target of UFMylation and a component of the ribosomal 60S subunit, is directly involved in pr...
BACKGROUND: UFMylation plays an essential role in multiple physiological processes. Ribosomal protein L26 (RPL26), a principal target of UFMylation and a component of the ribosomal 60S subunit, is directly involved in protein synthesis. However, the biological significance of RPL26 UFMylation in intestinal epithelial cells (IECs) and intestinal homeostasis remains largely unknown. METHODS: IEC-specific RPL26K132/134R mutant (RPL26 UFMylation deficiency) mouse model (CKI) were constructed to investigate the role of RPL26 UFMylation in intestinal development and homeostasis. RESULTS: RPL26 UFMylation deficiency led to a loss of 70 kD and 25-35 kD UFMylated proteins, indicating reduced modification efficiency. Notably, CKI mice exhibited a significantly higher incidence of rectal prolapse and elevated inflammatory levels. More importantly, the small intestine and colon were markedly shortened, with a significant reduction in goblet and Paneth cells. Consistent with the loss of Paneth cells, lysozyme expression was profoundly decreased, accompanied by the downregulation of genes critical for Paneth cell differentiation, development, and lysozyme secretion. Further research found that RPL26 UFMylation deficiency suppressed endoplasmic reticulum aotophagy (ER-phagy) by promoting the ubiquitin-mediated degradation of autophagy related 16 like 1 (ATG16L1), consequently triggering ER stress-dependent apoptosis in Paneth cells. CONCLUSION: Our findings reveal a critical role for RPL26 UFMylation in maintaining IEC function and intestinal homeostasis, providing novel insights into the genetic mechanisms underlying intestinal health.
Chlorogenic acid (CGA) exerts antidepressant-like effects by regulating SIRT1/FoxO3a/PINK1/Parkin pathway in LPS-induced depressive mice.
Piao X, Song J, Piao J … +4 more , Shang Y, Jin Y, Cui R, Li B
Cell Signal · 2026 Aug · PMID 41962727 · Publisher ↗
A growing focus in nutritional psychiatry is examining dietary interventions as a therapeutic strategy for depression. Chlorogenic acid (CGA), a naturally occurring polyphenol, has demonstrated promising anti-inflammator...
A growing focus in nutritional psychiatry is examining dietary interventions as a therapeutic strategy for depression. Chlorogenic acid (CGA), a naturally occurring polyphenol, has demonstrated promising anti-inflammatory and neuroprotective effects. This study aimed to elucidate the underlying molecular targets and mechanisms responsible for CGA's antidepressant-like actions. The potential targets and pathways of CGA related to FoxO3a were initially predicted using network pharmacology and molecular docking. In vitro, the protective effects of CGA were investigated in HO-stimulated HT-22 cells by assessing cell viability, reactive oxygen species (ROS) levels, mitochondrial membrane potential, and the expression of mitophagy-related proteins. In vivo, a depression model was established in male mice via intraperitoneal injection of lipopolysaccharide (LPS). The antidepressant efficacy of CGA was evaluated through a behavioral test battery. Microglial activation was detected via immunofluorescence. Furthermore, mitochondrial ultrastructure was examined by transmission electron microscopy (TEM), and the expression of mitophagy-related proteins was additionally validated by Western blotting. Finally, the direct interaction between SIRT1 and FoxO3a was examined by co-immunoprecipitation. In vitro, CGA pretreatment improved HT-22 cells viability under HO-induced oxidative stress, reduced ROS levels, and restored mitochondrial membrane potential. In vivo, CGA reduced neuroinflammation by lowering the levels of proinflammatory cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), inhibited microglial activation, and alleviated depressive-like behaviors in LPS-treated mice. Additionally, CGA activated the sirtuin 1 (SIRT1) / forkhead box O3a (FoxO3a) / PTEN-induced kinase 1 (PINK1) / Parkin signaling pathway, promoting hippocampal mitophagy. The antidepressant-like effects of CGA were suppressed upon SIRT1 antagonism with EX527. This study suggests that CGA may serve as a potential therapeutic agent for depression.
Hippocampal HDAC7 induces perioperative neurocognitive disorders via an NF-κB-MFN2-ACSL4 ferroptosis pathway.
Guo J, Chi W, Zhang K … +4 more , Huang Y, Zhang B, Guo X, Meng F
Cell Signal · 2026 Aug · PMID 41962726 · Publisher ↗
Perioperative neurocognitive disorders (PND) are common complications in elderly surgical patients, yet the molecular mechanisms underlying this condition remain poorly understood. Accumulating evidence suggests that HDA...
