Cell. Signal. [JOURNAL]
Sun
200 papers
CKB overexpression mitigates osteoarthritis by delaying chondrocyte senescence via activation of the RAP1/PI3K/AKT signaling pathway.
Zhang G, Liu D, Liu S … +2 more , Zou X, Yang L
Cell Signal · 2026 Sep · PMID 42128154 · Publisher ↗
BACKGROUND: Osteoarthritis (OA) is an age-related degenerative joint disease characterized by alterations in cellular senescence phenotypes. Although the pathogenesis of OA remains incompletely understood, chondrocyte se...
BACKGROUND: Osteoarthritis (OA) is an age-related degenerative joint disease characterized by alterations in cellular senescence phenotypes. Although the pathogenesis of OA remains incompletely understood, chondrocyte senescence is considered a key driver in the OA pathological process. Therefore, this study aimed to identify pivotal senescence-related genes during OA and investigate their potential value as therapeutic targets. METHODS: The hub gene CKB for OA was identified by analyzing OA-related sequencing datasets (GSE169077 and GSE42295) from the GEO database in conjunction with a senescence-associated gene set. Western blotting, immunohistochemistry, and immunofluorescence were subsequently employed to detect CKB expression levels in human and rat OA tissues. An IL-1β-induced senescence model in rat primary chondrocytes was established, and a lentiviral vector overexpressing CKB was constructed to validate its functional role. Subsequently, combined analysis of CKB co-expression genes and OA-related gene sets was performed to screen and identify the downstream RAP1/PI3K/AKT signaling pathway. Rescue experiments further confirmed the effect of CKB on the RAP1/PI3K/AKT pathway and the associated changes in senescence-related phenotypes. Finally, a rat knee joint OA model was used to evaluate the therapeutic effect of CKB overexpression. RESULTS: CKB expression was decreased in OA tissues. In vitro experiments demonstrated that CKB overexpression suppressed IL-1β-induced chondrocyte senescence. Further mechanistic investigation revealed that CKB overexpression upregulates RAP1 expression, thereby activating the PI3K/AKT signaling pathway to delay chondrocyte senescence. In vivo experiments showed that CKB overexpression delayed the progression of OA in rat knee joints. CONCLUSION: The findings of this study indicate that CKB, as a potential therapeutic target for OA, activates the RAP1/PI3K/AKT signaling pathway to delay chondrocyte senescence, thereby ameliorating OA progression.
Tumor cell-derived HSP47 promotes pancreatic Cancer metastasis via Homotrimeric collagen-mediated M2 macrophage polarization.
Ling X, Zhang Y, Zhu L … +7 more , Xu Z, Bao Y, Lin H, Wu J, Shi J, Liu L, Dong Q
Cell Signal · 2026 Sep · PMID 42128153 · Publisher ↗
The metastatic progression of pancreatic ductal adenocarcinoma (PDAC) is governed by dynamic interactions between cancer cells and immune cells within the tumor microenvironment; yet the underlying mechanisms remain larg...
The metastatic progression of pancreatic ductal adenocarcinoma (PDAC) is governed by dynamic interactions between cancer cells and immune cells within the tumor microenvironment; yet the underlying mechanisms remain largely elusive. Here, single-cell analysis identifies the collagen-specific chaperone HSP47 as predominantly expressed in PDAC epithelial cells. High HSP47 expression drives liver metastasis and serves as a predictor of poor survival in PDAC patients. Mechanistically, tumor cell-derived HSP47 promotes PDAC metastasis by creating an immunosuppressive microenvironment. It drives the secretion of a homotrimeric, tumor-specific form of collagen I (α1/α1/α1, also referred to as COL1) into the extracellular matrix (ECM) (rather than modulating its protein expression), which is essential for HSP47-mediated immunosuppression in PDAC. The accumulated COL1 polarizes tumor-associated macrophages (TAMs) toward an immunosuppressive M2 phenotype via the integrin α2β1/MAPK/ERK signaling pathway. These reprogrammed M2 macrophages, in turn, establish a feedforward loop by enhancing epithelial-mesenchymal transition (EMT) in PDAC cells through macrophage-derived Phosphoglycerate mutase 1 (PGAM1) in an ACTG1-dependent manner (Actin Gamma 1, ACTG1). In summary, our findings highlight the critical role of the HSP47-COL1-PGAM1 axis in PDAC metastasis, unveiling a previously unrecognized pro-metastatic regulatory circuit that provides mechanistic insights into PDAC progression.
ZNF503 reduces chemotherapy sensitivity in prostate cancer by activating ISL1 and Notch1 signaling.
Nie Y, Fu L, Zeng X … +4 more , Peng X, Zhu Q, Li Q, Ye L
Cell Signal · 2026 Sep · PMID 42128152 · Publisher ↗
Prostate cancer (PCa) remains a leading cause of cancer-related mortality, with reduced sensitivity to chemotherapy significantly compromising treatment efficacy. The zinc finger protein 503 (ZNF503) has recently emerged...
