Cell. Signal. [JOURNAL]
Sun
200 papers
Grape-derived exosome-like nanoparticles suppress nasopharyngeal carcinoma progression by targeting the FASN/MAPK axis.
Zhang Y, Zheng L, Zhu G … +4 more , Xu H, Huang S, Jin M, Chen X
Cell Signal · 2026 Sep · PMID 42191056 · Publisher ↗
Nasopharyngeal carcinoma (NPC) is an epithelial malignancy with distinct geographic clustering, highly prevalent in southern China and Southeast Asia. Grape-derived exosome-like nanoparticles (GELNs) represent a promisin...
Nasopharyngeal carcinoma (NPC) is an epithelial malignancy with distinct geographic clustering, highly prevalent in southern China and Southeast Asia. Grape-derived exosome-like nanoparticles (GELNs) represent a promising natural delivery platform for cancer intervention; however, the intrinsic resveratrol (RSV) of GELNs and their regulatory effects on lipid metabolism in NPC remain poorly defined. In this study, GELNs were isolated from grape peels by ultracentrifugation and characterized morphologically and biochemically. The therapeutic efficacy of GELNs-RSV was evaluated in HNE-1 cells and nude mouse xenografts using CCK-8, Transwell, in vivo imaging and histological analyses. Transcriptomic profiling, pathway enrichment and gain-of-function experiments were applied to dissect molecular mechanisms. Results revealed that GELNs effectively delivered RSV into NPC cells, and markedly attenuated cell proliferation, migration and xenograft tumor growth. Mechanistically, GELNs-RSV repressed fatty acid synthase (FASN) expression and inactivated the MAPK pathway via decreased ERK phosphorylation, thereby disrupting lipid metabolism and constraining NPC progression. These findings identify GELNs as a natural RSV delivery system that targets the FASN/MAPK axis, providing preclinical evidence for the development of novel NPC therapeutic strategies.
CBLB inhibits papillary thyroid cancer malignancy via negatively regulating MYCBP/c-Myc axis.
Yang Y, Pei X, Yang Q … +1 more , Hu X
Cell Signal · 2026 Sep · PMID 42191055 · Publisher ↗
Papillary thyroid carcinoma (PTC) has shown a marked rise in incidence worldwide in recent decades, yet its molecular mechanisms remain largely unclear. Here, we reported that CBLB acts as a tumor suppressor in PTC. Anal...
Papillary thyroid carcinoma (PTC) has shown a marked rise in incidence worldwide in recent decades, yet its molecular mechanisms remain largely unclear. Here, we reported that CBLB acts as a tumor suppressor in PTC. Analysis of public databases (GEPIA, UALCAN) and PTC cell lines confirmed reduced CBLB expression in tumor tissues compared to normal thyroid tissue. Functional experiments revealed that CBLB knockdown promoted malignant phenotypes, while its overexpression suppressed tumorigenic behaviors. Mechanistically, CBLB directly binds to MYCBP and promotes its poly-ubiquitination and proteasomal degradation via K48-linked ubiquitination at the K20 residue. MYCBP stabilization upon CBLB depletion activated the c-Myc pathway, upregulating oncogenic targets (CCND1, CDK4, ZEB1, E2F1, c-Jun) and downregulating E-cadherin. Collectively, our findings identify the CBLB/MYCBP/c-Myc axis as a critical regulatory pathway in PTC progression, highlighting CBLB's therapeutic potential as a targeted suppressor of MYCBP-driven oncogenesis.
Galectin-3 in sepsis: A multifaceted regulator of innate immunity, vascular dysfunction, and organ injury.
Yu Q, Cao Y, Zhu J … +4 more , Bi S, Wang Z, Yu J, Xu X
Cell Signal · 2026 Sep · PMID 42184932 · Publisher ↗
Sepsis is a life-threatening syndrome characterized by dysregulated host responses, endothelial injury, microcirculatory disturbance, and progressive organ dysfunction. Galectin-3 (Gal-3), a β-galactoside-binding lectin...
Sepsis is a life-threatening syndrome characterized by dysregulated host responses, endothelial injury, microcirculatory disturbance, and progressive organ dysfunction. Galectin-3 (Gal-3), a β-galactoside-binding lectin with diverse intracellular and extracellular activities, has emerged as an important mediator in inflammatory and fibrotic diseases. Increasing evidence suggests that Gal-3 is involved in multiple pathophysiological processes relevant to sepsis, rather than acting within a single pathway. In this review, we summarize the structural and functional features of Gal-3 and discuss its roles in the pathobiology of sepsis, with emphasis on innate immune activation, macrophage and neutrophil responses, inflammasome-related injury, endothelial dysfunction, immunothrombosis, extracellular matrix remodeling, and organ damage. Current studies indicate that Gal-3 can amplify inflammatory signaling, promote leukocyte recruitment and trafficking, modulate phagocyte function, and contribute to vascular barrier impairment and microvascular failure. In addition, Gal-3 appears to participate in post-inflammatory tissue remodeling and fibrosis, suggesting a broader role in the transition from acute injury to maladaptive repair. Beyond its mechanistic relevance, circulating Gal-3 has shown potential as an adjunctive biomarker for disease severity assessment, organ injury stratification, and short-term prognosis, although its specificity and clinical utility remain to be fully established. Emerging experimental evidence also supports Gal-3 as a therapeutic target in sepsis, but its context-dependent and compartment-specific functions require further clarification. Overall, Gal-3 represents a multifunctional molecule that links immune dysregulation, vascular injury, and tissue remodeling in sepsis and may provide new opportunities for biomarker development and mechanism-based intervention.