Perioperative neurocognitive disorders (PND) are common complications in elderly surgical patients, yet the molecular mechanisms underlying this condition remain poorly understood. Accumulating evidence suggests that HDAC7-a member of the class IIa histone deacetylase (HDAC) family-plays a crucial role in brain injury and can activate the NF-κB pathway independently of its deacetylase activity. In the present study, we investigated whether upregulation of hippocampal HDAC7 contributes to PND through NF-κB-mediated mitochondrial dysfunction and ferroptosis. A tibial fracture model was established in 18-month-old mice, and elevated levels of HDAC7 and phosphorylated NF-κB (P-NF-κB) were detected in the hippocampal CA3 region 3 days after surgery. Moreover, bilateral injections of HDAC7 AAV-shRNA into the CA3 region reduced P-NF-κB levels and alleviated mitochondrial damage. HDAC7 knockdown restored mitofusin 2 (MFN2) expression, reversed the upregulation of acyl-CoA synthetase long-chain family member 4 (ACSL4) and the loss of glutathione peroxidase 4 (GPX4), normalized the levels of ferroptosis-related markers (Fe, MDA, GSH, and SOD), and improved cognitive performance. In vitro, HT22 neurons exposed to conditioned medium from lipopolysaccharide (LPS)-activated BV2 microglia underwent ferroptotic cell death, which was prevented by ferrostatin-1 but not by apoptosis or autophagy inhibitors. Notably, pharmacological inhibition of the enzymatic activity of class IIa HDACs with TMP269 failed to attenuate ferroptosis, whereas HDAC7 knockdown suppressed P-NF-κB activation, restored MFN2 expression, corrected ACSL4/GPX4 abnormalities, and suppressed ferroptosis, further supporting a deacetylase-independent role of HDAC7. Furthermore, treatment with MASM7, an MFN2 activator, alleviated ferroptosis in vitro without affecting HDAC7 expression or NF-κB phosphorylation. In vivo, MASM7 administration also improved cognitive function and mitigated ferroptosis-related changes after surgery. Taken together, these findings demonstrate that HDAC7 promotes neuronal ferroptosis through the NF-κB-MFN2-ACSL4 pathway, thereby contributing to the development of PND.
Sulforaphane prevents abdominal aortic aneurysm formation through the inhibition of phenotypic switching of vascular smooth muscle cells and inflammation via the activation of Nrf2.
Huang Z, Tao Y, Liu C … +7 more , Wang J, Deng C, Han Z, Yun T, Li T, Lu W, Lai Y
Cell Signal · 2026 Aug · PMID 41941990 · Publisher ↗
OBJECTIVE: Targeted therapy for the phenotypic switching of vascular smooth muscle cell(VSMC) is a critical strategy for mitigating disease progression in patients with abdominal aortic aneurysms (AAAs). Sulforaphane (SF...
OBJECTIVE: Targeted therapy for the phenotypic switching of vascular smooth muscle cell(VSMC) is a critical strategy for mitigating disease progression in patients with abdominal aortic aneurysms (AAAs). Sulforaphane (SFN), a nuclear factor E2 factor-related factor (Nrf2) activator, has anti-inflammatory and antioxidant properties and might regulate the phenotypic switching of VSMCs. However, the role of SFN in AAA formation is unknown. In this study, we explored the inhibitory effect of SFN on AAA formation and its underlying mechanisms. METHODS: Quantitative PCR, western blotting and immunohistochemistry were used to determine biomarkers of the contractile state of VSMC expression and proinflammatory factor expression in cell and mouse AAA samples. SFN treatment and Nrf2 knockout were performed to investigate the role of SFN in AAA formation. In vivo VSMC Nrf2 conditional knockout experiments were performed to determine the critical role of Nrf2 in the protective effect of SFN on AAA. RESULTS: SFN alleviated AAA formation and inhibited VSMC phenotype switching and vascular inflammation. Mechanistically, SFN retained the contractile state of VSMCs and inhibited inflammation via the activation of Nrf2. Moreover, Nrf2 deficiency significantly counteracted the protective effect of SFN in inhibiting VSMC phenotype switching and macrophage activation, thereby promoting AAA formation. CONCLUSION: SFN inhibited AAA formation by suppressing VSMC phenotype switching and vascular inflammation. SFN is a potential effective treatment for AAA.
A novel diagnostic and prognostic biomarker FSD1L facilitates EMT and Lenvatinib resistance via the WNT/β-catenin pathway in hepatocellular carcinoma.
Zhou Y, Hu G, Zhou L … +3 more , Zhou J, Jiang Y, Luo F
Cell Signal · 2026 Aug · PMID 41935591 · Publisher ↗
BACKGROUND: FSD1L, a gene involved in cytoskeletal organization and cell adhesion, is highly expressed in hepatocellular carcinoma (HCC) tissues with invasion/metastasis and lenvatinib-resistant cells, but its role in HC...
