Li Y, Hou Y, Han Y
… +9 more, Feng W, Zong W, Wang X, Chen G, Tan X, Zhang B, Ju L, Wang F, Qi J
Cell Signal
· 2026 Oct · PMID 42285192
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Mounting evidence has suggested that enhancer RNAs (eRNAs) play vital roles in tumor progression. However, the molecular mechanisms of eRNAs involvement in the occurrence and development of hepatocellular carcinoma (HCC)...Mounting evidence has suggested that enhancer RNAs (eRNAs) play vital roles in tumor progression. However, the molecular mechanisms of eRNAs involvement in the occurrence and development of hepatocellular carcinoma (HCC) remain to be explored. Herein, bioinformatics analysis was used to screen a new differential expression eRNA in HCC, namely AL109933.1. Moreover, A series of in vitro and in vivo experiments were performed to evaluate the biological significance and potential mechanism of AL109933.1 in HCC. The results showed that AL109933.1 was lowly expressed in HCC and was correlated with tumor histological grade, TNM stage, T stage and the prognosis of HCC patients. Moreover, functional assays revealed that AL109933.1 impeded HCC cell proliferation and metastasis. Additionally, mechanistic studies showed that AL109933.1 acted as a molecular decoy to block YY1-induced transcriptional activation of PKM2 and PIK3R1, thereby inhibiting the Warburg effect through inactivating PI3K/AKT/mTOR/HIF-1α signaling pathway, which was resulted in handicapping HCC progression. Besides, both the nude mouse xenograft model and orthotopic HCC mouse model further confirmed that AL109933.1 suppressed HCC growth through hindering the Warburg effect and downregulating PKM2 and PIK3R1. In conclusion, AL109933.1 can inhibit HCC progression and it is expected to be an emerging therapeutic target for HCC.
Chen Z, Yang Z, Hu Z
… +6 more, Lei M, Li Q, Zhang W, Chen L, Su Y, Ni N
Cell Signal
· 2026 Oct · PMID 42285191
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Proliferative vitreoretinopathy (PVR) is a major cause of blindness. Surgery remains the primary clinical intervention, but its outcomes are frequently unsatisfactory. A deeper understanding of PVR pathophysiology is the...Proliferative vitreoretinopathy (PVR) is a major cause of blindness. Surgery remains the primary clinical intervention, but its outcomes are frequently unsatisfactory. A deeper understanding of PVR pathophysiology is therefore essential for developing new treatments. TRAF6 is a multifunctional intracellular adaptor protein that regulates diverse biological processes, yet its role in PVR is unknown. Here, we investigated the function of TRAF6 in PVR and its downstream mechanisms using a mouse model and ARPE-19 cells. The results demonstrated that TRAF6 expression was upregulated in the retinas of PVR model mice and in ARPE-19 cells. Knockdown of TRAF6 alleviated PVR progression in mice by suppressing inflammation and the epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells. Conversely, TRAF6 overexpression in ARPE-19 cells exacerbated TGF-β1-induced EMT. Mechanistically, TRAF6 positively regulated MAP3K7 expression via a protein-protein interaction. Knockdown of TRAF6 inhibited P38/MAPK signaling pathway activation by reducing MAP3K7 expression. Furthermore, knockdown of TRAF6 attenuated the promoting effect of MAP3K7 overexpression on TGF-β1-induced EMT in RPE cells. In conclusion, TRAF6 knockdown protects against PVR in mice by inhibiting the MAP3K7 and p38 MAPK pathways.
