Cell. Signal. [JOURNAL]
Sun
200 papers
Nicotinamide N-methyltransferase as a stress-responsive metabolic-epigenetic regulator of tubular senescence in chronic kidney disease.
Liu A, Zhu XJ, Sun WD … +3 more , Bi SZ, Zhang CY, Li JH
Cell Signal · 2026 Oct · PMID 42331207 · Publisher ↗
Chronic kidney disease (CKD) is characterized by persistent cellular stress, tubular dysfunction, and progressive tubulointerstitial fibrosis. Increasing evidence suggests that senescence of renal tubular epithelial cell...
Chronic kidney disease (CKD) is characterized by persistent cellular stress, tubular dysfunction, and progressive tubulointerstitial fibrosis. Increasing evidence suggests that senescence of renal tubular epithelial cells (RTECs) represents an important pathological process linking chronic injury to fibrotic remodeling. Nicotinamide N-methyltransferase (NNMT), a metabolic enzyme involved in nicotinamide methylation, has recently attracted attention because of its potential role in stress-associated metabolic and epigenetic regulation. In this review, we summarize current evidence regarding stress-responsive regulation of NNMT and discuss its potential involvement in tubular senescence during CKD progression. Available studies suggest that NNMT expression can be dynamically altered under various stress conditions, though the direction of change varies with cell type and context. Through consumption of nicotinamide and S-adenosylmethionine, sustained NNMT activation may influence nicotinamide adenine dinucleotide (NAD) homeostasis, methyl donor balance, and homocysteine metabolism, thereby affecting redox regulation, epigenetic remodeling, and senescence-associated signaling pathways. We further discuss the potential interactions between NNMT-associated metabolic dysregulation, chronic stress responses, tubular senescence, and fibrosis. Current evidence, though largely correlative, suggests that NNMT may represent a stress-associated metabolic regulator and a potential therapeutic target in CKD.
Znrf2-mediated ST2L degradation limits IL-33/ST2L anti-fibrotic signaling and promotes post-infarction cardiac fibrosis.
Bao H, Huang R, Chen X … +6 more , Chen B, Cao Z, Zhou W, Yan F, Li W, Chen Z
Cell Signal · 2026 Oct · PMID 42331206 · Publisher ↗
Myocardial infarction (MI) remains a major cause of heart failure, largely driven by maladaptive ventricular remodeling and excessive cardiac fibrosis. The IL-33/ST2L axis exerts cardioprotective and anti-fibrotic effect...
Myocardial infarction (MI) remains a major cause of heart failure, largely driven by maladaptive ventricular remodeling and excessive cardiac fibrosis. The IL-33/ST2L axis exerts cardioprotective and anti-fibrotic effects, but how the availability of the membrane receptor ST2L is controlled under stress conditions remains incompletely understood. Here, we investigated whether ubiquitin-proteasome-dependent turnover of ST2L, mediated by the E3 ligase Znrf2, constrains IL-33/ST2L signaling and promotes post-MI fibrosis. Using neonatal mouse cardiac fibroblasts, cycloheximide chase and pharmacological inhibition experiments revealed that ST2L is a short-lived protein degraded predominantly through the proteasome rather than the lysosome. IL-33 stimulation enhanced ST2L internalization and induced robust polyubiquitination, thereby accelerating proteasomal degradation. Candidate screening and gain-of-function analyses identified Znrf2 as a functional E3 ligase-associated regulator of ST2L turnover: Znrf2 overexpression selectively reduced ST2L, but not sST2, in a dose-dependent manner, whereas proteasome inhibition stabilized ST2L. Mapping experiments showed that the Znrf2 zinc-finger domain recognizes a 306-315 amino acid motif in ST2L, and deletion of this motif rendered ST2L resistant to Znrf2-induced degradation. In a mouse MI model, Znrf2 expression was upregulated in the infarcted myocardium, accompanied by increased collagen deposition. Systemic administration of the proteasome inhibitor MG-132 or cardiac-specific Znrf2 knockdown preserved ST2L, particularly at the plasma membrane, attenuated myocardial fibrosis, and improved echocardiographic indices of left ventricular function. Importantly, AAV9-mediated silencing of ST2L blunted the anti-fibrotic and functional benefits of MG-132 and Znrf2 knockdown, indicating that these interventions act, at least in part, through ST2L. Collectively, our data identify Znrf2-dependent ST2L ubiquitination and proteasomal degradation as a negative regulatory mechanism that limits IL-33/ST2L cardioprotection after MI. Targeting the Znrf2-ST2L axis to preserve functional ST2L may represent a promising strategy to restrain post-infarction cardiac fibrosis and remodeling.
Tubular basement membrane damage promotes renal fibrosis via an ETV5/TGFB1/SOX9 axis in proximal tubular epithelial cells after acute kidney injury.
Dier AK, Zhou W, Song N … +13 more , Jin S, Shen Z, Tan X, Zhang L, Cai J, Li F, Li Y, Li J, Lu Y, Zhang W, Chen Y, Ding X, Zhao S
Cell Signal · 2026 Oct · PMID 42331205 · Publisher ↗
The interaction between injured proximal tubular epithelial cells (PTECs) and the microenvironment has been widely associated with post-AKI fibrosis; however, the underlying mechanisms remain largely unclear. In this stu...