BACKGROUND: FSD1L, a gene involved in cytoskeletal organization and cell adhesion, is highly expressed in hepatocellular carcinoma (HCC) tissues with invasion/metastasis and lenvatinib-resistant cells, but its role in HCC remains unclear. Therefore, this study aimed to investigate the function of FSD1L in HCC progression as well as the underlying molecular mechanisms. METHODS: Database mining identified upregulated genes in invasive/metastatic HCC lesions and lenvatinib-resistant HCC cells. FSD1L expression was analyzed across 9 HCC cohorts (8 with normal tissues). Kaplan-Meier survival, ROC (diagnostic efficacy), and Cox regression (prognostic value) analyses were performed. Correlations between FSD1L and proliferation (MKI67/PCNA)/metastasis (MMP2/9) markers were examined. FSD1L was silenced via siRNA/shRNA in MHCC-97H, Huh7, and lenvatinib-resistant Huh7 cells, whereas Hep3B cells were subjected to overexpression plasmid transfection. Cell proliferation (CCK-8), apoptosis (flow cytometry), migration (wound-healing), and lenvatinib sensitivity (IC₅₀/CCK-8) were assessed in vitro, complemented by in vivo xenograft studies in nude mice to evaluate tumorigenicity. GSEA explored dysregulated oncogenic pathways. WNT agonist LiCl was used in rescue experiments to verify the role of WNT/β-catenin pathway in FSD1L-mediated EMT, proliferation, migration, and lenvatinib resistance. RESULTS: FSD1L was consistently upregulated in lenvatinib-resistant cells and HCC lesions with invasion/metastasis. FSD1L/Fsd1l overexpression was observed in all 8 human HCC cohorts and a transgenic mouse HCC model (all p < 0.05). High FSD1L correlated with poor overall survival (OS) in TCGA-LIHC (HR = 1.77, p < 0.001), positively correlated with PCNA, KI67, MMP2, and MMP9. It showed favorable diagnostic efficacy (AUC: 0.645-0.97, all p < 0.05) and was an independent prognostic factor (multivariate Cox: HR = 3.207, p = 0.002). Loss- and gain-of-function studies established FSD1L as a promoter of malignancy and lenvatinib resistance, validated by xenograft tumor suppression upon sh-FSD1L-1 treatment. GSEA indicated enrichment of WNT/β-catenin pathway in FSD1L-high HCC. Mechanistically, FSD1L knockdown reduced β-catenin, c-Myc, p-GSK3β (Ser9), and modulated EMT markers; these effects were reversed by LiCl. CONCLUSION: FSD1L is a novel oncogenic driver in HCC that is selectively enriched in metastatic and lenvatinib-resistant contexts. It activates the WNT/β-catenin pathway to regulate HCC proliferation, EMT and lenvatinib resistance. FSD1L holds promise as a dual biomarker for diagnosis/prognosis and a potential therapeutic target for lenvatinib resistance in HCC.
Chloride intracellular channel 4 contributes to Aβ-induced cognitive impairment in mice through the regulation of mitochondrial fission. CLIC4 promotes mitochondrial fission.
Wang J, Mao X, Zheng R … +11 more , Gao H, Chen G, Zhang Y, Xu M, Lin Q, Nivar J, Tao YX, Sun M, Cao H, Zhang J, Li J
Cell Signal · 2026 Aug · PMID 41935590 · Publisher ↗
Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by impaired memory and cognitive decline. The early stages of AD in mice present with neuropathy in the hippocampus. Excessive mitochondria...
Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by impaired memory and cognitive decline. The early stages of AD in mice present with neuropathy in the hippocampus. Excessive mitochondrial fragmentation and dysfunction are critical pathological features of AD. Chloride intracellular channel 4 (CLIC4) is involved in neuronal apoptosis and regulates mitochondrial functions. Glial maturation factor β (GMFβ) inhibits mitochondrial DNA replication and energy metabolism, causes mitochondrial dysfunction, and regulates apoptosis. Dynamic related protein 1 (DRP1), a key protein in mitochondrial division, exhibits increased activity when its Ser616 site is phosphorylated. However, the role of CLIC4 in Aβ-induced cognitive impairment through the modulation of GMFβ and p-DRP1 (Ser616) to induce mitochondrial dysfunction remains unclear. This study examined the role of CLIC4 in Aβ-induced cognitive impairment in AD mice, focusing on its regulation of GMFβ and p-DRP1 (Ser616) and the subsequent effects on mitochondrial hyperfission and dysfunction. Our findings demonstrate that overexpression of CLIC4 in the mouse hippocampus or in HT22 cells resulted in pathological changes analogous to those observed following Aβ exposure. These changes include elevated levels of GMFβ and p-DRP1 (Ser616) proteins, mitochondrial fission, and increased intracellular ROS production. Conversely, CLIC4 knockdown mitigated Aβ-induced neuronal damage. These findings indicate that CLIC4 may be crucial in Aβ-induced hippocampal neurological damage in mice by regulating GMFβ and DRP1 phosphorylation.
RNF130 inhibits the proliferation, migration and invasion of osteosarcoma through DAB1 mediated suppression of the PI3K/AKT signaling pathway.
Liu W, Guo L, Liu Z … +1 more , Guo W
Cell Signal · 2026 Aug · PMID 41933674 · Publisher ↗
BACKGROUND: Ring finger protein 130 (RNF130) is also known as Goliath. It is the mammalian homolog of the Drosophila E3 ligase Goliath (dGoliath), which is localized to the protease-associated (PA) domain. Although RNF13...