Wang X, Jin G, Cheng Z
… +3 more, Sang Y, Ji T, Huang Z
Cell Signal
· 2026 Oct · PMID 42285190
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BACKGROUND: Chemoresistance is the primary hindrance to effective gastric cancer (GC) treatment. Artemin (ARTN) exerts oncogenic roles in various malignancies (including GC), yet its involvement in GC chemoresistance rem...BACKGROUND: Chemoresistance is the primary hindrance to effective gastric cancer (GC) treatment. Artemin (ARTN) exerts oncogenic roles in various malignancies (including GC), yet its involvement in GC chemoresistance remains unelucidated. This work sought to clarify the function of ARTN and the mechanism in GC chemoresistance. METHODS: ARTN expression was detected via qPCR and western blotting. The functions of ARTN in GC chemoresistance were evaluated in vitro by CCK-8, apoptosis, and colony formation assays, which were also determined in vivo using a xenograft mouse model. Immunohistochemistry was adopted to measure Ki67 (a marker of proliferation) and cleaved caspase 3 (a marker of apoptosis) in tumor tissues. ELK4 phosphorylation was assessed through immunoprecipitation and western blotting. ChIP-qPCR was employed to determine the binding of ELK4 and ABCB1. RESULTS: ARTN was aberrantly upregulated in GC cells, particularly in chemo-resistant GC cells; its knockdown efficaciously sensitized chemo-resistant GC cells to 5-fluorouracil (5-FU), reduced proliferation, and enhanced apoptosis. In vivo, ARTN deficiency restrained tumor growth in chemo-resistant xenograft mice under 5-FU treatment, with downregulated Ki67 and upregulated cleaved caspase 3 in tumor tissues. Molecular mechanism experiments revealed that ARTN facilitated ELK4 phosphorylation and increase ABCB1 expression in GC cells by activating KRAS/ERK signaling. Crucially, ARTN overexpression impaired GC cell sensitivity to 5-FU in vitro, which was abrogated by ELK4 or ABCB1 knockdown. CONCLUSION: ARTN promotes GC chemoresistance by upregulating ABCB1 expression via modulating ELK4 phosphorylation, offering a likely therapeutic approach to reverse GC chemoresistance.
Xie W, Deng W, Zhang J
… +5 more, Chang S, Chen D, Qu H, Zeng X, Liu F
Cell Signal
· 2026 Oct · PMID 42285189
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Hypersensitivity pneumonitis (HP) is an immune-mediated interstitial lung disease caused by inhaled environmental antigens, and effective targeted therapies remain limited. Berberine (BBR) has established anti-inflammato...Hypersensitivity pneumonitis (HP) is an immune-mediated interstitial lung disease caused by inhaled environmental antigens, and effective targeted therapies remain limited. Berberine (BBR) has established anti-inflammatory activity, but its role in HP is unclear. Here, we combined network pharmacology with experimental validation to investigate the therapeutic potential and mechanism of BBR in HP. We identified 38 overlapping targets between BBR and HP, with network analysis highlighting tumor necrosis factor (TNF), interleukin 1 beta (IL1β), interleukin 6 (IL6), B-cell lymphoma/leukemia-2 (BCL2) and caspase 3 (CASP3). Functional enrichment implicated TNF signaling, apoptosis and autophagy, suggesting that disruption of cellular homeostasis is central to HP progression and may be targeted by BBR. In a 1,3-β-glucan (β-glucan)-induced model of HP-like lung inflammation, BBR markedly reduced pulmonary inflammatory responses and increased autophagy-related protein expression in neutrophil-dominant lesions. In β-glucan-stimulated differentiated HL-60 cells, BBR attenuated inflammatory injury, limited apoptosis and preserved cellular function. Mechanistically, BBR restored defective autophagic flux by promoting transcription factor EB (TFEB) nuclear translocation, thereby improving neutrophil homeostasis and reducing inflammatory damage. These findings identify TFEB-dependent restoration of autophagic flux as a key mechanism underlying the protective effects of BBR in experimental HP-like lung inflammation and support BBR as a potential therapeutic candidate for HP.