The interaction between injured proximal tubular epithelial cells (PTECs) and the microenvironment has been widely associated with post-AKI fibrosis; however, the underlying mechanisms remain largely unclear. In this study, we identified three distinct injury patterns of the tubular basement membrane (TBM) in kidney tissues from patients with acute kidney injury. Phosphorylated H3 and transforming growth factor-β1 (TGFB1) were co-localized in PTECs exhibiting TBM injury. To mimic this condition, we employed a low-attachment culture system (LACS). LACS induced in PTECs a morphology resembling that of maladaptive repaired PTECs, accompanied by G2/M cell-cycle arrest, as well as upregulation and secretion of TGFB1. The expression of TGFB1 was markedly suppressed when PTECs were re-attached to normal culture dishes or to medium supplemented with Matrigel. Furthermore, TGFB1 expression was not directly linked to G2/M arrest in PTECs. Mechanistically, knockdown of TGFB1 or SMAD3 attenuated the LACS-induced upregulation of SOX9, whereas SOX9 knockdown did not downregulate TGFB1 expression. We further demonstrated that TBM injury-induced upregulation of TGFB1 is mediated by ETV5. Collectively, these findings indicate that TBM damage triggered by AKI promotes renal fibrosis via activation of the ETV5/TGFB1/SMAD3/SOX9 pathway in proximal tubular epithelial cells following AKI.
Morroniside alleviates CoCrMo particle-induced osteogenic impairment by activating Wnt/β-catenin signalling.
Han J, Zhu Z, Gao S … +4 more , Wu B, Meng M, Zhang S, Wang D
Cell Signal · 2026 Oct · PMID 42331204 · Publisher ↗
Periprosthetic osteolysis (PPO) is the main cause of aseptic loosening after total joint arthroplasty, often resulting from wear particle-induced osteogenic impairment. Morroniside (Mor), a major bioactive iridoid glycos...
Periprosthetic osteolysis (PPO) is the main cause of aseptic loosening after total joint arthroplasty, often resulting from wear particle-induced osteogenic impairment. Morroniside (Mor), a major bioactive iridoid glycoside from C. officinalis, has been shown to have protective effects in osteoporosis. However, its efficacy against wear particle-induced osteolysis remains elusive. Herein, we evaluated the anti-PPO efficacy of Mor using a CoCrMo particle (CoP)-induced murine calvarial osteolysis model, and investigated the protective effects and signalling pathways associated with osteogenesis in CoP-stimulated mice and MC3T3-E1 cells. The results demonstrated that Mor effectively attenuated CoP-induced osteolysis in mice. Additionally, it reversed osteogenic impairment in both CoP-stimulated mice and MC3T3-E1 cells. Mechanistically, this protection was mediated by activating the Wnt/β-catenin signalling pathway in both in vivo and in vitro models. Notably, inhibiting the Wnt signalling pathway with XAV939 abolished the protective effects of Mor in both models. These findings indicate that Mor alleviates CoP-induced osteolysis by restoring osteogenic function via the Wnt/β-catenin pathway, highlighting its potential as a therapeutic agent for PPO.
Neuroinflammation-centered pathophysiology and therapeutic strategy design in Alzheimer's disease: Cutting-edge developments.
Li D, Zhang Z, Lu L … +5 more , Liu J, Cai W, Hou J, Lu Y, Yu G
Cell Signal · 2026 Oct · PMID 42331203 · Publisher ↗
Alzheimer's disease (AD) is a multifactorial and progressive neurodegenerative disorder characterized by complex interactions among amyloid-β (Aβ) deposition, tau protein hyperphosphorylation, neuroinflammation, oxidativ...
Alzheimer's disease (AD) is a multifactorial and progressive neurodegenerative disorder characterized by complex interactions among amyloid-β (Aβ) deposition, tau protein hyperphosphorylation, neuroinflammation, oxidative stress, metal dyshomeostasis, and impaired autophagy. Increasing evidence positions neuroinflammation not merely as a secondary response but as a central driver of disease progression, dynamically interacting with amyloid and tau protein pathology and contributing to synaptic dysfunction and neuronal loss. Among inflammatory mechanisms, microglial activation pathways-particularly TREM2 signaling, NLRP3 inflammasome activation, and complement cascade dysregulation-are currently the most clinically actionable targets, supported by genetic, biomarker, and therapeutic evidence. Emerging data suggest that modulation of innate immune pathways is most likely to confer benefit during the prodromal and early symptomatic stages of AD, when neuroinflammatory responses remain partially adaptive and neuronal networks retain functional reserve. Despite decades of drug development, many candidates have failed due to limited efficacy or safety concerns. Recent FDA approvals of anti-amyloid monoclonal antibodies, including aducanumab and lecanemab, represent important advances toward disease-modifying therapy, although their long-term clinical impact and safety profiles remain under evaluation. These developments underscore the importance of biomarker-guided patient selection, disease-stage stratification, and vigilant safety monitoring, particularly regarding amyloid-related imaging abnormalities. Therapeutic strategies are increasingly shifting toward multi-target approaches that integrate amyloid modulation, tau protein-directed interventions, and attenuation of maladaptive neuroinflammatory responses. Concurrently, inflammatory mediators and peripheral metabolic biomarkers are gaining recognition as tools for early detection, risk stratification, and therapeutic response monitoring, potentially enabling precision-based intervention. This review synthesizes current understanding of AD pathogenesis through an inflammation-centered framework, highlighting clinically actionable immune pathways and stage-specific therapeutic windows. By integrating mechanistic insights with biomarker-driven strategies, we aim to delineate translational paths toward more precise, safe, and clinically meaningful disease modification.