BACKGROUND: Ring finger protein 130 (RNF130) is also known as Goliath. It is the mammalian homolog of the Drosophila E3 ligase Goliath (dGoliath), which is localized to the protease-associated (PA) domain. Although RNF130 has been investigated in other research areas, its functional role in osteosarcoma remains poorly defined. METHODS: We initially analyzed the expression of RNF130 in osteosarcoma via an online database and explored its association with patient survival prognosis. Subsequently, the influence of RNF130 on osteosarcoma malignancy was verified using in vivo phenotypic assays. Furthermore, the molecular mechanism underlying RNF130-mediated regulation of osteosarcoma progression was elucidated by transcriptome sequencing and co-immunoprecipitation. Finally, a xenograft tumor model was constructed in nude mice to verify the regulatory effect of RNF130 on osteosarcoma growth in vivo. RESULTS: RNF130 expression was significantly decreased in osteosarcoma tissues and was associated with overall survival in the TCGA dataset. Functional assays demonstrated that overexpression of RNF130 inhibits the proliferation, migration, and invasion of osteosarcoma cells. Conversely, silencing of RNF130 promoted these malignant phenotypes. Mechanistic investigations revealed that RNF130 functions as a tumor suppressor in osteosarcoma by regulating the DAB1/PI3K/AKT/mTOR signaling axis via the ubiquitin-proteasome pathway. CONCLUSION: RNF130 may be associated with prognosis in osteosarcoma and suppresses malignant progression by regulating the DAB1/PI3K/AKT/mTOR signaling pathway. Its clinical prognostic value still requires validation in larger independent datasets.
Curcumin protects retinal photoreceptors in Glaucoma by activating prostaglandin D2 synthase-dependent NRF2 signaling.
Wang Y, Ma Y, Zhang S … +1 more , Nie L
Cell Signal · 2026 Aug · PMID 41933673 · Publisher ↗
Glaucoma, a leading cause of irreversible blindness, involves oxidative stress-mediated damage to retinal photoreceptors. This study elucidates the molecular mechanism by which curcumin, a natural compound, protects reti...
Glaucoma, a leading cause of irreversible blindness, involves oxidative stress-mediated damage to retinal photoreceptors. This study elucidates the molecular mechanism by which curcumin, a natural compound, protects retinal cells in glaucoma. Molecular docking and biochemical assays revealed that curcumin binds prostaglandin D2 synthase (PTGDS) with high affinity, leading to marked upregulation of PTGDS expression. In vitro experiments using HO-treated 661 W retinal cells showed that PTGDS overexpression suppressed reactive oxygen species (ROS) accumulation, inflammation, and apoptosis while enhancing proliferation. Transcriptomic profiling showed that PTGDS knockdown disrupted nuclear factor erythroid 2-related factor 2 (NRF2) signaling and downregulated key antioxidant genes. Mechanistically, curcumin-induced PTGDS expression activated NRF2, increased phosphorylation of AMP-activated protein kinase (AMPK) and ERK, upregulated Bcl-2, and inhibited Bax and caspase-3 cleavage. These effects were abolished by PTGDS knockdown. In vivo validation using a paraquat-induced glaucoma mouse model confirmed that curcumin improved visual function (via pattern electroretinography, optokinetic response, and visual evoked potentials), reduced retinal oxidative stress markers (malondialdehyde, superoxide dismutase, glutathione), and attenuated inflammatory cytokines (Interleukin [IL]-1β, Tumor Necrosis Factor Alpha [TNF-α]). PTGDS knockdown negated these therapeutic benefits. Together, these findings establish PTGDS as a critical mediator of curcumin-induced NRF2 activation, highlighting a novel cross-species neuroprotective pathway and a promising therapeutic target for glaucoma.
Mitochondrial IRF3 drives pulmonary fibrosis by impairing mitophagy and triggering ferroptosis.
Jiashu Z, Jingbao L, Hua F … +4 more , Meiqi S, Jing L, Mengyao W, Wei Z
Cell Signal · 2026 Aug · PMID 41932414 · Publisher ↗
BACKGROUND: Pulmonary fibrosis (PF) is a progressive, lethal lung disease with limited treatments. Although inflammation is involved, how it triggers specific oxidative cell death in epithelial cells remains unclear. The...
BACKGROUND: Pulmonary fibrosis (PF) is a progressive, lethal lung disease with limited treatments. Although inflammation is involved, how it triggers specific oxidative cell death in epithelial cells remains unclear. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is active in PF, but research has focused on its upstream inflammatory role. The function of its key effector, interferon regulatory factor 3 (IRF3), especially through non-canonical mechanisms, is largely unknown. We hypothesized that activated IRF3 translocates to mitochondria to disrupt quality control and promote ferroptosis, linking inflammation to fibrosis. METHODS: We employed a bleomycin-induced mouse PF model and TGF-β-stimulated A549 cells. Techniques included molecular analyses (western blot, RT-qPCR, Co-IP), imaging (TEM, immunofluorescence), mitophagy flux assays, and measurement of ferroptosis markers (Fe, MDA). Interventions involved H151, si-IRF3, Ferrostatin-1, and Mdivi-1. RESULTS: In PF, phosphorylated IRF3 translocated to mitochondria, interacting with PINK1 to impair mitophagy, shown by decreased PINK1, accumulated p62, and reduced LC3-II/LC3-I ratio. This triggered ferroptosis, evidenced by upregulated ACSL4, downregulated GPX4, elevated Fe/MDA, and mitochondrial damage. In TGF-β-stimulated A549 cells, IRF3 knockdown or STING inhibition restored mitophagy and suppressed ferroptosis. Mdivi-1 reversed si-IRF3's protection. In vivo, H151 treatment suppressed the IRF3-mitophagy-ferroptosis axis and alleviated PF. CONCLUSIONS: Mitochondrial IRF3 integrates cGAS-STING signaling with mitophagic dysfunction and ferroptosis to drive PF, revealing a novel therapeutic target.
PRPF4B drives hepatocellular carcinoma progression by modulating NF-κB signaling via TIA1-regulated alternative splicing.
Zhang C, Huang Z, Su Y … +6 more , Liu Y, Zhang C, Ge C, Tian W, Yang Y, Tian H
Cell Signal · 2026 Aug · PMID 41932413 · Publisher ↗
The splicing kinase family contributes significantly to tumor progression. As a member of this family, PRPF4B has been directly implicated in oncogenic processes. However, little is known about the precise role and under...
The splicing kinase family contributes significantly to tumor progression. As a member of this family, PRPF4B has been directly implicated in oncogenic processes. However, little is known about the precise role and underlying mechanisms of PRPF4B in hepatocellular carcinoma (HCC). In this study, we found that the expression of PRPF4B was upregulated and associated with a poor prognosis in HCC patients. PRPF4B knockdown significantly suppressed HCC cell proliferation, migration, and invasion while concurrently inducing apoptosis. Knockdown of PRPF4B induced DNA damage via reactive oxygen species (ROS) accumulation, leading to cell cycle arrest at the G2/M phase. This arrest was associated with increased phosphorylation of CDC2, elevated γ-H2AX levels, and downregulation of CDC25C and cyclin B1. In addition, we found that expression of PRPF4B was upregulated in sorafenib no-responders (NR) compared with sorafenib responders (R). PRPF4B knockdown sensitizes HCC cells to sorafenib treatment. Mechanistically, we demonstrated that knockdown of PRPF4B inhibited HCC proliferation through NF-κB pathway. Furthermore, PRPF4B interacts with TIA1. Knockdown of PRPF4B promotes the expression of a specific TIA1 splice variant, leading to altered mRNA splicing that inhibits NF-κB activity. Our findings reveal that PRPF4B interacts with TIA1 and modulates its splicing. Knockdown of PRPF4B triggers ROS-dependent DNA damage, cell cycle arrest, and suppression of HCC proliferation, while enhancing sorafenib sensitivity via inhibition of the NF-κB pathway. Therefore, PPRF4B may be a potential therapeutic target for HCC treatment and sorafenib sensitization.
Bone marrow mesenchymal stem cell-derived exosomes enhance tendon regeneration and promote TDSC migration and differentiation.
Lin J, Zhang H, Fu H … +4 more , Han X, Weng S, Yu X, Lin H
Cell Signal · 2026 Aug · PMID 41932412 · Publisher ↗
OBJECTIVE: To explore the role of bone marrow mesenchymal stem cell-derived exosomes (BMSCs-Exos) in promoting the motility and functional enhancement of tendon-derived stem cells (TDSCs) and assess their potential in te...
OBJECTIVE: To explore the role of bone marrow mesenchymal stem cell-derived exosomes (BMSCs-Exos) in promoting the motility and functional enhancement of tendon-derived stem cells (TDSCs) and assess their potential in tendon regeneration and repair. METHODS: In vitro experiments involved the isolation and characterization of BMSCs-Exos from cultured bone marrow mesenchymal stem cells. The exosomes were analyzed for their size, morphology, and protein content using nanoparticle tracking analysis (NTA) and western blotting for exosomal markers. Tendon stem cell (TDSC) migration was assessed using a scratch assay. For in vivo analysis, a rat tendon injury model was used to evaluate the therapeutic effects of BMSCs-Exos on tendon healing and tissue regeneration. Rats were injected with BMSCs-Exos at varying doses, and the healing process was monitored through histological analysis and assessment of angiogenesis and collagen deposition. RESULTS: The results demonstrated successful extraction of BMSCs-Exosomes, confirmed by positive expression of exosomal markers (CD9, CD63, and ALIX) and the absence of cellular contaminants via western blot and uniform particle size (median 134.8 nm, concentration 8.7 × 10 particles/mL). Immunofluorescence showed a time-dependent uptake of purified PKH26-labeled Exosomes by TDSCs. While no significant difference in proliferation or survival was observed, Exosomes promoted scratch closure (p < 0.05) and osteogenic differentiation, as evidenced by increased ALP activity, calcium deposition (ARS), and upregulation of Runx-2/COL-1 expression. In vivo, Exosomes promoted collagen synthesis (COL-1) and angiogenesis (CD31), improving tendon structural integrity (H&E staining). CONCLUSION: BMSCs-Exos demonstrate therapeutic potential for tendon repair by orchestrating key regenerative processes, including tendon stem cell motility and differentiation.
Membrane receptor TGR5 upregulates IP3R-induced calcium overload: Key mechanism of bile acid-induced acute pancreatitis.
Zhong Z, Cheng L, Jiang Z … +9 more , Zhu Y, Zhao C, Deng C, Yang T, Chen M, Yu Q, Xie C, Dai X, Wang T
Cell Signal · 2026 Aug · PMID 41921768 · Publisher ↗
INTRODUCTION: Acute pancreatitis (AP) is a digestive system emergency with acomplex pathogenesis, with pathological calcium overload identified as a key driving factor. Excessive or improper exposure to bile acids (BAs)...
INTRODUCTION: Acute pancreatitis (AP) is a digestive system emergency with acomplex pathogenesis, with pathological calcium overload identified as a key driving factor. Excessive or improper exposure to bile acids (BAs) is the main pathogenic factor of AP, but the role of its membrane receptor TGR5 in AP and its downstream mechanisms has not been fully elucidated. METHOD: A BAs-induced rat model of AP was established. The expression of TGR5 was detected. TGR5's role in AP was evaluated by knocking down TGR5. Pathological manifestations, serum indicators, inflammatory factor expression, oxidative stress levels, cell ultrastructure, and TGR5/IP3R expression were measured in each group. In vitro, AR42J cells received TGR5/IP3R intervention. Immunofluorescence, WB, and RT-qPCR were used to evaluate the roles and interrelationships of TGR5 and IP3R in AP. Calcium imaging technology was used to detect their effects on intracellular calcium ions. RESULT: We found that TGR5 was widely expressed in pancreatic tissue. Its expression significantly increased in BAS-induced AP. In the AP rat model, knockdown of TGR5 can effectively alleviate pancreatic injury. It reduces serum enzymatic indicators and inflammatory factor levels, relieves oxidative stress, and improves mitochondrial structure. Cell experiments further confirmed that BAs can upregulate the expression of IP3R through TGR5. This upregulation causes intracellular calcium overload in acinar cells. Inhibiting or knocking down TGR5/IP3R expression and activity can play a protective role. CONCLUSION: In conclusion, our research indicates that bile acids can trigger AP through the TGR5-IP3R‑calcium overload axis. Inhibiting TGR5/IP3R can alleviate calcium overload and exert a protective effect, providing new insights into the pathogenesis of AP.
The role of the triggering receptor expressed on myeloid cells family in metabolic syndrome: A review.
Li Y, Wang Y, Li H … +3 more , Gao R, Zhang W, Yang X
Cell Signal · 2026 Aug · PMID 41916487 · Publisher ↗
Metabolic syndrome (MetS) is a cluster of highly interrelated metabolic disorders, characterized by central obesity, insulin resistance, dyslipidemia, and hypertension, which collectively elevate the risk of developing t...
Metabolic syndrome (MetS) is a cluster of highly interrelated metabolic disorders, characterized by central obesity, insulin resistance, dyslipidemia, and hypertension, which collectively elevate the risk of developing type 2 diabetes, cardiovascular diseases, and non-alcoholic fatty liver disease. Chronic low-grade inflammation is a key pathological driver in the initiation and progression of MetS, wherein the abnormal activation of monocytes and macrophages plays a pivotal role. The Triggering Receptors Expressed on Myeloid cells (TREMs) family serves as a critical bridge connecting innate immune responses with metabolic regulation. Within this family, TREM2, distinct from the pro-inflammatory TREM1, exhibits a tissue-protective phenotype, primarily involved in maintaining tissue homeostasis, promoting damage repair, and suppressing excessive inflammatory responses. In recent years, the crucial role of TREM2 in obesity-associated metabolic disturbances has been gradually elucidated. In high-fat diet-induced obesity models, TREM2 has been identified as a core marker and functional regulator of "lipid-associated macrophages (LAMs)" within adipose tissue, deeply involved in lipid droplet phagocytosis, cholesterol metabolic reprogramming, and the homeostasis of the local inflammatory microenvironment. This review systematically summarizes the diverse functions of TREM2 in metabolic syndrome, with a focus on analyzing its molecular mechanisms of action in adipose tissue, liver, and the vascular system. It explores its potential value as a disease biomarker and prospects the development of novel therapeutic strategies targeting the TREM2 signaling pathway, thereby providing new insights and a theoretical foundation for the treatment of metabolic diseases.
E3 ubiquitin ligases and deubiquitinases: Promising therapeutic targets for diabetic kidney disease.
Wu Y, Jia H, Sun F … +3 more , Yang Y, Li Z, Liu WJ
Cell Signal · 2026 Jul · PMID 41912103 · Publisher ↗
Diabetic kidney disease (DKD) is a common complication of diabetes and a major contributor to chronic kidney disease and end-stage renal disease. E3 ubiquitin ligases and deubiquitinases participate in numerous cellular...