Artematrolide F suppresses communication between hepatocellular carcinoma cells and hepatic stellate cells to attenuate liver cancer progression through targeting YKT6.
Li QH, Li TZ, Wang YC … +2 more , Yang Y, Chen JJ
Cell Signal · 2026 Sep · PMID 42177960 · Publisher ↗
Hepatocellular carcinoma (HCC) remains a highly malignant cancer with limited treatment options. HCC cells (HCCs) activate hepatic stellate cells (HSCs) and transform them into cancer-associated fibroblasts (CAFs), formi...
Hepatocellular carcinoma (HCC) remains a highly malignant cancer with limited treatment options. HCC cells (HCCs) activate hepatic stellate cells (HSCs) and transform them into cancer-associated fibroblasts (CAFs), forming a vicious cycle for hepatocarcinogenesis. Therefore, inhibition of the communication between HCCs and HSCs is expected to emerge as a novel strategy for HCC treatment. Artematrolide F (AF), a sesquiterpenoid dimers (SDs) isolated from Artemisia atrovirens, exhibited significantly inhibitory activity on tumor cells in our previous report, but its mechanism remains unknown. This further study demonstrated that AF significantly inhibited the proliferation, colony formation and metastasis of HCCs. Notably, the inhibitory effect was enhanced when HCCs were cocultured with HSCs, suggesting that AF may suppress tumor progression through regulating the crosstalk of HCCs and HSCs. The vesicular transport protein YKT6 was identified as a target of AF through integrating bioinformatics analysis and machine learning model, which were verified by DARTS, CETSA, molecular docking, molecular dynamics simulation, and knockdown experiments. Further mechanistic research revealed that AF targeting YKT6 disrupted the crosstalk between HSCs and HCCs, suppressed HSC-driven tumor proliferation by inhibiting extracellular vesicles (EVs) secretion from HCCs, and blocked tumor autophagy by disrupting vesicular transport. These findings demonstrate that AF could serve as a novel therapeutic candidate for HCC treatment through regulating YKT6 to suppress HCCs-HSCs communication, block EV-dependent tumor progression, and inhibit tumor autophagy.
N-acetylcysteine-induced transcriptomic reprogramming regulates Nrf2-mediated signaling and redox homeostasis in experimental hepatocellular carcinoma.
Caloca-Camarena F, Arceo-Orozco S, Flores-Peña R … +6 more , Salto-Sevilla JA, Sandoval-Rodriguez A, Rosas-Campos R, Monroy-Ramirez HC, Armendariz-Borunda J, Galicia-Moreno M
Cell Signal · 2026 Sep · PMID 42177959 · Publisher ↗
Hepatocellular carcinoma (HCC) is the most common primary liver cancer, marked by dysregulated cellular processes and limited treatment options, highlighting the need for preventive therapeutic strategies. N-acetylcystei...
Hepatocellular carcinoma (HCC) is the most common primary liver cancer, marked by dysregulated cellular processes and limited treatment options, highlighting the need for preventive therapeutic strategies. N-acetylcysteine (NAC), widely used to treat acetaminophen overdose and as a mucolytic agent, has not been mechanistically characterized in HCC. Here, we evaluated the effects of NAC in experimental HCC models, including its role in modulating the Nrf2/Keap1 signaling pathway. HCC was induced in male Fischer-344 rats using diethylnitrosamine (DEN) and 2-acetylaminofluorene (2-AAF), along with daily NAC administration for 16 weeks. In parallel, HepG2 cells were used to evaluate the cytoprotective effects of NAC in vitro. Biochemical, molecular, transcriptomic, histological, and immunostaining analyses were performed in serum, liver tissue, and cell samples. Our findings demonstrate that NAC exerted hepatoprotective effects that limit protumorigenic progression, fibrosis, and tumor cell proliferation. Notably, NAC regulates the Nrf2/Keap1 pathway enhancing antioxidant defenses and preserving biomolecular integrity. Transcriptomic analyses revealed that NAC partially restored disease-associated gene expression patterns by downregulating oncogenic pathways and genes involved in HCC development. In conclusion, these findings indicate that NAC modulates key cellular processes involved in HCC development and regulates disease-associated gene expression patterns, supporting its repositioning as a potential adjuvant therapeutic strategy.