Integrative single-cell and bulk transcriptomics reveal cuproptosis subtypes, prognostic models, and COL5A1 as a key gene in glioblastoma.
Zhan Y, Zhang Y, Miao J … +6 more , Qu X, Li Y, Li X, Dong Y, Liu B, Song Y
Cell Signal · 2026 Oct · PMID 42331202 · Publisher ↗
Glioblastoma (GBM) remains one of the most aggressive primary brain tumors with limited therapeutic options. Cuproptosis, a recently identified copper-dependent form of regulated cell death, has emerged as a potential th...
Glioblastoma (GBM) remains one of the most aggressive primary brain tumors with limited therapeutic options. Cuproptosis, a recently identified copper-dependent form of regulated cell death, has emerged as a potential therapeutic vulnerability in cancer. Here, we systematically investigated the molecular and clinical significance of cuproptosis-related genes (CRGs) in GBM using integrated bulk and single-cell transcriptomic analyses. Based on the expression profiles of 31 differentially expressed CRGs, GBM patients were classified into two molecular subtypes with distinct prognostic and immune characteristics. Cluster 2 exhibited poorer survival and increased immune and stromal infiltration. To further assess the prognostic value of CRGs, we constructed a risk model using 110 subtype-associated genes and systematically compared 101 machine-learning algorithms. The SuperPC model achieved the best predictive performance and was successfully validated in two independent CGGA cohorts. The resulting risk score was closely associated with tumor microenvironment infiltration. Integrated single-cell analysis and experimental validation identified COL5A1 as a key GBM-associated gene. COL5A1 was specifically enriched in tumor cells across independent scRNA-seq datasets and positively correlated with the cuproptosis-related genes LOXL2 and SPARC. Functional assays demonstrated that COL5A1 knockdown suppressed GBM cell migration and invasion, reduced LOXL2 and SPARC expression, and enhanced sensitivity to cuproptosis induction. Collectively, our study establishes a robust cuproptosis-associated prognostic framework for GBM and identifies COL5A1 as a potential regulator linking extracellular matrix remodeling, malignant progression, and cuproptosis-related vulnerability, providing new insights into GBM biology and potential therapeutic targets.
NUSAP1 mediates enzalutamide resistance in prostate cancer via Wnt/β-catenin signalling-dependent regulation of AR and AR-V7.
Wang N, Li Y, Li J … +6 more , Jiang C, Jia Y, Yang X, Wang L, Zhao R, Nie L
Cell Signal · 2026 Oct · PMID 42331201 · Publisher ↗
BACKGROUND: Castration-resistant prostate cancer (CRPC) demonstrates significant resistance to androgen deprivation therapy (ADT), presenting a substantial therapeutic challenge. Although the reactivation of androgen rec...
BACKGROUND: Castration-resistant prostate cancer (CRPC) demonstrates significant resistance to androgen deprivation therapy (ADT), presenting a substantial therapeutic challenge. Although the reactivation of androgen receptor (AR) signalling is a key driver of this resistance, the specific regulatory mechanisms involved remain unclear. Nucleolar and spindle-associated protein 1 (NUSAP1) is overexpressed in various malignancies; however, its function in mediating resistance to enzalutamide (ENZ) has yet to be elucidated. This study aims to clarify the influence of NUSAP1 on ENZ resistance in prostate cancer. METHODS: Bioinformatics analyses were conducted on three GEO datasets (GSE3325, GSE27616, and GSE35988) to identify potential genes linked to metastatic CRPC. Subsequent functional experiments, such as CCK-8, colony formation, Wound-healing, and Transwell assays, were carried out to assess the impact of knockdown NUSAP1 on proliferation, migration, and invasion in ENZ-resistant prostate cancer cells (MDVR and 22Rv1). Western blot and RT-qPCR analyses were employed to explore underlying molecular mechanisms. Pharmacological interventions and rescue experiments utilizing R1881, Laduviglusib, and DK419 were executed to investigate pathway interactions. Additionally, a xenograft mouse model was established to validate the observed in vivo effects. RESULTS: Bioinformatics analysis revealed NUSAP1 as a pivotal prognostic gene significantly linked to overall survival (OS, P = 0.02) and disease-free survival (DFS, P = 0.0018) in prostate cancer. Elevated NUSAP1 expression was observed in ENZ-resistant prostate cancer cells. Knockdown of NUSAP1 markedly impeded cell proliferation, migration, and invasion, while increasing the cells' sensitivity to ENZ both in vitro and in vivo. Subsequent investigations illustrated that NUSAP1 promotes β-Catenin translocation to the nucleus and increased Wnt/β-Catenin signalling activity, and then amplifies downstream AR signalling. CONCLUSIONS: The results indicate that NUSAP1 enhanced prostate cancer ENZ resistance through activation of the Wnt/β-Catenin-AR/AR-V7 signalling pathway. Targeting NUSAP1 could offer a potential therapeutic approach to address ENZ resistance in CRPC.
NFAT5 in alveolar macrophages exacerbates seawater-induced acute lung injury via PFKP-driven glycolysis.
Wang X, Guo X, Wang Y … +9 more , Gao Y, Wang L, Fang Y, Gao F, Yuan F, Gao B, Li Y, Yang L, Jin F
Cell Signal · 2026 Oct · PMID 42323965 · Publisher ↗
Seawater-induced acute lung injury (ALI) shares pathological features with other forms of ALI, characterised by high mortality; however, it presents unique traits, particularly persistent hypoxemia. Nuclear Factor of Act...