Diabetic kidney disease (DKD) is a common complication of diabetes and a major contributor to chronic kidney disease and end-stage renal disease. E3 ubiquitin ligases and deubiquitinases participate in numerous cellular processes, and emerging evidence has highlighted that alterations in their activity or expression are closely associated with the onset and progression of DKD. Ubiquitination mediated by E3 ubiquitin ligases and deubiquitination mediated by deubiquitinases play critical roles in the pathogenesis of DKD through regulating downstream signaling pathways. This review aimed to summarize the roles of E3 ubiquitin ligases and deubiquitinases in DKD, outline their underlying molecular mechanisms, and highlight their potential as therapeutic targets. The findings of this review provide new insights into developing strategies for DKD prevention and treatment, and offer new directions for future drug development.
Corrigendum to 'Dapagliflozin activates the RAP1B/NRF2/GPX4 signaling and promotes mitochondrial biogenesis to alleviate vascular endothelial ferroptosis' [Cell Signal. 2025 Aug, 132:111824].
Zhu Y, Yang J, Zhang JL … +4 more , Liu H, Yan XJ, Ge JY, Wang FF
Cell Signal · 2026 Aug · PMID 41904088 · Publisher ↗
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A fission yeast-based platform for nematode PDE inhibitor discovery.
Bibeau S, Chen N, Sutoris H … +15 more , Ly J, Eberhard J, Hubbell SM, Banda E, Povh E, Anindya CS, Berwanger MR, Sinise SE, Zhang X, Morken JP, Galande KK, Cote RH, Dranchak PK, Inglese J, Hoffman CS
Cell Signal · 2026 Jul · PMID 41903918 · Full text
Class I cyclic nucleotide phosphodiesterases (PDEs) form a family of enzymes that hydrolyze the signaling molecules cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Highly potent and selec...
Class I cyclic nucleotide phosphodiesterases (PDEs) form a family of enzymes that hydrolyze the signaling molecules cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Highly potent and selective inhibitors of mammalian PDEs have been developed, demonstrating that this enzyme family is eminently druggable. The genomes of the free-living nematode and model organism Caenorhabditis elegans and those of related parasitic nematodes possess six PDE genes representing six of the eleven PDE families found in mammals. Here, we expressed the C. elegans PDEs or their catalytic domains in the fission yeast Schizosaccharomyces pombe and screened a collection of small molecule inhibitors of mammalian PDEs obtained from our previous high throughput screens for ones with activity against one or more C. elegans PDEs. Consistent with an earlier study, the C. elegans PDE-4 enzyme is relatively insensitive to mammalian PDE4 inhibitors such as Rolipram, as are PDE-4 enzymes from three parasitic nematodes. Much of this is due to a single amino acid difference between mammalian PDE4s and nematode PDE4, as replacing arginine 580 with threonine in C. elegans PDE-4 restores substantial sensitivity to Rolipram. Finally, several of the most effective C. elegans PDE inhibitors were tested for their impact on C. elegans growth and fertility, two of which displayed toxic effects on C. elegans viability and fecundity using two different assessment methods, while a third showed a significant effect on fecundity. The strategy described herein offers an approach for discovery of novel anthelmintic and nematicidal compounds targeting parasitic nematode PDEs.
Peripheral regional anesthesia alleviates skeletal muscle injury and inflammation caused by acute compartment syndrome by inhibiting PI3K/AKT/NF-kB pathway and regulating macrophage polarization.
Wang T, Cao J, Zhang J … +3 more , Deng Y, Hou Z, Zhang Q
Cell Signal · 2026 Aug · PMID 41903917 · Publisher ↗
BACKGROUND: Acute compartment syndrome (ACS) is a serious complication of tibial fractures that can cause muscle necrosis. Although the protective effects of peripheral regional anesthesia (PRA) in ACS have been document...
BACKGROUND: Acute compartment syndrome (ACS) is a serious complication of tibial fractures that can cause muscle necrosis. Although the protective effects of peripheral regional anesthesia (PRA) in ACS have been documented recently, the exact mechanism is still unknown. This research aimed to investigate the therapeutic efficacy and potential mechanism of PRA in skeletal muscle injury caused by ACS. METHODS: Sprague-Dawley (SD) rats were randomly divided into three groups (fracture group, FG; ACS group, AG; ACS + PRA group, PG). We established the ACS model and performed PRA guided by ultrasound. We assessed edema and blood flow of the affected limb, as well as apoptosis and fibrosis of skeletal muscle. RNA sequencing of skeletal muscle was used to observe enrichment analysis. Then, immunofluorescence and western blot were used to verify the expression of key proteins. RESULTS: PRA not only can significantly reduce edema, fibrosis and apoptosis of skeletal muscle caused by ACS but also it can alleviate ischemia. The data of RNA sequencing showed that PRA can ameliorate skeletal muscle injury by inhibiting PI3K/AKT/NF-kB pathway and we found that the protective role of PRA in skeletal muscle may be related to macrophage polarization, which was verified by immunofluorescence analyses. After adding the agonist of PI3K/AKT/NF-kB pathway, the beneficial effects of PRA were attenuated. CONCLUSION: Our research indicates that PRA may effectively reduce skeletal muscle damage and inflammation caused by ACS by inhibiting the PI3K/AKT/NF-kB pathway and regulating macrophage polarization, offering a new therapeutic strategy for ACS.