Guo Y, Niu Y, Zhu Q
… +4 more, He R, Yang Q, Jin Z, He Y
Cell Signal
· 2026 Oct · PMID 42276401
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Corneal neovascularization (CNV) and corneal lymphangiogenesis (CL) disrupt corneal immune privilege after injury and drive transplant rejection. This study investigated how the bone morphogenetic protein 4 (BMP4)-Smad p...Corneal neovascularization (CNV) and corneal lymphangiogenesis (CL) disrupt corneal immune privilege after injury and drive transplant rejection. This study investigated how the bone morphogenetic protein 4 (BMP4)-Smad pathway regulates both vascular arms of the corneal wound response. Bioinformatic analysis of a rat corneal suture-injury dataset showed that sustained injury induced a coordinated inflammatory, angiogenic, lymphangiogenic, and BMP/TGFβ-Smad transcriptional program, with predicted SMAD5-binding motifs in vascular- and lymphatic-related gene promoters. In vitro, BMP4 inhibited the proliferation and migration of human umbilical vein endothelial cells (HUVEC) and human lymphatic endothelial cells (HLEC) and downregulated CD31, VEGFA, LYVE-1, and VEGFC, whereas the BMP antagonist Noggin reversed these effects. BMP4 increased phosphorylated Smad1/5/8 (p-Smad1/5/8) and promoted its nuclear translocation, confirming canonical pathway activation. In a rat corneal suture model, BMP4 reduced inflammatory-cell infiltration and suppressed CNV and CL, as demonstrated by slit-lamp examination, lineage-resolved CD31/CD45 and LYVE-1/Prox1 co-staining, transmission electron microscopy, and molecular assays; Noggin antagonized each effect. BMP4 further activated corneal p-Smad1/5/8 signaling and induced endogenous BMP4 expression in a Noggin-sensitive manner, suggesting a self-amplifying loop. Together, these findings indicate that BMP4 coordinately restrains the vascular and lymphatic arms of the corneal immune response through canonical BMP4-Smad1/5/8 signaling and may help preserve corneal immune privilege during injury repair.
Zhang Y, Li Q, Xu S
… +3 more, Luo Y, Liu W, Liu Y
Cell Signal
· 2026 Oct · PMID 42270026
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We previously demonstrated that a novel growth-friendly system can alleviate pulmonary hypoplasia in piglets with early-onset scoliosis combined with thoracic insufficiency syndrome (EOS + TIS) by improving the mechanica...We previously demonstrated that a novel growth-friendly system can alleviate pulmonary hypoplasia in piglets with early-onset scoliosis combined with thoracic insufficiency syndrome (EOS + TIS) by improving the mechanical microenvironment. Transcriptomic analyses indicated that mechanical stress (MS) may exert its effects by regulating immune responses and metabolic pathways. Building upon this foundation, the present study further investigates the implications of MS on macrophage polarization and metabolic reprogramming, as well as the underlying molecular mechanisms. In this study, MS at a 10% amplitude effectively downregulated M1-type markers (CD86, IL-1β, iNOS, TNF-α) in RAW264.7 cells, while upregulating M2-type markers (TGF-β, CD206, IL-10). Transcriptomic analysis further suggested that MS influences lung development by regulating glycolysis, metabolic reprogramming, and immune-related pathways. Further experiments demonstrated that the MS downregulated glycolytic enzymes (PKM2, GLUT1, PGK1, and LDHA), reduced lactate production and extracellular acidification rate, while enhancing oxygen consumption rate and promoting the tube-forming capacity of human umbilical vein endothelial cells, induced by conditioned media from RAW264.7 cells. Mechanistically, MS activated the SOCS3/STAT3 pathway by upregulating Integrin Subunit Alpha D (ITGAD) expression, thereby facilitating M2 polarization and suppressing glycolytic metabolic reprogramming in RAW264.7 cells. ITGAD knockdown reversed these implications. In conclusion, MS activates the SOCS3/STAT3 pathway by upregulating ITGAD, thereby promoting macrophage polarization toward the M2 phenotype, suppressing glycolytic metabolic reprogramming, and enhancing their pro-angiogenic function. This discovery reveals a novel mechanism of MS in the pulmonary microenvironment, providing a new molecular perspective for understanding the pathological processes of EOS + TIS-associated pulmonary dysplasia.