Prostate cancer (PCa) remains a leading cause of cancer-related mortality, with reduced sensitivity to chemotherapy significantly compromising treatment efficacy. The zinc finger protein 503 (ZNF503) has recently emerged as a potential regulator of cancer progression, but its role in prostate cancer and chemotherapy resistance has yet to be fully elucidated. In this study, we investigate the functional role of ZNF503 in prostate cancer and its involvement in mediating chemotherapy resistance. Using a combination of RNA sequencing, functional assays, and in vivo models, we demonstrate that ZNF503 expression is elevated in chemotherapy-resistant prostate cancer cells and tissues. ZNF503 overexpression enhances tumor cell proliferation, migration, and protects cells from chemotherapy -induced apoptosis following acute exposure to agents such as docetaxel and cisplatin. Mechanistically, we show that ZNF503 activates the Notch1 signaling pathway, a key driver of aggressive cancer phenotypes, and this effect is associated with increased expression of the transcription factor ISL1. Further analysis revealed that ISL1 is required for ZNF503-induced Notch1 activation. Knockdown of ISL1 significantly attenuates ZNF503-induced Notch1 expression and restores chemotherapy sensitivity, underscoring the critical role of the ZNF503-ISL1-Notch1 axis in prostate cancer progression and drug resistance. In clinical samples, high ZNF503 expression correlates with poor prognosis and reduced chemotherapy sensitivity, suggesting that ZNF503 is a candidate prognostic marker that requires further validation in larger, independent cohorts with multivariate analysis. Our findings provide novel insights into the molecular mechanisms underpinning chemotherapy resistance in prostate cancer and position ZNF503 as a promising therapeutic target to overcome drug resistance and improve patient outcomes.
The GRPR signaling axis in cancer: Molecular mechanisms and oncogenic outcomes.
Marcolin JC, Lichtenfels M, Roesler R … +1 more , de Farias CB
Cell Signal · 2026 Sep · PMID 42119836 · Publisher ↗
The gastrin-releasing peptide (GRP) and its receptor (GRPR) constitute a biologically versatile signaling axis with essential physiological roles and growing relevance in cancer biology. GRPR is frequently expressed acro...
The gastrin-releasing peptide (GRP) and its receptor (GRPR) constitute a biologically versatile signaling axis with essential physiological roles and growing relevance in cancer biology. GRPR is frequently expressed across multiple tumor types, where its activation modulates key cellular processes associated with malignant progression. Through engagement of diverse intracellular effectors and extensive crosstalk with receptor tyrosine kinases and other signaling systems, GRPR regulates pathways controlling tumor cell proliferation, survival, migration, invasion, angiogenesis, and transcriptional reprogramming. This review provides a comprehensive overview of the molecular mechanisms underlying GRPR-mediated signaling in cancer, integrating evidence from different tumor models. Importantly, the antitumor effects observed following pharmacological inhibition or genetic silencing of GRPR further underscore its therapeutic relevance. Collectively, these findings position GRPR as a central signaling integrator in tumor progression and a promising target for diagnostic, prognostic, and therapeutic strategies in oncology.
FHIT suppresses cervical squamous cell carcinoma progression by negatively regulating UBE2I-mediated SUMO modification of NOTCH1.
Zheng S, Shao F, Shao L … +5 more , Zhang L, Pan Q, Zhuang S, Hu Y, Hu M
Cell Signal · 2026 Sep · PMID 42119835 · Publisher ↗
PURPOSE: FHIT functions as a tumor suppressor frequently silenced by promoter hypermethylation in multiple cancers, including cervical cancer. This study elucidates its role in progression and immunoregulation of cervica...
PURPOSE: FHIT functions as a tumor suppressor frequently silenced by promoter hypermethylation in multiple cancers, including cervical cancer. This study elucidates its role in progression and immunoregulation of cervical squamous cell carcinoma (CSCC) and identifies downstream molecular mechanisms. METHODS: GEO datasets containing CSCC tissue data were mined to screen aberrantly expressed genes. TCGA database was queried to analyze FHIT expression and DNA methylation patterns between cervical cancer and normal tissues; findings were validated by RT-qPCR, MSP-PCR and Western blot in CSCC versus normal cell lines. Gain- and loss-of-function experiments overexpressing or knocking down FHIT investigated its impact on proliferation, metastasis and macrophage modulation. Potential upstream regulators and pathway involvement were further explored. RESULTS: FHIT was predicted to be hypermethylated and downregulated in CSCC. Overexpression of FHIT in CSCC cells significantly suppressed cell proliferation, migration, and invasion. Furthermore, when co-cultured with macrophages, FHIT-overexpressing CSCC cells promoted the polarization of macrophages toward the anti-tumor M1 phenotype. Mechanistically, FHIT was found to bind to UBE2I protein and downregulate its expression. Overexpression of UBE2I reversed the tumor-suppressive effects of FHIT. UBE2I was shown to mediate SUMO modification at lysine residue K1607 of NOTCH1. Mutation at the K1607 site of NOTCH1 abolished the oncogenic effects induced by UBE2I in CSCC. CONCLUSIONS: In summary, this study focuses on the antitumor role and molecular mechanisms of FHIT in CSCC. The FHIT/UBE2I/NOTCH1 regulatory axis may serve as a potential therapeutic target for CSCC through immunomodulatory strategies.