Seawater-induced acute lung injury (ALI) shares pathological features with other forms of ALI, characterised by high mortality; however, it presents unique traits, particularly persistent hypoxemia. Nuclear Factor of Activated T cells 5 (NFAT5), initially recognised as a tonicity-responsive enhancer-binding protein, has emerged as acritical regulator of inflammation. Nonetheless, its specific function in alveolar macrophages (AMs) during hyperosmolar seawater-induced ALI remains unclear. This study establishes a murine model of seawater-induced ALI, revealing significantly elevated NFAT5 expression in lung macrophages. Siglec1-specific NFAT5 knockout effectively mitigated seawater-induced lung injury. Mechanistically, NFAT5 was found to directly bind the promoter region of Phosphofructokinase, Platelet type (PFKP) in AMs, enhancing its transcriptional activity. NFAT5 knockdown resulted in downregulation of PFKP expression and suppression of glycolysis, which inhibited M1 macrophage polarisation while promoting M2 macrophage polarisation, thereby reducing the release of inflammatory cytokines. Additional in vitro and in vivo experiments demonstrated that PFKP overexpression counteracts the protective effects of Siglec1-specific NFAT5 knockout in seawater-induced ALI by restoring glycolytic activity. Collectively, these findings illustrate that the NFAT5-PFKP signaling axis in AMs regulates macrophage polarisation and inflammatory responses through glycolytic reprogramming, playing a critical pathogenic role in seawater-induced ALI. These insights enhance understanding of the energy metabolism in AMs, previously regarded as less relevant in inflammation, and identify the NFAT5-PFKP axis as a promising therapeutic target for seawater-induced ALI.
Corrigendum to "The lamin A/C-P4HB interaction axis regulates endoplasmic reticulum stress and apoptosis in myocardial ischemia-reperfusion injury via a calreticulin-associated mechanism" [Cell Signalling 143 (2026) 112479].
Zhou J, Li X, Li N … +2 more , Wang M, Sun G
Cell Signal · 2026 Oct · PMID 42315397 · Publisher ↗
Abstract loading — click title to view on PubMed.
RNA-binding protein ZMAT3 protects against MASLD by regulating SEPT11 mRNA stability.
Sun L, Huang Z, Wang A … +11 more , Zhang X, Zhong H, Wang P, Yu W, Gu B, Chen J, Bai J, Ren B, Liu S, Tan P, Fu W
Cell Signal · 2026 Oct · PMID 42309235 · Publisher ↗
BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive hepatic disorder that is closely associated with metabolic syndrome. Zinc finger matrin-type protein 3 (ZMAT3), an RNA-binding...
BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive hepatic disorder that is closely associated with metabolic syndrome. Zinc finger matrin-type protein 3 (ZMAT3), an RNA-binding protein implicated in various malignancies, has not been fully clarified in the context of MASLD. METHODS: To investigate the role of ZMAT3 in MASLD, a murine model was established using a choline-deficient amino acid (CDAA) diet, combined with hepatocyte-specific ZMAT3 overexpression. An in vitro model was generated by treating AML12 hepatocytes with free fatty acids to evaluate the effects of ZMAT3 overexpression and knockdown. SEPT11, a potential interacting partner of ZMAT3 in lipid metabolism, was identified through the BioGRID database. Relevant molecular biology assays were subsequently performed. RESULTS: ZMAT3 expression was significantly downregulated in liver tissues from patients with early-stage MASLD, as well as in both animal and cellular models of the disease. In AML12 cells, ZMAT3 modulated intracellular lipid accumulation and ameliorated metabolic disturbances. In MASLD mice, hepatic overexpression of ZMAT3 attenuated liver injury and inflammation and reduced hepatic lipid accumulation. Furthermore, ZMAT3 was shown to regulate SEPT11 mRNA stability, thereby influencing the RhoA/ROCK1/AMPK/SREBP-1c signaling pathway, which has been implicated in the pathogenesis of MASLD. CONCLUSION: ZMAT3 acts as a protective factor in MASLD, influencing lipid metabolism and the SEPT11/RhoA/ROCK1/AMPK/SREBP-1c pathway. These findings offer insights into MASLD development and suggest ZMAT3 as a potential therapeutic target.
BMP5 suppresses malignant progression of clear cell renal cell carcinoma by promoting DNA damage accumulation and sustained DNA damage response signaling.
Rexiati N, Zhao X, Wang Y … +6 more , Tang F, Chen Z, Han W, Peng J, Liu T, Yang Z
Cell Signal · 2026 Oct · PMID 42303195 · Publisher ↗
Clear cell renal cell carcinoma (ccRCC) is a prevalent malignancy of the urinary system that lacks effective biomarkers for early diagnosis and prognosis. Bone morphogenetic protein 5 (BMP5), a member of the bone morphog...