Two decades and beyond: What we know and still need to learn about the TWEAK/Fn14 pathway.
Verma P, Tuli HS, Paudel KR … +1 more , Gupta M
Cell Signal · 2026 Sep · PMID 42177958 · Publisher ↗
TWEAK is a multifunctional cytokine that exists in both membrane-bound and soluble forms. TWEAK interacts with its sole receptor, Fn14, leading to the activation of various downstream signaling pathways, including MAPK,...
TWEAK is a multifunctional cytokine that exists in both membrane-bound and soluble forms. TWEAK interacts with its sole receptor, Fn14, leading to the activation of various downstream signaling pathways, including MAPK, NF-κB, JAK/STAT, Smad, etc., thereby regulating cell fate. The TWEAK/Fn14 signaling cascade is a unique pathway that is involved in the development mechanisms of different diseases targeting cardiovascular, pulmonary, dermatological, cancer, etc. Activation of the signaling pathway results in cytokines and chemokines production, which exert their role by communicating with neighboring cells, promoting cell differentiation, proliferation, angiogenesis, apoptosis, autophagy, etc. However, the function and process of the TWEAK/Fn14 signaling pathway in various diseases have not been completely understood. Furthermore, clinical translation of TWEAK/Fn-14-mediated targeted therapies faces several challenges, including a lack of specific biomarkers, limited clinical evidence, and disease-specific heterogeneity. In this review, we have systematically outlined the current knowledge about the structural, functional, and pharmacological functions of the TWEAK/Fn14 signaling pathway. We have outlined how further experimental research is necessary to understand the molecular mechanisms associated with the pathway. Additionally, we also highlight the emerging potential of small druggable molecules targeting the TWEAK/Fn14 signaling cascade, emphasizing future directions for the management of various diseases.
ADAR1-mediated destabilization of INPP5J mRNA promotes PI3K/AKT/mTOR signal to inhibit autophagy in lung adenocarcinoma.
Zhou Q, Gao Y, Yuan T … +2 more , Liang Y, Lian N
Cell Signal · 2026 Sep · PMID 42173180 · Publisher ↗
OBJECTIVE: The specific autophagic roles of adenosine deaminase RNA-specific 1 (ADAR) and inositol Polyphosphate-5-Phosphatase J (INPP5J) and their relationship in lung adenocarcinoma (LUAD) are poorly understood. This s...
OBJECTIVE: The specific autophagic roles of adenosine deaminase RNA-specific 1 (ADAR) and inositol Polyphosphate-5-Phosphatase J (INPP5J) and their relationship in lung adenocarcinoma (LUAD) are poorly understood. This study sought to explore the involvement of ADAR and INPP5J in autophagy and their functional interaction in LUAD. METHODS: Cancer tissues and the adjacent normal tissues from LUAD patients were obtained to analyze the expression of ADAR1 and Inositol Polyphosphate-5-Phosphatase J (INPP5J), as well as the autophagy-related PI3K/AKT/mTOR signal. LUAD cell (A549 and NCI-H1975) was treated with sh-ADAR1 alone or in combination with sh-INPP5J or 740 YP (a PI3K activator) to investigate their effects on autophagy. The binding between ADAR1 and INPP5J mRNA was determined by RIP-qPCR. Subsequently, A549 cells were subcutaneously injected into the nude mice, and sh-ADAR1 was administered with or without sh-INPP5J to explore their roles in tumor formation and autophagy. RESULTS: Compared to the adjacent normal tissues, the mRNA level and the protein level of INPP5J expression were downregulated in cancer tissues, while those of ADAR1 were upregulated. In LUAD patients, the ratios of p-PI3K/PI3K, p-AKT/AKT, p-mTOR/mTOR, and the level of p62 were elevated in cancer tissues compared to the adjacent normal tissues, whereas LC3II/I and Beclin1 expression were reduced. Silencing ADAR1 downregulated the PI3K/AKT/mTOR pathway and p62 expression in LUAD cells, while upregulating LC3II/I and Beclin1 expression, but these effects were blocked by sh-INPP5J. Overexpression of INPP5J inhibited the PI3K/AKT/mTOR signaling pathway and p62 expression in LUAD cells, and upregulated LC3II/I and Beclin1 expression, but these effects were blocked by 740 YP. Silencing ADAR1 suppressed LUAD cell viability, colony formation, scratch healing, and tumor formation, but these effects were blocked by sh-INPP5J. CONCLUSION: ADAR1 inhibits the LUAD-associated autophagy by modifying INPP5J to activate the PI3K/AKT/mTOR pathway, providing a novel adjuvant therapeutic target for LUAD.