HSP60-mediated UPR overactivation drives triptolide-induced hepatocellular lipoapoptosis.
Yu Z, Hu L, Ding J … +9 more , Li X, Zhang Q, Zhang Q, Chen S, Zhang P, Zhang J, Jiang B, Zhou X, Zhou L
Cell Signal · 2026 Sep · PMID 42119834 · Publisher ↗
BACKGROUND: The mitochondrial unfolded protein response (UPR) maintains proteostasis, but its dysregulation dictates cell fate. This study aimed to elucidate the signaling mechanism by which triptolide (TP), a bioactive...
BACKGROUND: The mitochondrial unfolded protein response (UPR) maintains proteostasis, but its dysregulation dictates cell fate. This study aimed to elucidate the signaling mechanism by which triptolide (TP), a bioactive component of Tripterygium wilfordii Hook. f., triggers hepatocellular Lipoapoptosis, focusing on HSP60-mediated UPR overactivation. METHODS: A TP-induced mouse liver injury model was established. Serum biochemistry, histopathology, and liver proteomics were performed. Key proteins (HSP60, UPR components, SREBP-1c, FASN, cleaved caspase-3) were validated by Western blot and RT-qPCR both in vivo and in AML-12 hepatocytes, while co-immunoprecipitation (Co-IP) was conducted in AML-12 cells. Functional validation used siRNA knockdown. RESULTS: TP induced liver injury, lipid deposition, and apoptosis. Proteomic screening implicated UPR activation, with HSP60 subsequently validated as a central upregulated component. TP downregulated MFN2 and upregulated HSP60, ClpP, DRP1, SREBP-1c, FASN, and cleaved caspase-3. Co-IP confirmed a direct HSP60-SREBP-1c interaction. Moreover, HSP60 knockdown attenuated the entire TP-induced cascade, including UPR overactivation, mitochondrial dysfunction, lipid dysregulation, and apoptosis. CONCLUSION: This study delineates a novel mitochondria-to-nucleus pathway wherein TP induces HSP60-mediated UPR overactivation, which promotes SREBP-1c/FASN-driven lipid accumulation, culminating in lipoapoptosis. The "HSP60-UPR-SREBP-1c/FASN-lipoapoptosis" axis links dysregulated organelle stress signaling to metabolic cell death. These findings establish HSP60 as a key signaling node and a potential therapeutic target for intercepting this pathological cascade.
PCBP1 suppresses autophagic degradation of STAT6 to promote M2-like TAM polarization in hepatocellular carcinoma.
Luo Y, Zhang X, Yang H … +7 more , Yao Y, Wu H, Zhang Z, Ye D, Pan B, Wang X, Tang N
Cell Signal · 2026 Sep · PMID 42119668 · Publisher ↗
Immunotherapies have been widely applied to the treatment of hepatocellular carcinoma (HCC), but to date only a minority of patients exhibit dramatic responses. Tumor-associated macrophages (TAMs) are vital components in...
Immunotherapies have been widely applied to the treatment of hepatocellular carcinoma (HCC), but to date only a minority of patients exhibit dramatic responses. Tumor-associated macrophages (TAMs) are vital components in the tumor microenvironment and are involved in HCC progression. Herein, we confirm the upregulation of PCBP1 expression in TAMs correlates with poor prognosis in HCC patients. The loss of PCBP1 in TAMs promotes M1 like macrophages polarization and suppresses the migration capability of HCC cells in vitro. Additionally, overexpression of PCBP1 increases M2 macrophage infiltration and promotes tumor growth in vivo. Mechanistically, PCBP1 negatively regulates autophagy flux induction in TAMs to hinder STAT6 degradation from autophagy pathway, thereby facilitating M2-like macrophage phenotype and HCC malignant progression. Collectively, our findings describe the role of PCBP1 in orchestrating TAMs polarization and suggest that blocking PCBP1 is an effective approach in combating the cancerous advancement of HCC.
IKKα signalling at the crossroads of development, disease and drug discovery.
Tinto K, Cunningham M, Plevin R
Cell Signal · 2026 Sep · PMID 42119667 · Publisher ↗
IκB kinase alpha (IKKα) is a central regulator of non-canonical NF-κB signalling and contributes modestly to canonical NF-κB signalling, both of which mediate well-established aspects of immune function and inflammation....
IκB kinase alpha (IKKα) is a central regulator of non-canonical NF-κB signalling and contributes modestly to canonical NF-κB signalling, both of which mediate well-established aspects of immune function and inflammation. Emerging evidence now indicates that IKKα also performs a wide range of atypical functions, influencing NF-κB indirectly or acting through mechanisms independent of either NF-κB pathway. Several IKKα substrates have been identified outwith these classical signalling routes, and a recently described truncated isoform, p45-IKKα, has further expanded its known roles. This review examines how IKKα, through these diverse signalling modalities, contributes to disease processes including inflammatory disorders and cancer. Particular attention is given to both NF-κB-dependent and NF-κB-independent mechanisms that shape disease development, tumor biology, and ageing. Recent studies have also linked IKKα gene variants (CHUK) to altered IKKα function and patient outcomes, and advances in medicinal chemistry combined with early pharmacological testing have produced the first selective inhibitors of this kinase. Together, this review provides an updated and integrated overview of the complex biology of IKKα and its emerging potential as a therapeutic target.