Clear cell renal cell carcinoma (ccRCC) is a prevalent malignancy of the urinary system that lacks effective biomarkers for early diagnosis and prognosis. Bone morphogenetic protein 5 (BMP5), a member of the bone morphogenetic protein family within the TGF-β superfamily, is known to participate in the regulation of cellular differentiation, proliferation, and apoptosis. Bioinformatics analyses indicated that BMP5 expression is significantly reduced in ccRCC and is associated with unfavorable patient outcomes. Gain- and loss-of-function experiments in ccRCC cell lines showed that BMP5 overexpression markedly inhibited cell proliferation, migration, and invasion, promoted G1-phase arrest and apoptosis, and suppressed tumor growth in a xenograft mouse model, whereas BMP5 silencing produced the opposite effects. Rescue experiments further confirmed the specificity of BMP5-mediated phenotypes. RNA sequencing, Western blotting, comet assays, and immunohistochemical analyses further demonstrated that BMP5 overexpression was accompanied by increased markers of DNA double-strand breaks and sustained activation of DNA damage response (DDR) signaling. Time-course γ-H2AX analysis further revealed sustained DNA damage signals following genotoxic stress, consistent with increased DNA damage burden and delayed resolution of DNA lesions. In addition, pathway perturbation experiments further supported the contribution of DDR signaling to BMP5-associated cell fate regulation. Collectively, these findings suggest that BMP5 is associated with increased DNA damage burden and sustained DDR activation, which likely contribute to tumor-suppressive effects in ccRCC, highlighting its potential prognostic relevance and the possible therapeutic significance of BMP5-associated DDR signaling.
Resveratrol suppresses GATA4/Sortilin pathway to attenuate vascular smooth muscle cell senescence-associated secretory phenotype and vascular aging-related atherosclerosis.
Li H, Wang Y, Zhang S … +3 more , Li S, Jiang L, Lv Y
Cell Signal · 2026 Oct · PMID 42303194 · Publisher ↗
This study aimed to investigate the role of Sortilin in vascular smooth muscle cell (VSMC) senescence and the senescence-associated secretory phenotype (SASP) and to explore whether GATA4 promotes VSMC senescence and aor...
This study aimed to investigate the role of Sortilin in vascular smooth muscle cell (VSMC) senescence and the senescence-associated secretory phenotype (SASP) and to explore whether GATA4 promotes VSMC senescence and aortic atherosclerosis by transcriptionally regulating Sortilin. Furthermore, we examined the potential of resveratrol (Res) to alleviate vascular aging and atherogenesis via the GATA4/Sortilin pathway. Bioinformatics analysis and experimental validation revealed co-upregulation of GATA4 and Sortilin in senescent VSMCs. Sortilin overexpression promoted VSMC senescence and SASP secretion, whereas its silencing resulted in the opposite effects. GATA4 transcriptionally activated Sortilin expression via direct binding to the Sort1 promoter, as confirmed by dual-luciferase reporter and chromatin immunoprecipitation (ChIP)-qPCR assays. Although GATA4-induced VSMC senescence was enhanced by co-overexpression of Sortilin, Sortilin knockdown did not significantly reverse GATA4-driven senescence, suggesting the involvement of additional mechanisms. Res treatment suppressed GATA4 and Sortilin expression, thereby attenuating VSMC senescence and the SASP. In apolipoprotein E-deficient (ApoE) mice fed a high-fat diet, AAV-mediated GATA4 overexpression promoted Sortilin expression, vascular oxidative stress, inflammation and accelerated aortic aging and atherosclerosis. These effects were counteracted by either AAV-Sortilin shRNA or dietary Res supplementation, which also improved blood lipid and glucose metabolism. In summary, GATA4 transcriptionally upregulates Sortilin expression, thereby promoting VSMC senescence and vascular aging. Res inhibits the GATA4/Sortilin pathway, suggesting a potential therapeutic strategy for ameliorating atherosclerosis.
Circadian gene BMAL1 attenuates gingival fibroblast senescence to suppress diabetic periodontitis progression.
Liu Y, Rong X, Ji Y … +5 more , Zhang M, Yuan R, Luo S, Chen L, Li M
Cell Signal · 2026 Oct · PMID 42297065 · Publisher ↗
In a hyperglycemic environment, periodontal inflammatory responses and the destruction of periodontal supporting tissues are exacerbated, leading to a severe form of diabetes periodontitis (DPD). Diabetes and periodontit...
In a hyperglycemic environment, periodontal inflammatory responses and the destruction of periodontal supporting tissues are exacerbated, leading to a severe form of diabetes periodontitis (DPD). Diabetes and periodontitis exhibit a bidirectional relationship that significantly increases the complexity and severity of each condition. A key pathological feature in this process is the functional impairment of gingival fibroblasts (GFs) within the high-glucose inflammatory microenvironment. In this study, a DPD mouse model was established. It was found that diabetes significantly aggravated alveolar bone resorption and accelerated GFs senescence, which was accompanied by a marked downregulation of brain and muscle ARNT-like 1 (BMAL1) expression. Pharmacological activation of BMAL1 effectively mitigated GFs senescence and mitochondrial dysfunction, and consequently alleviated alveolar bone destruction in DPD mice. By simulating the high-glucose inflammatory microenvironment in vitro, we confirmed that the combination of high glucose (HG) and lipopolysaccharide (LPS) activates the JAK1-STAT3 signaling pathway, downregulates BMAL1, disrupts mitochondrial homeostasis, and ultimately induces GFs senescence. This study elucidates the pathological mechanism underlying GFs senescence in the high-glucose inflammatory microenvironment, thereby providing a novel perspective for the targeted therapy of DPD.
Navigating the metabolic crossroads: A bibliometric analysis of the SLC7A11/xCT field from oxidative stress to ferroptosis and disulfidptosis.