Cell Signal
· 2026 Oct · PMID 42263898
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BACKGROUND: Breast cancer remains a leading cause of cancer-related mortality in women, largely due to therapeutic resistance. Ferroptosis, a regulated form of cell death driven by lipid peroxidation, represents a promis...BACKGROUND: Breast cancer remains a leading cause of cancer-related mortality in women, largely due to therapeutic resistance. Ferroptosis, a regulated form of cell death driven by lipid peroxidation, represents a promising strategy to suppress tumor progression, yet its regulatory mechanisms in breast cancer are not fully defined. This study aimed to investigate the anti-cancer effects of betaine (BET) and its potential involvement in ferroptosis. METHODS: Network pharmacology, bioinformatics analyses of The Cancer Genome Atlas and Gene Expression Omnibus datasets, and molecular docking were used to identify potential BET targets and construct a BET-target-breast cancer interaction network. Functional assays in MDA-MB-231 and MCF-7 cells evaluated proliferation, migration, oxidative stress, mitochondrial function, and ferroptosis. RESULTS: BET treatment was associated with inhibition of cell proliferation, clonogenicity, and migration, while increasing reactive oxygen species and lipid peroxidation. Mechanistically, BET enhanced KEAP1-NRF2 interaction, thereby increasing NRF2 ubiquitination and proteasomal degradation. Consequently, NRF2 nuclear accumulation was reduced, leading to suppression of downstream antioxidant and ferroptosis-protective targets, including xCT and GPX4. The resulting depletion of glutathione and accumulation of lipid peroxidation products promoted ferroptosis-associated cellular damage. BET also disrupted mitochondrial membrane potential and oxidative phosphorylation, further exacerbating oxidative stress. Notably, the KEAP1 R483S mutation or NRF2 overexpression partially rescued BET-induced oxidative stress and ferroptosis-associated phenotypes, supporting a role for enhanced KEAP1-dependent NRF2 turnover in mediating BET activity. CONCLUSIONS: BET may promote ferroptosis-associated cell death and suppress breast cancer cell malignant phenotypes, potentially through modulation of the KEAP1/NRF2/xCT/GPX4 pathway. These findings suggest a possible therapeutic relevance of BET in breast cancer, although further validation in additional in vivo models and clinical studies is required.
Zhang R, Wang F, Li J
… +8 more, Li H, Zhang N, Chen H, Liu X, Li X, Wei Z, Zhong F, Zhu F
Cell Signal
· 2026 Oct · PMID 42263897
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The mechanism by which chemotherapy induces primary ovarian insufficiency (POI) remains unclear. This study aims to investigate the role of HMGCR in cisplatin-induced ovarian toxicity and its downstream molecular pathway...The mechanism by which chemotherapy induces primary ovarian insufficiency (POI) remains unclear. This study aims to investigate the role of HMGCR in cisplatin-induced ovarian toxicity and its downstream molecular pathways. We established a cisplatin-induced POI mouse model. The protein levels were validated by immunohistochemistry (IHC), immunofluorescence (IF) and western blot (WB). Granulosa cell line KGN were used for in vitro experiments. RNA sequencing (RNA-seq) analyzed gene expression changes in mouse ovaries and KGN cells after HMGCR inhibition. Rescue experiments used exogenous cholesterol, and p53 agonist Nutlin-3a and inhibitor Pifithrin-α (PFT-α) for functional validation. Transcriptome analysis revealed that the cholesterol synthesis pathway was significantly suppressed in the ovaries of POI mice, with HMGCR-the rate-limiting enzyme in cholesterol biosynthesis-being markedly downregulated. Inhibition or knockdown of HMGCR in KGN cells led to increased ROS accumulation, elevated levels of lipid peroxidation (LPO), and enhanced apoptosis. Exogenous supplementation of cholesterol effectively mitigated these effects, confirming that cholesterol deficiency is the causative factor. Furthermore, RNA-seq analysis demonstrated that HMGCR suppression significantly activated the p53 signaling pathway, as evidenced by increased p53 phosphorylation, acetylation (K382), and upregulation of downstream pro-apoptotic targets p21 and PUMA. Pharmacological inhibition of p53 with PFT-α attenuated HMGCR inhibition-induced oxidative damage and apoptosis. In conclusion, cisplatin-induced ovarian injury is mediated through defects in cholesterol synthesis and subsequent p53 activation, identifying the HMGCR-cholesterol-p53 axis as a potential therapeutic target for POI.