FTO demethylates Cyclin E1/D1 mRNA and inhibits non-small cell lung cancer cell EMT and proliferation.
Sun Z, Shi L, Wang Y … +2 more , Zhou Z, Liu J
Cell Signal · 2026 Sep · PMID 42173179 · Publisher ↗
The progression of Lung cancer (LC) remains a major challenge in clinical practice, and the molecular mechanism underlying malignant tumor progression are still poorly defined. Fat mass and obesity-associated protein (FT...
The progression of Lung cancer (LC) remains a major challenge in clinical practice, and the molecular mechanism underlying malignant tumor progression are still poorly defined. Fat mass and obesity-associated protein (FTO) has been identified as a critical RNA N-methyladenosine (mA) demethylase involved in growth, development, and disease progression. However, the biological roles and underlying mechanisms of FTO-mediated epithelial-mesenchymal transition (EMT) and proliferation in LC remain unclear. Here, we first demonstrate that the expression of FTO is significantly downregulated in non-small-cell lung cancer (NSCLC). FTO overexpression suppresses NSCLC cells EMT and proliferation, whereas FTO knockdown promotes these phenotypic changes. FTO overexpression reduces the expression and mRNA stability of Cyclin E1 and Cyclin D1, while FTO knockdown leads to opposing effects. In addition, mA-binding proteins IGF2BP2 promotes the expression of Cyclin E1 and Cyclin D1, and knockdown of IGF2BP2 suppresses EMT and proliferation in NSCLC cells. Mechanistically, FTO reduces the expression and mRNA stability of Cyclin E1 and Cyclin D1 by erasing mA modification in NSCLC cells. FTO attenuates IGF2BP2-mediated mRNA stability of Cyclin E1 and Cyclin D1, supporting the notion that FTO suppresses EMT and proliferation in NSCLC cells via an IGF2BP2-dependent mechanism. Taken together, our findings highlight the critical role of FTO in regulating Cyclin E1 and Cyclin D1, and establish the interaction mechanism between FTO and Cyclin E1/Cyclin D1 in controlling EMT and proliferation in NSCLC cells.
The CCL2 network in pulmonary hypertension: Potential therapeutic targets.
Lu H, Zhang M, Gong S … +5 more , Liang N, Li Z, Xiao Q, Wang A, Lei X
Cell Signal · 2026 Sep · PMID 42173178 · Publisher ↗
Pulmonary hypertension (PH) is a progressive and life-threatening disease characterized by pulmonary vascular remodeling, inflammation, and right ventricular dysfunction. Increasing evidence suggests that the chemokine C...
Pulmonary hypertension (PH) is a progressive and life-threatening disease characterized by pulmonary vascular remodeling, inflammation, and right ventricular dysfunction. Increasing evidence suggests that the chemokine CCL2 and its receptor CCR2 are critically involved in PH pathogenesis by promoting inflammatory cell recruitment, macrophage activation, and vascular remodeling. In this review, we summarize the emerging roles of the CCL2/CCR2 axis across different PH subtypes, including pulmonary arterial hypertension, PH associated with left heart disease, PH associated with chronic lung disease, and chronic thromboembolic PH. We also discuss the current pharmacological strategies targeting this pathway, including neutralizing antibodies, small-molecule CCR2 antagonists, and combination approaches. Finally, we highlight key challenges that remain to be addressed, including pathway redundancy, cell type specificity, and the need for robust biomarkers to identify patients most likely to benefit from CCL2/CCR2-targeted therapy.
Inhibition of ferroptosis or NF-κB signalling protects LPS-induced TIMP1 overexpression-induced cell damage.
Chen J, Wu Z, Ye J … +8 more , Wang H, Wang Z, Li W, Liu G, Yu X, Li G, Pan S, Gao C
Cell Signal · 2026 Sep · PMID 42173177 · Publisher ↗
BACKGROUND: Acute lung injury (ALI) is characterized by excessive inflammation and oxidative stress, with ferroptosis emerging as a critical pathological mechanism. However, the role of tissue inhibitor of metalloprotein...
BACKGROUND: Acute lung injury (ALI) is characterized by excessive inflammation and oxidative stress, with ferroptosis emerging as a critical pathological mechanism. However, the role of tissue inhibitor of metalloproteinases 1 (TIMP1) in regulating ferroptosis during ALI remains unclear. METHODS: Lipopolysaccharide (LPS)-induced ALI models were established in vivo and in vitro. TIMP1 expression was modulated using siRNA and overexpression approaches. Ferroptosis-related indicators, including lipid peroxidation, intracellular iron levels, and the expression of GPX4 and SLC7A11, were assessed by biochemical assays and qRT-PCR. The involvement of the TLR4/NF-κB signalling pathway was evaluated using pharmacological inhibitors and co-immunoprecipitation analysis. RESULTS: TIMP1 expression was significantly upregulated in LPS-induced ALI models. TIMP1 knockdown markedly reduced lipid peroxidation levels (∼45% decrease), intracellular Fe accumulation (∼38% reduction), and restored GPX4 and SLC7A11 expression (P < 0.01), indicating suppression of ferroptosis. Mechanistically, TIMP1 was found to interact with TLR4, enhancing its stability and promoting NF-κB activation, as evidenced by increased p65 phosphorylation (∼2.3-fold). Inhibition of TLR4 or NF-κB abrogated TIMP1-induced ferroptotic responses. CONCLUSION: TIMP1 promotes ferroptosis in ALI through activation of the TLR4/NF-κB signalling pathway. Targeting TIMP1 may represent atherapeutic strategy for mitigating ferroptosis-associated lung injury.