Lu S, Du X, Liu F
Cell Signal · 2026 Oct · PMID 42297064 · Publisher ↗
The cystine/glutamate transporter SLC7A11 is a central node in regulated cell death and tumor metabolism. Here, we performed a bibliometric analysis of 4998 publications to map the knowledge structure and temporal evolut...
The cystine/glutamate transporter SLC7A11 is a central node in regulated cell death and tumor metabolism. Here, we performed a bibliometric analysis of 4998 publications to map the knowledge structure and temporal evolution of SLC7A11 research, alongside the rapidly expanding disulfidptosis literature. We observed exponential growth post-2012, with a recent surge driven by collaborative networks centered in China with strong links to the United States. Keyword timelines revealed a distinct three-phase trajectory: from foundational redox biology, through a ferroptosis-dominated period, to the emerging concept of disulfidptosis. Currently, ferroptosis remains the core theme in keyword co-occurrence networks, tightly interconnected with oxidative stress, apoptosis, and metabolism. Concurrently, disulfidptosis research is branching into oncology, prognostic modeling, machine learning, the tumor microenvironment (TME), and glucose starvation. Based on these trends, we highlight key translational frontiers, including data-driven patient stratification, spatiotemporal dynamics of the tumor metabolic landscape, and crosstalk among cell death modalities. Crucially, our mapping reveals notable gaps at the interface of disulfidptosis and tumor immunity. Although the immunological implications of disulfidptosis are gaining traction, studies explicitly focused on tertiary lymphoid structures (TLS) are currently absent, and the upstream ncRNA regulatory layer remains underexplored. We propose that nanomedicine-enabled platforms may help bridge disulfidptosis-driven metabolic injury with immune priming and spatial immune organization, while SLC7A11-AS1 regulatory circuits warrant systematic investigation. Together, these findings provide an evidence-informed framework for the precise targeting of SLC7A11-defined metabolic vulnerabilities.
FOLR2 tumor-associated macrophages drive metastatic microenvironment remodeling and lymphatic dissemination in colorectal cancer.
Yao J, He Z, Wang M … +1 more , Huang F
Cell Signal · 2026 Oct · PMID 42297063 · Publisher ↗
The accumulation of specialized tumor-associated macrophage (TAM) subpopulations within the immune-excluded microenvironment critically drives colorectal cancer (CRC) progression and therapeutic resistance. Although the...
The accumulation of specialized tumor-associated macrophage (TAM) subpopulations within the immune-excluded microenvironment critically drives colorectal cancer (CRC) progression and therapeutic resistance. Although the FOLR2 macrophage lineage has been identified in the niche of several malignancies, the mechanisms by which tumor cells regulate FOLR2 expression and the pathways through which these cells facilitate metastasis are not well understood. Herein, we found that FOLR2 expression defines a distinct macrophage state associated with advanced clinical stages and unfavorable outcomes in CRC. Tumor cells induce FOLR2 expression via activation of AKT signaling, which is essential for establishing and sustaining the M2-like functional phenotype of TAMs. FOLR2 TAMs facilitate tumor cell migration, invasion, and lymphangiogenesis, and they preferentially localize to collagen-rich perivascular niches within the tumor microenvironment. Mechanistically, FOLR2 drives PLA2G7 production to mediate extracellular matrix remodeling and tumor cell motility, but FOLR2 facilitates lymphangiogenesis through a distinct, PLA2G7-independent mechanism. In vivo, this dual-track cascade was successfully recapitulated: pharmacological inhibition of PLA2G7 with darapladib blunted stromal collagen deposition and primary tumor growth, whereas FOLR2 silencing uniquely suppressed peritumoral lymphangiogenesis and popliteal lymph node metastasis. Bioinformatic analysis further revealed that high co-expression of FOLR2 and PLA2G7 correlates with elevated TIDE scores and increased IC50 values to oxaliplatin and targeted agents, predicting intrinsic immune evasion and therapy resistance. Together, this work establishes FOLR2 as a pivotal regulator of the CRC stroma and suggest that therapeutic strategies targeting the FOLR2/PLA2G7 axis could improve clinical outcomes by disrupting the supportive metastatic niche.
PDCD4 exacerbates atrial fibrillation by inducing mitochondrial fission and activating Ca/CaMKII signaling via ROS.
Liu Q, Zheng M, Wang R … +1 more , Muhuyati
Cell Signal · 2026 Oct · PMID 42297062 · Publisher ↗
BACKGROUND: Atrial fibrillation (AF) is characterized by severe structural and electrical remodeling that is driven in part by calcium (Ca) mishandling and mitochondrial dysfunction. While programmed cell death 4 (PDCD4)...
BACKGROUND: Atrial fibrillation (AF) is characterized by severe structural and electrical remodeling that is driven in part by calcium (Ca) mishandling and mitochondrial dysfunction. While programmed cell death 4 (PDCD4) has been implicated in several cardiovascular pathologies, its precise role in AF remains unclear. METHODS: In vivo AF mouse models (Ang II infusion combined with burst pacing) and in vitro models using rapidly paced AC16 cardiomyocytes were established. Atrial electrophysiology, fibrosis, mitochondrial dynamics, reactive oxygen species (ROS) production, mitochondrial membrane potential, and Ca transients were evaluated using multi-electrode recordings, histological staining, transmission electron microscopy, fluorescence imaging, flow cytometry, and calcium imaging. RESULTS: PDCD4 was significantly upregulated in both AF atrial tissues and paced cardiomyocytes. In vivo, PDCD4 overexpression exacerbated AF inducibility, prolonged AF duration, shortened the atrial effective refractory period, and aggravated atrial fibrosis. Mechanistically, PDCD4 promoted excessive mitochondrial fission, as evidenced by upregulated DRP1 and FIS1 and downregulated MFN1/2 and OPA1, resulting in mitochondrial fragmentation, ROS overproduction, and loss of membrane potential. This oxidative stress subsequently triggered hyperactivation of the CaM/CaMKII signaling pathway, leading to intracellular Ca overload and prolonged excitation-contraction coupling. Notably, pharmacological blockade of mitochondrial fission using Mdivi-1 blunted ROS production, suppressed CaMKII hyperactivation, and reversed PDCD4-induced atrial remodeling and calcium dyshomeostasis. CONCLUSION: PDCD4 exacerbates atrial fibrillation by orchestrating a pathogenic mitochondrial fission/ROS/CaMKII axis that disrupts calcium homeostasis and promotes fibrotic remodeling. Targeting the PDCD4-mediated mitochondrial dynamics pathway offers a promising therapeutic strategy for mitigating AF progression.
Interaction between FKBP10 and HSP10 activates the TGF-β/Smad pathway to promote the maintenance of osteosarcoma stemness.
Chen J, Deng Y, Li J … +8 more , Cao J, Sui W, Yang J, Wei W, Zhang Z, Yang J, Zhang MJ, Zhang Y
Cell Signal · 2026 Oct · PMID 42297061 · Publisher ↗
Osteosarcoma is a primary malignant bone tumor with high incidence in adolescents. Its characteristics of high recurrence, high metastasis, and cancer stem cell (CSC)-mediated treatment resistance are major obstacles to...
Osteosarcoma is a primary malignant bone tumor with high incidence in adolescents. Its characteristics of high recurrence, high metastasis, and cancer stem cell (CSC)-mediated treatment resistance are major obstacles to improving patient prognosis. This study aimed to systematically investigate the role and molecular mechanism of FK506-binding protein 10 (FKBP10) in regulating osteosarcoma stemness and malignant progression. Clinical sample analysis showed that High expression of FKBP10 is negatively correlated with prognosis in osteosarcoma, and positively correlated with the expression of stemness markers SOX2 (SRY-box transcription factor 2) and Nanog (Homeobox transcription factor Nanog). Cellular experiments confirmed that FKBP10 dose-dependently upregulated the transcriptional and protein levels of stemness markers such as CD44 (CD44 molecule), CD105 (Endoglin), SOX2, and Nanog, expanded the populations of CD105 and CD44 stem cells, and enhanced the self-renewal (tumor sphere formation), clonogenic proliferation (colony formation), and invasion/migration abilities of osteosarcoma cells. Conversely, FKBP10 knockdown significantly inhibited these stemness characteristics and malignant phenotypes without affecting the proliferative activity of general tumor cells. Animal experiments demonstrated that FKBP10 knockdown remarkably reduced the volume of xenograft tumors in nude mice, decreased the frequency of CD105 CSCs, and prolonged the survival time of tumor-bearing mice. At the molecular level, immunofluorescence staining and co-immunoprecipitation experiments confirmed that FKBP10 and heat shock protein 10 (HSP10) exhibited subcellular co-localization and direct interaction in osteosarcoma cells, with no mutual regulation of protein expression between FKBP10 and HSP10. HSP10 knockdown mimicked the effect of FKBP10 knockdown to inhibit osteosarcoma stemness. RNA sequencing and functional validation revealed that FKBP10 and HSP10 jointly regulated the expression of stemness markers and malignant phenotypes by activating the TGF-β/Smad pathway, and the regulatory effect of FKBP10 was completely dependent on this pathway. In addition, although HSP10 was involved in stemness regulation, it had no significant association with patient prognosis. This study is the first to clarify the core role of the "FKBP10-HSP10-TGF-β (Transforming growth factor-beta)/Smad (Sma- and Mad-related protein)" regulatory axis in maintaining osteosarcoma stemness, confirming that FKBP10 is a potential biomarker for osteosarcoma prognosis and a key target for targeted therapy. It provides a new theoretical basis and experimental foundation for the development of precision treatment strategies targeting CSCs in osteosarcoma.
Mild hypothermic pretreatment alleviates hepatic ischemia-reperfusion injury by reducing CIRP-dependent NETosis-related hepatocyte pyroptosis.
Cao F, Zhang X, Ye Q … +5 more , Liu Z, Liu J, Tang J, Xiao J, Xiao Q
Cell Signal · 2026 Oct · PMID 42297060 · Publisher ↗
BACKGROUND: Hepatic ischemia-reperfusion injury (HIRI) is a serious clinical complication with limited effective interventions. Although mild hypothermic pretreatment (MHP) has demonstrated protective potential, the prec...