Mu Q, Wang X, Guo L
… +3 more, Liu Y, Liu D, Xia B
Cell Signal
· 2026 Oct · PMID 42259465
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Ovarian carcinoma (OC) is a fatal malignant tumor that seriously threatens the health and survival of women. Olaparib is a highly promising drug for OC treatment of ovarian cancer. Long non-coding RNA (lncRNA) THUMPD3-AS...Ovarian carcinoma (OC) is a fatal malignant tumor that seriously threatens the health and survival of women. Olaparib is a highly promising drug for OC treatment of ovarian cancer. Long non-coding RNA (lncRNA) THUMPD3-AS1, which is related to autophagy, has been proven to be carcinogenic in OC. However, the effects and mechanisms of THUMPD3-AS1 combined with Olaparib on ovarian cancer remain unclear. Upregulation of THUMPD3-AS1 was observed in OC tissues and cells. Loss-of-function assays unraveled that silencing THUMPD3-AS1 contributed to autophagy and promoted cell apoptosis and DNA damage in OC cells. Besides, our findings validated that olaparib exerted a stimulative role in autophagy, cell apoptosis and DNA damage. Of note, knockdown of THUMPD3-AS1 intensified the effects of olaparib on OC cells. Subsequently, we certified that THUMPD3-AS1 depletion enlarged the suppression of PI3K/AKT/mTOR pathway caused by olaparib. The function of THUMPD3-AS1 in olaparib-treated OC cells was achieved by regulating PI3K/AKT/mTOR signaling. Animal experiment further confirmed that downregulating THUMPD3-AS1 enhanced olaparib sensitivity to hinder the in vivo growth of OC cells through inhibiting PI3K/AKT/mTOR pathway. Our research revealed THUMPD3-AS1 as a promising target for OC therapy.
Sun M, Liu S, Li Q
… +11 more, Yu T, Dang T, You Y, Sun H, Zhang L, Li X, He X, Ren R, Liu J, Tang J, Zhang Y
Cell Signal
· 2026 Oct · PMID 42259464
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Bone morphogenetic protein 9 (BMP9), the most potent osteogenic member of the bone morphogenetic protein (BMP) family, is well-documented to potently induce the osteogenic differentiation of bone marrow mesenchymal stem...Bone morphogenetic protein 9 (BMP9), the most potent osteogenic member of the bone morphogenetic protein (BMP) family, is well-documented to potently induce the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). However, its role in regulating osteogenesis in the breast cancer (BC) bone microenvironment remains poorly understood. By constructing BMP9-overexpressing MDA-MB-231 cell lines through adenovirus-mediated exogenous overexpression of BMP9 or adding BMP9 recombinant protein to the culture system, as well as establishing a nude mouse humerus injection model, we explored the effect and mechanism of BMP9 in the BC bone metastasis microenvironment. We also clarified the relevant molecular mechanisms using techniques such as exosome miRNA sequencing, qRT-PCR, Western blot, histochemical staining, immunofluorescence staining, and bioinformatics. Through a series of experiments and the nude mouse humerus injection model, we verified that BMP9 promotes osteogenic differentiation of BMSCs and collagen fiber regeneration in nude mice by downregulating the level of lncRNA SNHG3 in BC. From a mechanistic perspective, exosome miRNA sequencing and bioinformatics analysis revealed that downregulation of lncRNA SNHG3 can facilitate the osteogenic differentiation of BMSCs, while suppressing the proliferation, migration, and invasion of MDA-MB-231 cells by delivering exosomal miR-619-5p. This study reveals that BMP9/lncRNA SNHG3/miR-619-5p axis promotes osteogenic differentiation of BMSCs in breast cancer, suggesting that BMP9 and miR-619-5p may become new strategies for treating BC bone metastasis, and lncRNA SNHG3 can act as a potential therapeutic target.
Hou H, Song B, Jiang Y
… +6 more, Zhang C, Yang X, Chen R, Ji M, Jiang B, Yang X
Cell Signal
· 2026 Oct · PMID 42259463
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Lung squamous cell carcinoma (LUSC) is a major subtype of non-small cell lung cancer (NSCLC) with limited therapeutic targets and poor prognosis. Zinc finger CCHC-type RNA-binding protein 1 (ZCRB1) has been implicated in...Lung squamous cell carcinoma (LUSC) is a major subtype of non-small cell lung cancer (NSCLC) with limited therapeutic targets and poor prognosis. Zinc finger CCHC-type RNA-binding protein 1 (ZCRB1) has been implicated in RNA metabolism, yet its role in LUSC remains largely unexplored. In this study, we found that ZCRB1 was significantly overexpressed in NSCLC tissues, particularly in LUSC, and high ZCRB1 expression was associated with poorer overall and disease-free survival. ZCRB1 knockdown markedly suppressed LUSC cell proliferation, migration, and invasion in vitro and inhibited tumor growth and pulmonary metastasis in vivo. Bioinformatic and experimental analyses identified DSG3 as a key downstream target positively correlated with ZCRB1 expression in LUSC tissues. Mechanistically, ZCRB1 directly bound to DSG3 mRNA and enhanced its stability. Importantly, DSG3 overexpression partially reversed the inhibitory effects of ZCRB1 knockdown on LUSC cell malignant phenotypes both in vitro and in vivo. In conclusion, ZCRB1 functions as an oncogenic RNA-binding protein in LUSC by promoting tumor growth and metastasis through stabilization of DSG3 mRNA. Targeting the ZCRB1-DSG3 axis may represent a novel therapeutic strategy for lung squamous cell carcinoma.
Long X, Yang L, Zhou J
… +3 more, Wang S, Wu M, Han X
Cell Signal
· 2026 Oct · PMID 42251945
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BACKGROUND AND OBJECTIVE: Intrauterine adhesion (IUA) often leading to recurrent miscarriage or infertility. The glycolytic activity and mitophagy level of endometrial stem cells (EnSCs) are crucial for endometrial regen...BACKGROUND AND OBJECTIVE: Intrauterine adhesion (IUA) often leading to recurrent miscarriage or infertility. The glycolytic activity and mitophagy level of endometrial stem cells (EnSCs) are crucial for endometrial regeneration. Although cyclin-dependent kinase 1 (CDK1) regulates both processes, its role in IUA is unknown. This study aimed to elucidate how CDK1 modulates EnSCs glycolysis and mitophagy during IUA progression. METHODS: Experiments were performed using a lipopolysaccharide (LPS)-stimulated cellular injury model in vitro, as well as an IUA rat model in vivo. Uterine pathological damage and collagen deposition were assessed by HE and Masson staining. Mitochondrial membrane potential and autophagosome formation were examined using flow cytometry and transmission electron microscopy. Immunofluorescence, ELISA, Western blotting, CCK-8 assays, and various biochemical kits were used to detect relevant proteins, inflammatory cytokines, and glycolytic activity. RESULTS: A reduced number of EnSCs was observed in IUA tissues, accompanied by impaired glycolysis and defective mitophagy. LPS stimulation markedly decreased EnSCs viability and proliferation, suppressed the stemness-related genes Oct4, Nanog, and Sox2, upregulated pro-apoptotic proteins Bax and cleaved caspase-3 as well as the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β, and downregulated the anti-apoptotic protein Bcl-2. CDK1 was lowly expressed in IUA, whereas CDK1 overexpression alleviated uterine injury, fibrosis, and inflammation in IUA rats, reduced stem cell loss, restored EnSCs proliferation and stemness, enhanced glycolysis and mitophagy, and inhibited apoptosis and inflammation. The beneficial effects of CDK1 overexpression were attenuated by the dynamin-related protein 1 (DRP1) inhibitor mitochondrial division inhibitor 1 (Mdivi-1) or the autophagy inhibitor 3-methyladenine (3-MA). CONCLUSION: CDK1 restores EnSCs function and alleviates IUA progression by promoting DRP1-mediated mitophagy and enhancing glycolysis.
Chen Z, Wang Y, Xu Y
… +6 more, Wang S, Xu Z, Tang X, Kang B, Zhou C, Meng X
Cell Signal
· 2026 Oct · PMID 42251944
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Exosomes serve as critical mediators in driving therapeutic resistance among tumor cells by delivering bioactive molecules, including circular RNAs (circRNAs). Through bioinformatics mining of public databases, we identi...Exosomes serve as critical mediators in driving therapeutic resistance among tumor cells by delivering bioactive molecules, including circular RNAs (circRNAs). Through bioinformatics mining of public databases, we identified circ_0097112 as a circular RNA implicated in icotinib resistance in lung adenocarcinoma (LUAD). Our subsequent experiments revealed that circ_0097112 was specifically upregulated in EGFR-TKI-resistant cells and in their secreted exosomes. To elucidate the functional role of circ_0097112 in EGFR-TKI-resistant lung cancer cells, we conducted in vitro experiments demonstrating that circ_0097112 promotes proliferation and concomitantly suppresses apoptosis in LUAD cells. Confocal microscopy revealed that drug-resistant lung cancer cells encapsulate circ_0097112 within exosomal vesicles and horizontally transfer this cargo to drug-sensitive recipient cells, thereby conferring acquired resistance. To delineate the mechanistic basis by which circ_0097112 confers drug resistance, we integrated bioinformatic prediction with experimental validation, including RNA pull-down and RNA immunoprecipitation assays. Our findings demonstrated that circ_0097112 directly interacts with UPF1 protein to assemble a functional complex, thereby suppressing decay of oncogenic NRAS. This molecular event consequently activates downstream RAF/MAPK signaling, attenuating apoptosis while promoting cellular proliferation and drug resistance. Collectively, this study reveals the pivotal involvement of the circ_0097112/UPF1/NRAS axis in driving EGFR-TKI resistance in LUAD and offers a new theoretical basis for targeting circ_0097112 to reverse EGFR-TKI resistance.
Cell Signal
· 2026 Oct · PMID 42251943
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The functional significance of the CXCL10/CXCR3 chemokine axis in pancreatic ductal adenocarcinoma (PDAC) remains incompletely defined. Through integrated analysis of clinical datasets, patient samples, and functional as...The functional significance of the CXCL10/CXCR3 chemokine axis in pancreatic ductal adenocarcinoma (PDAC) remains incompletely defined. Through integrated analysis of clinical datasets, patient samples, and functional assays, we demonstrate that CXCL10 and CXCR3 are frequently overexpressed in PDAC, with high levels correlating with advanced disease and poorer overall survival. Notably, CXCR3 expression emerged as an independent prognostic indicator. Functionally, CXCL10 treatment or overexpression enhanced PDAC cell proliferation, migration, invasion, clonogenicity, and epithelial-mesenchymal transition (EMT). Conversely, CXCL10 knockdown or pharmacological CXCR3 inhibition with AMG487 suppressed these oncogenic phenotypes. Mechanistically, CXCL10 signaling activated the ERK/MAPK pathway, and ERK inhibition abolished its tumor-promoting effects. This study establishes that CXCL10 drives PDAC progression through CXCR3-dependent ERK/MAPK activation, positioning this axis as a potential therapeutic target.