Caprin-1 silencing reverses YY1/HSP90α-mediated IDH1 stabilization to induce ferroptosis and sensitize cervical cancer to cisplatin.
Xie T, He Y, Tan M … +3 more , Gao Y, Tai Y, Zhang W
Cell Signal · 2026 Sep · PMID 42114793 · Publisher ↗
OBJECTIVE: To clarify how Caprin-1 regulates cisplatin resistance in cervical cancer (CC) and to find related biomarkers. METHODS: Tissues from 30 CC patients were analyzed. Caprin-1 and IDH1 expression was examined in c...
OBJECTIVE: To clarify how Caprin-1 regulates cisplatin resistance in cervical cancer (CC) and to find related biomarkers. METHODS: Tissues from 30 CC patients were analyzed. Caprin-1 and IDH1 expression was examined in cisplatin-sensitive and -resistant samples and cell lines (Hela/DDP, SiHa/DDP). The comprehensive analysis encompassed measuring viability via CCK-8, assessing cell death by propidium iodide staining, detecting ROS with 2', 7'- dichlorodihydrofluorescein diacetate, quantifying the GSH/GSSG ratio, MDA, and Fe levels using biochemical kits, evaluating ferroptosis-related protein (GPX4, SLC7A11, FTH1) expression by Western blot, determining mitochondrial membrane potential (ΔΨm) with JC-1 staining, and observing ultrastructure via transmission electron microscopy. RNA immunoprecipitation (RIP), RNA pull-down, and actinomycin D assays tested Caprin-1 binding to YY1 mRNA. Dual-luciferase, chromatin immunoprecipitation, and RIP assays assessed YY1-mediated HSP90AA1 transcription. Co-IP verified HSP90α-IDH1 interaction. IDH1 modulation and Ferrostatin-1 treatment were evaluated in CAPRIN1-knockdown context. A xenograft model tested Caprin-1's effect on cisplatin response. RESULTS: Caprin-1 and IDH1 were upregulated in cisplatin-resistant samples. Silencing CAPRIN1 induced ferroptosis, as evidenced by increased levels of MDA, ROS, and Fe, decreased ΔΨm with concomitant morphological damage, and reduced ferroptosis-related proteins. It also increased cisplatin sensitivity. Caprin-1 bound and stabilized YY1 mRNA. YY1 activated HSP90AA1 transcription. HSP90α bound IDH1 and inhibited its degradation. IDH1 overexpression reversed ferroptosis and restored cisplatin sensitivity after CAPRIN1 knockdown; Ferrostatin-1 counteracted IDH1-silencing effects. In vivo, CAPRIN1 knockdown promoted ferroptosis, suppressed tumor growth, and synergized with cisplatin. CONCLUSION: Caprin-1 silencing enhances cisplatin sensitivity in CC by suppressing the YY1/HSP90α axis, accelerating IDH1 degradation, and activating ferroptosis.
SIRT1-mediated deacetylation stabilizes cortactin to enhance glycolysis and drive cervical cancer progression.
Qi L, Zhu D, Qian L … +2 more , Yi B, Chen Y
Cell Signal · 2026 Sep · PMID 42114792 · Publisher ↗
BACKGROUND: Cervical cancer is a major cause of cancer-related death among women worldwide. Although cortactin (CTTN) has been implicated in tumor progression, its regulatory mechanisms and functional relevance in cervic...
BACKGROUND: Cervical cancer is a major cause of cancer-related death among women worldwide. Although cortactin (CTTN) has been implicated in tumor progression, its regulatory mechanisms and functional relevance in cervical cancer remain unclear. METHODS: CTTN expression in tissues and cell lines was examined by qRT-PCR, western blotting, and immunohistochemistry. Gain- and loss-of-function studies were performed to evaluate the role of CTTN in cell proliferation, colony formation, migration and invasion. Seahorse assays and biochemical analyses were used to assess the effects of CTTN on aerobic glycolysis. CTTN-SIRT1 interaction was examined by immunofluorescence and co-immunoprecipitation. Metabolic reprogramming was analyzed by qRT-PCR, western blotting of glycolytic enzymes, glucose uptake and lactate production assays, and Seahorse XF analysis. Rescue experiments were conducted to determine the dependence of SIRT1 activity on CTTN. Xenograft models were established to examine in vivo tumorigenesis. RESULTS: CTTN was significantly upregulated in cervical cancer tissues and cell lines. CTTN silencing suppressed cell proliferation, colony formation, migration, invasion, and glycolysis, whereas CTTN overexpression enhanced these phenotypes. Mechanistically, SIRT1 interacts with and deacetylates CTTN, thereby stabilizing cortactin protein expression. SIRT1 knockdown reduced cortactin levels and suppressed tumor cell growth and glycolytic activity, whereas ectopic expression of CTTN rescued these effects. In vivo, inhibition of either SIRT1 or CTTN significantly reduced tumor volume, weight, and Ki-67 expression. CONCLUSION: SIRT1 stabilizes cortactin through deacetylation, promoting aerobic glycolysis and malignant progression in cervical cancer. Targeting the SIRT1-CTTN axis may be a promising therapeutic strategy for cervical cancer.