Methylation of zinc-finger protein ZNF471 regulates MIS18A expression and inhibits proliferation and metastasis of hepatocellular carcinoma via negative regulation of the Wnt/β-catenin pathway, as well as enhances sensitivity to apatinib and donafenib.
Wang X, Jia L, Zhang C … +4 more , Bian C, Huang C, Ma K, Luo T
Cell Signal · 2026 Sep · PMID 42155792 · Publisher ↗
The present study aimed to investigate the specific role and underlying molecular mechanism of aberrant methylation of zinc-finger protein ZNF471 in the development and progression of hepatocellular carcinoma (HCC). We f...
The present study aimed to investigate the specific role and underlying molecular mechanism of aberrant methylation of zinc-finger protein ZNF471 in the development and progression of hepatocellular carcinoma (HCC). We first analyzed the expression and methylation levels of ZNF471 between HCC tissues and adjacent tissues using public databases. Subsequently, clinical tissue samples from HCC patients were collected to validate the expression and methylation status of ZNF471. The cellular functional assays were performed to determine the effects of ZNF471 on the proliferation, metastatic of HCC cells and sensitivity to apatinib and donafenib. Finally, transcriptome sequencing and molecular biological techniques were combined to further elucidate the regulatory mechanism of ZNF471 in the progression of HCC. We found that the expression level of ZNF471 was significantly downregulated in HCC tissues and cell lines compared with corresponding adjacent normal tissues and normal hepatocyte cell lines, due to the aberrant methylation of CpG sites in its promoter region. The overexpression of ZNF471 markedly inhibited the proliferation and metastasis of HCC cells. Mechanistic investigations revealed that ZNF471 can interact with MIS18A and suppress the proliferation and metastasis of HCC through the negative regulation of the Wnt/β-catenin signaling pathway and epithelial-mesenchymal transition (EMT) process. Meanwhile, the ZNF471-MIS18A axis can increase the sensitivity of HCC cells to apatinib and donafenib. As a crucial tumor suppressor, ZNF471 exerts its anti-tumor effects by regulating the ZNF471-MIS18A-Wnt/β-catenin signaling pathway. Concurrently, the ZNF471-MIS18A axis holds promise as a potential target for enhancing the efficacy of apatinib and donafenib in HCC.
IL-6-induced endothelial microparticles exacerbate juvenile ischemic osteonecrosis by promoting Osteoclastogenesis: Implications for Perthes disease.
Liao S, Wei Z, Liu J … +6 more , Huang Q, Shen K, Wu X, Fang X, Li B, Ding X
Cell Signal · 2026 Sep · PMID 42155791 · Publisher ↗
Perthes disease is a debilitating idiopathic osteonecrosis of the pediatric femoral head and is characterized by femoral head deformity driven by uncoupled bone remodelling, with excessive osteoclastic activity. However,...
Perthes disease is a debilitating idiopathic osteonecrosis of the pediatric femoral head and is characterized by femoral head deformity driven by uncoupled bone remodelling, with excessive osteoclastic activity. However, the systemic signals orchestrating this localized bone destruction remain poorly understood. In this study, we found that circulating microparticles (MPs) isolated from the plasma of patients with Perthes disease at the necrotic stage exhibited a greater capacity to promote osteoclast differentiation than MPs from healthy controls. Given the elevated interleukin-6 (IL-6) levels observed in these patients, we characterized endothelial microparticles (EMPs) generated from human umbilical vein endothelial cells (HUVECs) stimulated with IL-6 (IL-6-induced EMPs). Functionally, IL-6-induced EMPs markedly enhanced monocyte-endothelial adhesion, were actively internalized by bone marrow-derived macrophages (BMMs), and potentiated RANKL-induced osteoclastogenesis. In vivo, using a juvenile ischemic osteonecrosis (JIO) model, fluorescence tracking revealed that systemically administered EMPs accumulated in the skeletal tissue, with preferential localization to the ischemic epiphysis. Furthermore, administration of IL-6-induced EMPs exacerbated epiphyseal deformity and trabecular deterioration, accompanied by increased TRAP-positive osteoclast accumulation at the necrotic site. Collectively, these findings elucidate a pathogenic cellular signaling axis wherein inflammation-induced endothelial vesicles act as systemic messengers to trigger localized bone destruction, highlighting the IL-6-EMPs-osteoclast axis as a potential therapeutic target.