Zhao X, Fu YT, Qiu NZ
… +3 more, Pan YX, Zhang HT, Wang H
Cell Signal
· 2026 Oct · PMID 42251942
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Phosphodiesterases (PDEs) constitute a superfamily of enzymes comprising 11 distinct families that hydrolyze cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), thereby precisely regulating t...Phosphodiesterases (PDEs) constitute a superfamily of enzymes comprising 11 distinct families that hydrolyze cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), thereby precisely regulating the spatiotemporal dynamics of intracellular cyclic nucleotides. Among these PDEs, PDE8 is distinguished by its high affinity and specificity for cAMP and exerts diverse biological effects. The PDE8 family comprises two genes, Pde8a and Pde8b, which are widely distributed throughout the brain and are expressed in both neuronal and glial cells. The widespread distribution of PDE8 in the brain suggests its involvement in roles of the central nervous system (CNS). In this context, dysregulation of PDE8 has been implicated in the pathogenesis of several CNS diseases, including neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. This review aimed to enhance the understanding of the role of PDE8 in the mechanisms underlying neurodegenerative diseases, while providing a theoretical foundation and potential avenues for developing novel therapeutic strategies.
Zhang M, Wang Q, Wang X
… +9 more, Zhang S, Chen Y, Li S, Zhang L, Li L, Li G, Chen D, Leng J, Ran J
Cell Signal
· 2026 Oct · PMID 42251941
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BACKGROUND: Post-myocardial infarction (MI) cardiac fibrosis is a key driver of heart failure, with dysregulated cardiac metabolism playing a central role. The specific impact of circulating fatty acid metabolites on mit...BACKGROUND: Post-myocardial infarction (MI) cardiac fibrosis is a key driver of heart failure, with dysregulated cardiac metabolism playing a central role. The specific impact of circulating fatty acid metabolites on mitochondrial function and fibrotic remodeling remains unclear. Erucic acid, a very-long-chain fatty acid found in certain edible oils, has a historical association with cardiac lipidosis, yet its causal role and mechanism in post-MI fibrosis are unknown. METHODS: We employed an integrative, two-stage strategy. First, a hypothesis-free two-sample Mendelian Randomization (MR) analysis was performed using genome-wide association study (GWAS) data for 1400 serum metabolites and MI (FinnGen consortium) to identify causal risk metabolites. Second, the top-ranked metabolite, erucic acid, was functionally validated in vivo and in vitro. A murine MI model with graded dietary erucic acid supplementation was used to assess cardiac function, fibrosis, oxidative stress, mitochondrial ultrastructure, and energy metabolism. RNA-seq was performed to elucidate global pathway alterations. Complementary in vitro studies in TGF-β-stimulated HL-1 cardiomyocytes and in vivo AAV9-mediated cardiomyocyte-specific CD36 overexpression rescue experiments were conducted to dissect the molecular mechanism involving the CD36 lipid metabolism axis. RESULTS: MR analysis identified erucic acid as a putative causal risk metabolite for MI. In mice, erucic acid levels increased post-MI, and dietary supplementation dose-dependently exacerbated cardiac dysfunction, fibrosis, oxidative stress, and mitochondrial damage. High-dose erucic acid induced a severe metabolic shift, characterized by suppressed mitochondrial oxidative phosphorylation and enhanced glycolysis. In vitro, erucic acid suppressed the CD36 pathway and downstream lipid-handling enzymes, leading to aggravated lipid peroxidation (increased 4-HNE/rH2X, decreased SOD2). Crucially, in vitro CD36 overexpression rescued these detrimental metabolic and lipotoxic effects. Furthermore, in vivo cardiomyocyte-specific CD36 overexpression via AAV9-cTNT significantly attenuated erucic acid-induced cardiac fibrosis, mitochondrial damage, lipid peroxidation, and the glycolytic shift, firmly establishing CD36 as the central mediator. CONCLUSION: This study establishes erucic acid as a causal dietary metabolite that aggravates post-MI cardiac fibrosis. Its pathogenic mechanism involves the disruption of the cardioprotective CD36 lipid metabolism pathway, leading to mitochondrial dysfunction, lipotoxicity, and a detrimental bioenergetic shift. These findings highlight erucic acid and the CD36 axis as potential targets for risk stratification and dietary intervention following MI.