Multi-omics identifies RNF149 as a key molecular marker mediating neuron-glia interaction in temporal lobe epilepsy.
Wei B, Qian X, Mao R … +5 more , Yu K, Wang Y, Chen H, Xiong H, Li J
Cell Signal · 2026 Sep · PMID 42114791 · Publisher ↗
Epilepsy is a complex central nervous system disease with a high incidence and a significant social health burden. Although there are many antiepileptic drugs, about 30% of patients are insensitive to existing drug treat...
Epilepsy is a complex central nervous system disease with a high incidence and a significant social health burden. Although there are many antiepileptic drugs, about 30% of patients are insensitive to existing drug treatments, and it is urgently required to identify reliable molecular markers and therapeutic targets. Traditional research has focused on a single omics level, and it is difficult to establish a complete connection from genetic variation to changes in cell function. In this study, a multi-level analysis framework integrating transcriptome, proteome, Mendelian randomization, and single-cell omics was constructed, and the E3 ubiquitin ligase RNF149 was systematically screened and multi-dimensionally verified as a key candidate molecular marker for epilepsy. In external datasets (GSE88992, GSE127871, GSE255223) and animal models, RNF149 showed a stable trend of differential expression and was associated with hippocampal sclerosis and the severity of epileptic seizures. Single-cell communication investigation revealed that RNF149 may influence the pathological process of epilepsy by modulating the interaction between excitatory neurons and oligodendrocytes, particularly the NRG3-ERBB4 signaling axis. In conclusion, multi-omics integrated analysis highlighted RNF149's potential relevance as a molecular biomarker and treatment target for epilepsy, generating new ideas for precision diagnosis and mechanism research in temporal lobe epilepsy.
RNA methylation in kidney disorders: Insights into molecular machinery and therapeutic opportunities.
Li Z, Chen Y, Zhang X … +4 more , Lv J, Chen J, Chen D, Yao Q
Cell Signal · 2026 Sep · PMID 42114790 · Publisher ↗
Kidney disorders, including acute kidney injury (AKI), chronic kidney disease (CKD), diabetic nephropathy (DN), and clear cell renal cell carcinoma (ccRCC), represent major causes of morbidity and mortality worldwide and...
Kidney disorders, including acute kidney injury (AKI), chronic kidney disease (CKD), diabetic nephropathy (DN), and clear cell renal cell carcinoma (ccRCC), represent major causes of morbidity and mortality worldwide and remain significant challenges in clinical management because of their complex pathogenesis and limited therapeutic options. Recent advances in epitranscriptomics have highlighted RNA methylation as an important post-transcriptional regulatory mechanism involved in renal physiology and disease development. Diverse RNA modifications, including N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), N7-methylguanosine (m7G), and 3-methylcytidine (m3C), dynamically regulate RNA metabolism by affecting transcript stability, translation, splicing, and degradation. Increasing evidence demonstrates that RNA methylation regulators, including methyltransferases such as METTL3 and METTL14, demethylases such as FTO and ALKBH5, and reader proteins such as YTH domain-containing family members, participate in multiple pathogenic processes, including inflammation, fibrosis, oxidative stress, metabolic dysregulation, and tumor progression in renal disorders. Aberrant expression of these regulators has been closely associated with disease severity and progression. In this review, we summarize current knowledge regarding major RNA methylation modifications and their regulatory machinery in a spectrum of kidney diseases, with particular emphasis on the molecular mechanisms through which RNA methylation influences renal injury and repair. We further discuss the emerging value of RNA methylation-related molecules as potential biomarkers and therapeutic targets, aiming to provide new insights into epitranscriptomic regulation in kidney disease and its translational potential.
Isochlorogenic acid A alleviates angiotensin II-induced cardiac hypertrophy by regulating RIP3.
Xu J, Chen M, Lai L … +10 more , Hong W, Xiao D, Jiang S, Lin J, Wang Z, Li R, Liu Y, Huang Z, Song G, Shan Z
Cell Signal · 2026 Sep · PMID 42114789 · Publisher ↗
Pathological cardiac hypertrophy is a critical pathological process involved in the development of various cardiovascular diseases. Isochlorogenic acid A (ICAA) is a phenolic compound found in a wide spectrum of herbal m...
Pathological cardiac hypertrophy is a critical pathological process involved in the development of various cardiovascular diseases. Isochlorogenic acid A (ICAA) is a phenolic compound found in a wide spectrum of herbal medicines and plants, and several pharmacological properties of ICAA have been examined. However, there is currently no report on whether ICAA has therapeutic effect on pathological cardiac hypertrophy. Thus, the aim of this study was to explore the protective effects of ICAA on cardiac hypertrophy and clarify its potential mechanism. In our research, we found that ICAA effectively mitigated Ang II/TAC-induced cardiac hypertrophy and damage in vitro and in vivo. In terms of the mechanism, we proved that ICAA suppressed phosphorylation of receptor-interacting protein 3 (RIP3, RIPK3) and the activation of downstream calcium/calmodulin-dependent protein kinase II (CaMKII) signaling by directly binding to RIP3. MLKL was not required for RIP3 regulatory role in cardiac hypertrophy, and the effect of ICAA on cardiac hypertrophy was independent of RIP3/MLKL signaling cascade. Furthermore, RIP3 overexpression exacerbated Ang II-induced cardiac hypertrophy. Finally, we showed that ICAA had no obvious adverse effects on normal organs and even had protective effect. In conclusion, this study is the first to report that ICAA directly targets RIP3 to regulate the RIP3/CaMKII pathway, effectively inhibiting cardiac hypertrophy. Therefore, ICAA can be considered a novel therapeutic drug for the future prevention and treatment of cardiac hypertrophy.
Ginsenoside Rh2 from ginseng exosomes enhances chemotherapy sensitivity in non-small cell lung cancer by modulating the USP22-RRM2 axis.
Liu J, Wang M, Xia M … +9 more , Yan R, Xu E, Sun H, Zhong Y, Xu Y, Zhang Z, Xue F, Jin M, Huang Q
Cell Signal · 2026 Sep · PMID 42114788 · Publisher ↗
BACKGROUND: Non-small cell lung cancer (NSCLC) remains a prevalent and malignant cancer globally, characterized by chemotherapy resistance. The aim of this study was focused on the potential of ginsenoside (Gn)-Rh2 from...
BACKGROUND: Non-small cell lung cancer (NSCLC) remains a prevalent and malignant cancer globally, characterized by chemotherapy resistance. The aim of this study was focused on the potential of ginsenoside (Gn)-Rh2 from ginseng exosomes (Gn-Exos), a primary bioactive constituent of Panax ginseng, to enhance chemotherapy sensitivity in NSCLC. METHODS: In this study, Gn-Exo was isolated and identified. The intake and internal organ distribution of PKH26-labelled Gn-Exos was detected using immunofluorescence and in vivo imaging. Transwell migration, 5-ethynyl-2'-deoxyuridine (EdU) incorporation, cell counting, and wound healing experiments were performed to assess NSCLC cell proliferation and migration. A mouse tumor xenograft model was constructed to assess the roles of Gn-Exos and the main active ingredient Gn-Rh2 in NSCLC progression and metastasis in vivo. RESULTS: Gn-Exos can inhibit the proliferation, migration, cancer growth, and pulmonary metastasis of NSCLC cells. Mass spectrometry analysis confirmed that the main component of Gn-Exos was Gn-Rh2. The results also showed that Gn-Rh2 inhibited the proliferation and migration of NSCLC cells in both in vivo and in vitro experiments. Comprehensive proteomic analysis identified ribonucleotide reductase regulatory subunit M2 (RRM2) and ubiquitin-specific protease 22 (USP22) as key targets significantly downregulated by Gn-Rh2. Experimental results demonstrated that Gn-Rh2 disrupts the interaction to USP22, disrupting the interaction between USP22 and RRM2, leading to ubiquitination degradation of RRM2. Animal experiments further confirmed that Gn-Rh2 sensitized NSCLC cells to chemotherapy, particularly cisplatin. CONCLUSION: These findings provide novel insights into the molecular mechanisms of Gn-Rh2 in enhancing chemotherapy sensitivity and suggest a promising therapeutic strategy for NSCLC.
HO-1 enhances autophagy to alleviate oxidative damage in BMECs via Keap1/Nrf2 and AMPK/mTOR signaling.
Dong J, Zhang X, Liu X … +8 more , Peng D, Jing J, Xu S, Yang Q, Han Y, Liu Y, Li H, Wang Y
Cell Signal · 2026 Sep · PMID 42105892 · Publisher ↗
Heme oxygenase-1 (HO-1) plays an important role in maintaining Nrf2-mediated redox homeostasis. Lipopolysaccharide (LPS), a major pathogenic factor in bacterial mastitis, induces oxidative stress and inflammation in bovi...
Heme oxygenase-1 (HO-1) plays an important role in maintaining Nrf2-mediated redox homeostasis. Lipopolysaccharide (LPS), a major pathogenic factor in bacterial mastitis, induces oxidative stress and inflammation in bovine mammary epithelial cells (BMECs). HO-1-induced autophagy has been shown to mitigate oxidative damage across various tissues in previous studies. Therefore, we hypothesized that HO-1 may alleviate oxidative stress in BMECs by promoting autophagy via the Keap1/Nrf2 and AMPK/mTOR signaling pathways. We examined the effects of HO-1 on oxidative stress, including antioxidant enzyme production and inflammatory response, as well as autophagy in LPS-stimulated BMECs. In this study, overexpression and knockout of HO-1 or Nrf2 were performed in BMECs to verify the involvement of HO-1 in the Keap1/Nrf2 pathway. In addition, autophagy inhibitors and mTOR inhibitor were used to determine whether the antioxidant effects of HO-1 were mediated by autophagy via the AMPK/mTOR signaling pathway. We found that HO-1 alleviated LPS-induced inflammation response and improved the resistance of BMECs to oxidative stress. Furthermore, HO-1 activated the Keap1/Nrf2 signaling pathway, thereby enhancing antioxidant capacity, which was further confirmed by in vitro overexpression and knockout experiments targeting Nrf2 or HO-1. Meanwhile, HO-1 also upregulated the expression of autophagy-related genes, whereas treatment with an autophagy inhibitor attenuated the antioxidant effects of HO-1. In addition, administration of an mTOR inhibitor further indicated that HO-1-mediated autophagy was regulated via the AMPK/mTOR signaling pathway. In conclusion, HO-1 alleviates oxidative damage in BMECs by promoting autophagy through the Keap1/Nrf2 and AMPK/mTOR signaling pathways. These findings identify HO-1 as a potential therapeutic target for reducing tissue damage in bacterial mastitis.
FGF20 activates FGFR1-PI3K-AKT signaling to coordinate barrier integrity and alveolar coagulation in sepsis-induced lung injury.
Dong Q, Tao J, Yuan J … +8 more , Tian J, Cheng Y, Wang J, Xiao C, Chen X, Wang Y, Li W, Shen F
Cell Signal · 2026 Sep · PMID 42097317 · Publisher ↗
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are pathologically characterized by disruption of the alveolar-capillary barrier, excessive inflammatory responses, and dysregulated intra-pulmonary...
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are pathologically characterized by disruption of the alveolar-capillary barrier, excessive inflammatory responses, and dysregulated intra-pulmonary coagulation. Although inflammatory and thrombotic cascades have been extensively studied, endogenous epithelial-derived signaling mechanisms coordinating barrier stabilization with immunothrombotic restraint remain undefined. Here, we identify fibroblast growth factor 20 (FGF20) as a constitutive epithelial regulator suppressed in alveolar barrier-associated cells during sepsis-induced ALI. In a CLP rat model, both prophylactic and therapeutic administration of recombinant human FGF20 (rhFGF20) improved 7-day survival, attenuated pulmonary edema and inflammation, restored gas exchange, and preserved alveolar-capillary integrity. rhFGF20 restrained procoagulant and antifibrinolytic mediators tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) while suppressing NF-κB activation. Mechanistically, FGF20 acted through fibroblast growth factor receptor 1 (FGFR1) to engage the FGFR1-PI3K-AKT cascade. AKT activation bifurcated into two axes: (i) inhibition of NF-κB phosphorylation and nuclear translocation, restraining TF/PAI-1 transcription; and (ii) inhibitory phosphorylation of glycogen synthase kinase 3β (GSK3β) at Ser9, stabilizing epithelial and endothelial junctional proteins (E-cadherin, VE-cadherin, ZO-1). Pharmacological inhibition of FGFR1 or AKT abolished both barrier-protective and anticoagulant effects, confirming pathway dependency. Clinically, serum and bronchoalveolar lavage fluid FGF20 levels were reduced in ARDS patients and positively correlated with PaO₂/FiO₂ ratios, linking reduced FGF20 to disease severity. Collectively, these findings position FGF20 as an upstream integrator of structural and immunothrombotic homeostasis within the alveolar-capillary unit. Restoration of the FGF20-FGFR1 axis reconstitutes a proximal checkpoint stabilizing barrier architecture and constraining NF-κB-dependent procoagulant activation, highlighting FGF20 as a mechanistically grounded therapeutic target in sepsis-induced ALI/ARDS. CLINICAL SIGNIFICANCE.
The NLRP3 inflammasome in tuberculosis and its regulatory mechanisms.
Xiong L, Zhang Q, Abudukadier A … +1 more , Xie J
Cell Signal · 2026 Sep · PMID 42097316 · Publisher ↗
Tuberculosis (TB) is a severe infectious disease caused by Mycobacterium tuberculosis (Mtb). Host innate immunity plays a critical role in controlling Mtb infection, in which the NOD-like receptor family pyrin domain-con...
Tuberculosis (TB) is a severe infectious disease caused by Mycobacterium tuberculosis (Mtb). Host innate immunity plays a critical role in controlling Mtb infection, in which the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome serves as a key intracellular immune-sensing and signaling platform regulating infection-associated inflammatory responses. Activation of the NLRP3 inflammasome promotes the maturation and secretion of interleukin-1β (IL-1β) and IL-18 and induces pyroptosis, thereby exerting context-dependent dual effects in antimicrobial defense and inflammatory tissue injury. Multiple Mtb virulence factors, including ESAT-6, PPE13, and EST12, facilitate NLRP3 activation, whereas others, such as PknF, Zmp1, and Rv2569c, suppress its activity to mediate immune evasion. Moreover, NLRP3 expression and function are tightly regulated by epigenetic, transcriptional, post-transcriptional, and post-translational mechanisms. This review summarizes the structural and functional features of the NLRP3 inflammasome, highlights its activation and regulatory mechanisms in tuberculosis, and outlines recent advances in host-directed therapy (HDT) strategies targeting NLRP3, providing a theoretical basis for TB prevention and treatment.
ATRX loss promotes gliomagenesis by converged actions on neural differentiation and telomere maintenance.
Xu L, Li F, Wen N … +7 more , Wu C, Zhu A, Hou Y, Wang W, Zhao Y, Zheng H, Zhang L
Cell Signal · 2026 Sep · PMID 42097315 · Publisher ↗
The chromatin remodeler ATRX is frequently mutated or depleted in a range of human malignancies, including pediatric and adult gliomas, yet the mechanism underlying its tumor suppressor function remains unclear. Here we...
The chromatin remodeler ATRX is frequently mutated or depleted in a range of human malignancies, including pediatric and adult gliomas, yet the mechanism underlying its tumor suppressor function remains unclear. Here we combine primary murine and human neural stem/progenitor cell (NSC)-based systems to demonstrate that ATRX modulates glioma pathogenesis through two independent and convergent functions. Firstly, we show that ATRX regulates neural development by facilitating neuronal maturation. Depletion of ATRX blocks neural differentiation and promotes gliomagenesis. Concurrently, we show that ATRX is required for efficient telomere DNA replication in human but not murine NSCs, since Pot1b binding to telomeric G-rich single-strand DNA suppresses Atrx deletion-induced telomere defects in mouse cells. Loss of ATRX in human NSCs destabilizes telomere homeostasis, which triggers a robust DNA damage response (ATR-CHK1/CHK2 pathway) and induces ALT-like phenotypes that initially limit mutant cell proliferation. Only a small fraction (approximately 1-3%) of ATRX-null human NSCs stably activate ALT to escape growth restriction, consistent with the indolent clinical progression of human ATRX-mutant gliomas. These findings support a hypothetical three-step model that reconciles the initial indolence and eventual malignant progression of ATRX-deficient gliomas. Our study clarifies species-specific differences in ATRX function and has important mechanistic and clinical implications for the development of targeted therapies for ATRX-mutant gliomas.
Activation of tripartite motif-containing protein 16 improves cardiac function in aging mice by regulating Mfn2-dependent mitochondrial fusion through Sirt6.
Chen Y, Guo H, Ding X … +2 more , Lu L, Jin P
Cell Signal · 2026 Sep · PMID 42086121 · Publisher ↗
Aging increases susceptibility to various diseases, including cardiac injury. Which leads to cardiac dysfunction by increasing myocardial fibrosis and mitochondrial dynamics disorder. However, the molecular mechanisms in...
Aging increases susceptibility to various diseases, including cardiac injury. Which leads to cardiac dysfunction by increasing myocardial fibrosis and mitochondrial dynamics disorder. However, the molecular mechanisms in the aging heart have not been elucidated. The E3 ligase TRIM16 (tripartite motif-containing protein 16) functions as a regulator to alleviate cardiac injury. Sirt6 has been shown to play a cardioprotective role by maintaining mitochondrial dynamics. Our study aimed to elucidate the molecular mechanisms of the TRIM16-Sirt6-Mfn2 signaling pathway in the aging heart. We used aged mice and performed intracardiac injections of AAV-TRIM16/Sirt6. The results demonstrated that TRIM16 improved cardiac function by increasing Sirt6 expression in the aging heart. Further in vitro studies were conducted using D-galactose-cultured h9c2 cells to explore the relationship between TRIM16/Sirt6 and mitochondrial dynamics. The findings showed that TRIM16/Sirt6 protected D-galactose-cultured h9c2 cells by promoting Mfn2-dependent mitochondrial fusion and enhancing mitochondrial respiratory capacity. In conclusion, our results confirm that TRIM16 activation improves cardiac function via the Sirt6/Mfn2 signaling pathway in the aging heart. This study provides evidence that TRIM16/Sirt6/Mfn2 signaling plays a novel protective role in the aging heart and offers a promising therapeutic strategy for age-related heart failure.
Astragaloside IV enhances autophagy to suppress endoplasmic reticulum stress and pyroptosis after spinal cord injury.
Jiang Z, Wu Z, Jin Y … +12 more , Xu K, Shu W, Wu Y, Ying J, Wu J, Geng Y, Hong C, Shi J, Wang C, Zhou K, Qi J, Xu H
Cell Signal · 2026 Sep · PMID 42086120 · Publisher ↗
Spinal cord injury (SCI) is a devastating insult to the central nervous system that causes severe motor and sensory dysfunction; however, effective therapeutic strategies remain limited because the mechanisms underlying...
Spinal cord injury (SCI) is a devastating insult to the central nervous system that causes severe motor and sensory dysfunction; however, effective therapeutic strategies remain limited because the mechanisms underlying secondary injury are not fully understood. In this study, we investigated the therapeutic effects of the bioactive compound astragaloside IV (AST-IV) in a mouse model of SCI. Through functional, histological, and molecular analyses, we demonstrated that AST-IV treatment significantly improved neurological recovery after SCI. Mechanistically, AST-IV exerted neuroprotective effects through the activation of AMPK-mediated autophagy and the enhancement of autophagic flux, thereby preserving mitochondrial homeostasis, attenuating endoplasmic reticulum stress-associated apoptosis, and suppressing pyroptosis. Importantly, pharmacological inhibition of autophagy markedly attenuated the protective effects of AST-IV, indicating that the neuroprotective effect of AST-IV is mediated by autophagy. Collectively, these findings reveal an autophagy-dependent mechanism underlying AST-IV-mediated neuroprotection and support the therapeutic potential of AST-IV for mitigating secondary injury after SCI.
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