Hydrogen selenide and selenium donors: From Gasotransmitter biology to precision Neurotherapeutics.
Liu X, Du T, Gu Q … +6 more , Zhang Z, Hui L, Tao L, Shan H, Chen X, Zhang M
Cell Signal · 2026 Sep · PMID 42155790 · Publisher ↗
Hydrogen selenide (H₂Se), selenium's central metabolic intermediate, is emerging as the candidate fourth gasotransmitter. This membrane permeable gas mediates rapid redox signaling and serves as the obligate precursor fo...
Hydrogen selenide (H₂Se), selenium's central metabolic intermediate, is emerging as the candidate fourth gasotransmitter. This membrane permeable gas mediates rapid redox signaling and serves as the obligate precursor for selenoprotein biosynthesis, essential for neuronal redox homeostasis and survival. Engineered selenium donors, designed for controlled H₂Se release or targeted selenoprotein support, exert neuroprotection by attenuating oxidative stress, reducing neuroinflammation, inhibiting ferroptosis, and preserving synaptic integrity across Alzheimer's disease, Parkinson's disease, epilepsy, traumatic brain injury, and stroke. Advances in stimuli-responsive donor chemistry and nanocarrier platforms enable spatiotemporally precise delivery, mitigating selenium's narrow therapeutic window. However, H₂Se is cytoprotective at physiological concentrations but toxic at supraphysiological levels and its clinical translation demands rigorous pharmacokinetic optimization, context-aware targeting, and dynamic biomarkers. This review bridges gasotransmitter biology with translational pharmacology, delineating H₂Se metabolism, donor design principles, and disease-specific applications. By integrating mechanistic insights with precision delivery strategies, we provide a roadmap for harnessing H₂Se and selenium donors as next-generation, clinically viable neurotherapeutics.
TRIM56 inhibits M1 macrophage polarization and mitigates sepsis-induced acute lung injury via promoting STING ubiquitination-degradation.
Li B, Liu Y
Cell Signal · 2026 Sep · PMID 42155789 · Publisher ↗
Sepsis-induced acute lung injury (ALI) is a life-threatening clinical disorder with high mortality, and its pathogenesis is closely linked to excessive M1 macrophage polarization and overactivation of the STING signaling...
Sepsis-induced acute lung injury (ALI) is a life-threatening clinical disorder with high mortality, and its pathogenesis is closely linked to excessive M1 macrophage polarization and overactivation of the STING signaling pathway. TRIM56, an E3 ubiquitin ligase, is known to participate in immune and inflammatory regulation; however, its specific role and underlying molecular mechanism in sepsis-induced ALI remain largely unclear. Here, we aimed to determine whether TRIM56 alleviates sepsis-induced ALI by inhibiting M1 macrophage polarization via promoting STING ubiquitination and proteasomal degradation. We conducted in vivo and in vitro experiments: LPS-induced ALI mouse models were established, and MH-S alveolar macrophage experiments were performed, including TRIM56 silencing, TRIM56 overexpression, and treatment with the proteasome inhibitor MG132. Lung injury was assessed using hematoxylin-eosin (HE) staining and measurement of the lung wet/dry weight ratio. The expression levels of TRIM56, STING, M1 macrophage polarization markers (F4/80 iNOS cells and CD86), and pro-inflammatory cytokines (TNF-α and IL-6) were measured by western blot, RT-qPCR, immunofluorescence, and ELISA. The interaction and ubiquitination between TRIM56 and STING were verified via immunofluorescence co-localization, co-immunoprecipitation (Co-IP), and ubiquitination assays. In sepsis-induced ALI mouse models, the proportion of M1 macrophages was significantly increased, accompanied by marked downregulation of TRIM56 and upregulation of STING in alveolar macrophages. In vitro, TRIM56 silencing significantly elevated STING protein expression (without affecting its mRNA level) and promoted M1 macrophage polarization, whereas TRIM56 overexpression reduced STING protein expression and suppressed M1 polarization. Mechanistically, TRIM56 colocalized with and directly interacted with STING in the cytoplasm, thereby promoting STING ubiquitination and proteasomal degradation-an effect abrogated by MG132 treatment. In vivo, TRIM56 overexpression significantly alleviated lung injury, reduced M1 macrophage infiltration, and inhibited pro-inflammatory cytokine secretion by downregulating STING protein. In conclusion, TRIM56 inhibits M1 macrophage polarization by promoting STING ubiquitination and proteasomal degradation, thereby mitigating sepsis-induced ALI. The TRIM56-STING axis may serve as a novel and promising therapeutic target for sepsis- induced ALI.