The p75NTR/Mdm2 signaling axis promotes odontogenic differentiation and mineralization in ectomesenchymal stem cells.
Mao J, Pu X, Tian L … +6 more , Chen Y, Liu Y, Liu L, She R, Wang G, Wen X
Cell Signal · 2026 Jul · PMID 41881094 · Publisher ↗
Tooth development and regeneration depend on precise regulation of odontogenic stem cell fate. With advances in stem cell tissue engineering and regenerative medicine, biological tooth regeneration has become a focus of...
Tooth development and regeneration depend on precise regulation of odontogenic stem cell fate. With advances in stem cell tissue engineering and regenerative medicine, biological tooth regeneration has become a focus of regenerative medicine. As a positive marker of neural crest-derived ectomesenchymal stem cells, p75NTR actively participates in tooth development. Mdm2, a key negative regulator of p53, is functionally associated with p75NTR. However, the crosstalk between p75NTR and Mdm2 and their roles in tooth mineralization during development remain unclear. This study investigated the functions of p75NTR and Mdm2 in odontogenic differentiation and mineralization and their regulatory relationships. A p75NTR knockout mouse model was established to investigate the regulatory effect of p75NTR on Mdm2. Ectomesenchymal stem cells derived from mouse dental germs were used for in vitro experiments. The results revealed that Mdm2 expression was reduced in the dental tissues of p75NTR knockout mice and that p75NTR overexpression in EMSCs in vitro significantly upregulated Mdm2 expression. Moreover, Mdm2 enhanced the expression of Dspp, Dmp1, Runx2, and Opn in EMSCs. Luciferase reporter assays and coimmunoprecipitation experiments demonstrated that p75NTR increased the transcriptional activity of the Mdm2 gene while interacting with the Mdm2 protein in the nucleus. Furthermore, p75NTR overexpression reversed the inhibitory effects of Mdm2 knockdown on odontogenic differentiation and mineralization of EMSCs. These findings indicate that Mdm2 mediates p75NTR-induced odontogenic differentiation and mineralization of EMSCs and that p75NTR activates Mdm2 transcription while binding to the Mdm2 protein in the nucleus.
The mechanosensitive ion channel Piezo1 promotes colitis by modulating oxidative stress and ferroptosis-related markers.
Zhou J, Lu P, He H … +6 more , Yang D, Zhu W, Liu Q, Liu Q, Zhang G, Liu M
Cell Signal · 2026 Jul · PMID 41881093 · Publisher ↗
Piezo1 plays a crucial role in the gastrointestinal tract. However, whether Piezo1 induces intestinal dysfunction and mitochondrial damage in dextran sulfate sodium (DSS)-induced colitis, and the underlying mechanisms in...
Piezo1 plays a crucial role in the gastrointestinal tract. However, whether Piezo1 induces intestinal dysfunction and mitochondrial damage in dextran sulfate sodium (DSS)-induced colitis, and the underlying mechanisms involved, remains unclear. We aimed to investigate whether Piezo1 triggers oxidative stress, alters ferroptosis-associated markers, and induces intestinal epithelial injury in human intestinal epithelial cells (HIECs) and in the colonic tissues of mice with DSS-induced colitis. We established a DSS-induced colitis mouse model by administering 1.5% DSS in drinking water and performed Piezo1-related mechanical stimulation experiments in HIEC-6 cells. Western blotting and immunofluorescence were employed to explore the mechanism by which Piezo1 affects oxidative stress and ferroptosis-related markers in intestinal epithelial cells. Our results revealed significant inflammation and oxidative stress responses in intestinal epithelial cells. The Piezo1 agonist activated inflammatory and oxidative stress responses in intestinal epithelial cells, while the Piezo1 inhibitor GsMTx4 significantly reversed these responses. We also observed increased expression levels of NADPH oxidase (NOX), NOX4, and reactive oxygen species (ROS). Piezo1 activation increased protein kinase C expression, NOX activity, and ROS levels. Piezo1 was significantly upregulated in the colonic tissues of DSS-induced colitis mice and was associated with oxidative stress and inflammation. The Piezo1 inhibitor markedly attenuated ferroptosis-associated changes by reducing tissue ROS, malondialdehyde, Fe, and acyl-CoA synthetase long-chain family member 4 levels, while increasing glutathione, ferritin heavy chain 1, and glutathione peroxidase 4 levels. Our results indicate that Piezo1 may exacerbate DSS-induced colitis by promoting oxidative stress and modulating ferroptosis-associated markers in colonic tissue.
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