BACKGROUND: Hepatic ischemia-reperfusion injury (HIRI) is a serious clinical complication with limited effective interventions. Although mild hypothermic pretreatment (MHP) has demonstrated protective potential, the precise molecular mechanisms, particularly its role in modulating sterile inflammation and programmed cell death, remain poorly understood. METHODS: A murine model of 70% hepatic IR was established. Mice were pretreated with MHP (32 °C for 2 h) or normothermia. In vitro, AML-12 hepatocytes and isolated mouse neutrophils were subjected to oxygen-glucose deprivation (OGD) or stimulation with recombinant CIRP (rmCIRP). Inhibitors targeting CIRP (C23), TLR4 (TAK-242), and PAD4 (Cl-amidine) were used. Liver injury, inflammatory markers, NETosis markers (CitH3, PAD4), and pyroptosis (NLRP3, Caspase-1, GSDMD) were assessed via histology, ELISA, western blot, and immunofluorescence. RESULTS: MHP significantly attenuated liver damage, oxidative stress, and systemic inflammation following IR. It reduced the release of CIRP, neutrophil infiltration, and NETosis markers (PAD4 and CitH3). In vitro, CIRP released from injured hepatocytes directly induced NETosis via the TLR4/PAD4 pathway, which was inhibited by C23, TAK-242, or Cl-amidine (Cl). Furthermore, NETs promoted hepatocyte pyroptosis by upregulating NLRP3, Caspase-1, and GSDMD. MHP or inhibition of the CIRP-TLR4-PAD4 axis effectively suppressed both NETosis and pyroptosis. CONCLUSION: MHP protects against HIRI by inhibiting CIRP release, which subsequently reduces TLR4/PAD4-dependent NETosis and hepatocyte pyroptosis, thereby disrupting a self-amplifying inflammatory loop. These findings reveal a novel CIRP-NETs-pyroptosis axis as a key mechanism in HIRI and highlight potential therapeutic targets for liver I/R injury.
The multifaceted role of cAMP signalling in Leishmania pathogenesis and host immune modulation.
Das T, Brahmachari P, Das PK … +1 more , Ukil A
Cell Signal · 2026 Oct · PMID 42297059 · Publisher ↗
Cyclic adenosine monophosphate (cAMP) is a pivotal second messenger involved in regulating numerous cellular processes, including apoptosis, kinase activation, immune responses, and cell cycle progression. In the context...
Cyclic adenosine monophosphate (cAMP) is a pivotal second messenger involved in regulating numerous cellular processes, including apoptosis, kinase activation, immune responses, and cell cycle progression. In the context of Leishmania infection, emerging evidence highlights how different Leishmania species exploit host and parasite-derived cAMP signalling pathways to modulate host cell functions and promote their survival. This review consolidates current understanding of parasite-mediated modulation of host defence mechanisms through cAMP signalling, thereby emphasising its crucial role in establishing and maintaining a permissive intracellular environment. Furthermore, it elaborates on how cAMP-driven pathways regulate the expression of antioxidant enzymes, inflammatory cytokines and apoptosis, thereby orchestrating immune suppression and facilitating long-term parasite persistence within the host. Moreover, Leishmania further harnesses its endogenous cAMP signalling pathway to drive its differentiation and replication within the host. Understanding these molecular tactics has not only enriched basic science but also opened new avenues for therapeutic interventions. This review underscores the centrality of cAMP signalling in Leishmania pathogenesis and highlights the therapeutic promise of targeting these pathways to develop more effective treatments against leishmaniasis.
Testosterone disrupts trophoblast function and immune homeostasis via PTGER4/cAMP/RAP1 and ANXA1-FPR1 signaling in PCOS-complicated preeclampsia.
Jiang R, Wang T, Yao Y … +6 more , Wu J, Xu T, Guo X, Wang F, Jiang P, Qu F
Cell Signal · 2026 Oct · PMID 42285193 · Publisher ↗
BACKGROUND: Polycystic ovary syndrome (PCOS) and preeclampsia (PE) are closely associated conditions, with elevated testosterone levels in PCOS significantly increasing PE risk. This study aimed to elucidate the shared m...
BACKGROUND: Polycystic ovary syndrome (PCOS) and preeclampsia (PE) are closely associated conditions, with elevated testosterone levels in PCOS significantly increasing PE risk. This study aimed to elucidate the shared molecular mechanisms linking PCOS and PE, with a particular focus on testosterone-mediated placental dysfunction and immune dysregulation. METHODS: Integrative bioinformatics analysis of transcriptome data from PCOS and PE patients identified common differentially expressed genes. Human trophoblast cells (HTR-8/SVneo) were treated with testosterone (10 μM) to model pathogenesis. RNA sequencing, RT-qPCR, histopathology, scRNA-seq, and CellChat analysis were used to explore gene regulation and cellular interactions, with functional assays validating key pathways. RESULTS: We identified 418 common DEGs between PCOS and PE using bioinformatics analysis. In vitro, testosterone upregulated PTGER4 in HTR-8/SVneo cells, with PTGER4 showing stepwise increases in PCOS and PCOS-complicated PE, correlating with disease severity. Functional enrichment highlighted Ras-associated protein 1 (RAP1) and immune pathways. Mechanistically, testosterone treatment suppressed trophoblast function (migration and invasion) via PTGER4/cAMP/RAP1 axis suppression. Furthermore, PTGER4/cAMP/RAP1 signaling dysregulation reduced ANXA1 expression in trophoblasts, impaired ANXA1-FPR1-mediated EVT-macrophage communication, and promoted M1 macrophage polarization and pro-inflammatory responses, thereby contributing to the pathogenesis of PCOS-complicated PE. CONCLUSION: This study provides significant insights into the molecular mechanisms linking PCOS and PE, emphasizing the role of hyperandrogenism in placental dysfunction and immune dysregulation.
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