Oxytocin modulates glucose metabolism to protect against cardiac remodeling via the STAT3/eNOS Axis.
Zhao Y, Qian X, Wang Q … +8 more , Wang Z, Fu N, Wang L, Feng R, Yang W, Bai X, Qian J, Yang Y
Cell Signal · 2026 Sep · PMID 42142820 · Publisher ↗
Oxytocin (OT), an endogenous cardiovascular homeostatic hormone, is currently attracting considerable attention because it can improve energy metabolism and cardiac function. This study investigated whether OT mitigates...
Oxytocin (OT), an endogenous cardiovascular homeostatic hormone, is currently attracting considerable attention because it can improve energy metabolism and cardiac function. This study investigated whether OT mitigates cardiac remodeling in association with alterations in glucose metabolism. In vivo, cardiac hypertrophy and fibrosis were induced in C57BL/6 J mice via angiotensin II (Ang II), while in vitro H9c2 cardiomyoblasts and neonatal rat cardiac fibroblasts (NRCFs) were treated with Ang II or TGF-β1, respectively, with or without OT. We found that OT suppressed cardiac hypertrophy and fibrosis, increased ATP and glucose levels, reduced lactate accumulation, suppressed glycolysis, and enhanced glucose oxidation in cardiomyocytes. Mechanistically, OT upregulated its receptor and inhibited pyruvate kinase M2 (PKM2) in TGF-β1-stimulated NRCFs. In hypertrophic cardiomyocytes induced by Ang II, transcription factor STAT3 was activated and eNOS was downregulated, while OT suppressed STAT3 activation and nuclear translocation of p-STAT3, and enhanced the expression of eNOS. Either Stat3 overexpression or Nos3 downregulation attenuated OT's beneficial and metabolic effects. Additionally, we demonstrated that the transcription factor STAT3 is enriched at and interacts with the Nos3 promoter region. Overexpression of eNOS partially restored OT-associated protective effects that were attenuated by Stat3 overexpression. Collectively, these findings suggest that OT attenuates cardiac remodeling, at least in part, in association with modulation of glucose metabolism and the STAT3/eNOS pathway, providing mechanistic insight into its cardioprotective effects.
Corrigendum to "RBMS3 synergistically suppresses ovarian cancer progression at the post-transcriptional level by destabilizing ELAVL1 mRNA and inhibiting UPF1 methylation" [Cellular Signalling (2026) 112540].
Wang Y, Sun H, Hou X … +4 more , Xing W, Xu Z, Zhang Q, Yang B
Cell Signal · 2026 Sep · PMID 42140772 · Publisher ↗
Abstract loading — click title to view on PubMed.
Lysine methyltransferase 5C (KMT5C) promoted malignant growth of prostate cancer through FGFR1/STAT3 pathway and regulated the immune response.
Li S, Zhang L, Yu P
Cell Signal · 2026 Sep · PMID 42134516 · Publisher ↗
BACKGROUND: The role of KMT5C varies across different tumor types, while its expression and function in prostate cancer remain largely unreported. This study investigated KMT5C expression in prostate cancer and its effec...
BACKGROUND: The role of KMT5C varies across different tumor types, while its expression and function in prostate cancer remain largely unreported. This study investigated KMT5C expression in prostate cancer and its effects on tumor growth and immune response. METHODS: Following KMT5C knockdown and overexpression, we evaluated cell proliferation, cell cycle distribution and angiogenesis, and detected the activation of FGFR1/STAT3 pathway via Western blot. The molecular interaction between KMT5C and FGFR1 was bioinformatically predicted and experimentally validated. Subcutaneous xenograft models in nude and C57BL/6 mice were constructed to explore the effects of KMT5C on prostate cancer progression and tumor immune regulation. RESULT: Our findings showed that KMT5C was highly expressed in prostate cancer and functions as an oncogene to facilitate cell proliferation, angiogenesis, and G0/G1-to-S cell cycle transition. Conversely, KMT5C knockdown suppressed cell proliferation, angiogenesis and arrested the G0/G1/S phase transition. Mechanistically, the oncogenic properties of KMT5C were partially dependent on the activation of FGFR1/STAT3 signaling pathway. KMT5C depletion increased the proportion of CD8 T cells in the spleen and elevated the infiltration of CD8 cytotoxic T lymphocytes within the tumor microenvironment. Moreover, KMT5C silencing induced the polarization of tumor-associated macrophages (TAMs) from the M2-like immunosuppressive phenotype to the M1-like anti-tumor phenotype. CONCLUSION: KMT5C acts as a critical oncogenic driver in prostate cancer, which is closely associated with tumor malignancy and tumor immune homeostasis. Thus, KMT5C may serve as a promising therapeutic target for prostate cancer intervention. Collectively, our findings provide solid experimental evidence for the clinical relevance of KMT5C.
The role of macrophage senescence in cardiovascular diseases.
Sun Y, Chang Y, Lin H … +3 more , Fan G, Li L, Ma C
Cell Signal · 2026 Sep · PMID 42134515 · Publisher ↗
Macrophage senescence is a major contributor to organismal aging and acts as a vital pathological bridge that connects aging to the onset and progression of cardiovascular diseases(CVDs). This review highlights the key m...
Macrophage senescence is a major contributor to organismal aging and acts as a vital pathological bridge that connects aging to the onset and progression of cardiovascular diseases(CVDs). This review highlights the key molecular mechanisms underlying macrophage senescence, including DNA damage, telomere attrition, mitochondrial dysfunction, oxidative stress, and immune dysregulation. We further dissect the intrinsic association between macrophage senescence and CVDs, particularly atherosclerosis, myocardial infarction, and chronic heart failure. Moreover, we systematically summarize recent research progress on senescence-targeted therapeutic strategies for macrophages, intending to offer solid theoretical evidence for the prevention and clinical treatment of CVDs.
Phosphorylation at Ser182 and Thr186 blocks GSDMD pyroptotic activity.
Li M, Xu J, Li G … +14 more , He Q, Xing Y, Peng M, Zhang W, Zhang T, Gao C, Chen H, Wang R, Zheng X, Xing X, Zhang H, Zhang Z, Zheng P, Chu X
Cell Signal · 2026 Sep · PMID 42128156 · Publisher ↗
Pyroptosis, mediated by gasdermin D (GSDMD), is a form of programmed cell death highly associated with inflammatory and immune diseases. While its activation is well-studied, the precise negative regulatory mechanisms re...
Pyroptosis, mediated by gasdermin D (GSDMD), is a form of programmed cell death highly associated with inflammatory and immune diseases. While its activation is well-studied, the precise negative regulatory mechanisms remain to be fully elucidated. Here, we sought to investigate the regulatory role of phosphorylation on GSDMD activity. We identified that phosphorylation at murine Ser182/Thr186 (Ser181/Ser185 in humans) constitutes an inhibitory regulatory mechanism for the cytolytic activity of the GSDMD N-terminal fragment (GD-NT). Mechanistically, using structural modeling and site-directed mutagenesis, we found that phosphorylation at Ser182/Thr186 did not affect the auto-inhibition of full-length GSDMD or its cleavage by caspase-11. However, it severely impaired the pyroptotic activity of GD-NT by affecting its membrane localization and oligomerization. Consequently, the double phosphomimetic mutant of GD-NT (S182D/T186D) was non-lytic to cells. Thus, we define Ser182/Thr186 as critical post-cleavage checkpoint sites for inhibiting pyroptosis. This discovery enriches the regulatory network of GSDMD and provides potential therapeutic targets for modulating inflammatory diseases.
Inhibiting STING1 promotes recovery of cardiac function and structure after diabetic myocardial infarction by facilitating angiogenesis.
Wang X, Cai Y, Xu J … +6 more , Zang G, Ren X, Sun W, Li L, Tao Z, Wang Z
Cell Signal · 2026 Sep · PMID 42128155 · Publisher ↗
BACKGROUND AND PURPOSE: Diabetes can lead to serious complications and significantly increase the risk of myocardial infarction. This study aimed to elucidate the role of STING1 in angiogenesis after diabetic myocardial...
BACKGROUND AND PURPOSE: Diabetes can lead to serious complications and significantly increase the risk of myocardial infarction. This study aimed to elucidate the role of STING1 in angiogenesis after diabetic myocardial infarction. METHODS: We established a diabetic myocardial infarction model in wild-type and Sting1 mice. Myocardial structure, fibrosis, and cardiac function were assessed via histological analysis and echocardiography. In vitro, primary cardiac microvascular endothelial cells were transfected with siRNA targeting STING1 to evaluate their proliferation, migration, tube formation ability, and apoptosis. Pathway enrichment analysis was performed using Gene Set Enrichment Analysis. RESULTS: Wild-type diabetic myocardial infarction mice exhibited disordered myocardial structure, increased fibrosis, and impaired cardiac function. In contrast, Sting1 mice exhibited restored cardiac function and significantly enhanced angiogenesis. At the cellular level, STING1 inhibition alleviated endothelial cell damage, promoted proliferation, migration, and tube formation, and reduced apoptosis. GSEA further indicated significant enrichment of the Wnt, MAPK, TGF-β, Tight junction, and PI3K-Akt signaling pathways in this process. CONCLUSION: These findings demonstrate that inhibiting STING1 promotes the recovery of cardiac structure and function after diabetic myocardial infarction by facilitating angiogenesis. This protective effect may involve the regulation of the Wnt, MAPK, TGF-β, Tight junction, and PI3K-Akt signaling pathways.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe