Cell. Signal. [JOURNAL]
Sun
200 papers
Orphan nuclear receptors: structural mechanisms, ligand discovery, and therapeutic potential.
Liu Y, Wei S, Wang Z … +4 more , Yang H, Chen Z, Ren M, Fu X
Cell Signal · 2026 Oct · PMID 42250787 · Publisher ↗
Orphan nuclear receptors (ONRs) are members of the nuclear receptor superfamily initially identified without clearly defined endogenous high-affinity ligands. Nevertheless, increasing evidence demonstrates that they play...
Orphan nuclear receptors (ONRs) are members of the nuclear receptor superfamily initially identified without clearly defined endogenous high-affinity ligands. Nevertheless, increasing evidence demonstrates that they play essential roles in regulating metabolism, development, neural function, and tumorigenesis. Recent advances in structural biology, chemical biology, and systems biology have improved understanding of ligand recognition and regulatory mechanisms in these receptors. This review summarizes current progress in ONRs ligand research. ONRs are categorized according to their physiological roles in metabolic homeostasis, development and reproduction, and neuro-immune and cancer-related regulation, highlighting their involvement in diseases such as metabolic disorders, cancers, neurological diseases, and reproductive abnormalities. We discuss the structural basis of ligand recognition, focusing on conserved features of the ligand-binding domain (LBD) and structural variations, particularly in the α10 and AF-2 helices, that influence ligand accessibility and transcriptional regulation. Structural studies have revealed ligand-receptor complexes for representative ONRs, including ROR, HNF-4, REV-ERB, ERR, SF-1, and LRH-1, identifying ligand types such as lipids, heme, and phospholipids. In contrast, other receptors, including TR4, DAX-1, COUP-TFII, and Nur77, currently have only functional evidence supporting potential ligand interactions. Key strategies for ligand discovery include endogenous ligand co-purification, phenotype-based high-throughput screening, structural biology approaches, and structure-based virtual screening combined with molecular dynamics simulations. Major challenges include difficulties in endogenous ligand identification, context-dependent regulation, and limitations in achieving receptor subtype selectivity in drug development. Future progress will rely on integrating structural, biochemical, and multi-omics approaches to facilitate therapeutic targeting of ONRs.
Stage-specific expression dynamics of ESRRG orchestrate zygotic genome activation in mouse embryos.
Sun J, Liao S, Lin Z … +7 more , Lian X, Xu W, Liu Y, Wang X, Lin Z, Zhang D, Wang S
Cell Signal · 2026 Oct · PMID 42248279 · Publisher ↗
The estrogen-related receptor (ERR) family, comprising ESRRA (estrogen-related receptor alpha), ESRRB (estrogen-related receptor beta), and ESRRG (estrogen-related receptor gamma), plays a crucial role in regulating meta...
The estrogen-related receptor (ERR) family, comprising ESRRA (estrogen-related receptor alpha), ESRRB (estrogen-related receptor beta), and ESRRG (estrogen-related receptor gamma), plays a crucial role in regulating metabolic and developmental processes. However, the functional significance of ERRs during preimplantation embryo development remains largely unclear. In the present study, we aimed to systematically characterized ERRs expression dynamics in mouse preimplantation embryo development and elucidated the mechanistic involvement of ERRs in blastocyst formation. Our findings demonstrate that among the estrogen-related receptor family, ESRRG is uniquely and highly expressed at the 2-cell embryo stage and is essential for blastocyst formation. Knockdown of Esrrg significantly reduced global transcriptional activity in the 2-cell embryos, thereby impairing zygotic genome activation (ZGA) and disrupting the 2-cell to 4-cell embryo transition. Given the crucial role of ESRRG in ZGA, the mechanisms governing its own transcriptional regulation are of paramount interest. To this end, we searched for upstream regulators and identified trichorhinophalangeal syndrome I (TRPS1) as a key transcription factor that directly binds to the Esrrg promoter to modulate its expression. Furthermore, the TRPS1-ESRRG regulatory axis orchestrates mouse preimplantation development by controlling the expression of critical ZGA factors, such as Sp1 transcription factor and tankyrase 2. These results establish the TRPS1-ESRRG axis as a critical regulator of mouse preimplantation development through its essential role in modulating zygotic genome activation.
Targeting NFAT5 attenuates high sodium-induced vascular aging by re-sensitizing senescent smooth muscle cells to apoptosis.
Bian S, Jiang Y, Yu Y … +4 more , Li B, Dai Z, Yuan W, Zhong W
Cell Signal · 2026 Oct · PMID 42248278 · Publisher ↗
Chronic high sodium intake precipitates vascular aging; however, the molecular signaling remain poorly defined. Nuclear factor of activated T cells 5 (NFAT5) is a central regulator of the cellular osmotic stress response...
Chronic high sodium intake precipitates vascular aging; however, the molecular signaling remain poorly defined. Nuclear factor of activated T cells 5 (NFAT5) is a central regulator of the cellular osmotic stress response; however, its specific role in modulating vascular senescence signaling remains unknown. Here, we investigated whether NFAT5 signaling mediates high‑sodium-induced vascular aging and evaluated the therapeutic potential of the specific NFAT5 inhibitor KRN5. We utilized C57BL/6 J mice fed a high‑sodium diet and cultured primary vascular smooth muscle cells (VSMCs) under hypertonic conditions to model vascular aging in vivo and in vitro. Mechanistic studies, including RNA sequencing, chromatin immunoprecipitation, and luciferase reporter assays, were performed to identify NFAT5 transcriptional targets. We found high sodium accelerated vascular aging and VSMC senescence, accompanied by a marked upregulation and nuclear activation of NFAT5. KRN5 significantly attenuated these aging phenotypes and suppressed the senescence-associated secretory phenotype (SASP) in vivo. Mechanistically, activated NFAT5 conferred robust apoptosis resistance to senescent VSMCs by shifting the Bcl-2 family balance towards cell survival. Specifically, NFAT5 directly binds to a conserved region of the Bcl-XL promoter to drive its transcription. Consequently, KRN5 effectively re-sensitizing senescent VSMCs to apoptosis. Collectively, our findings identify the NFAT5 signaling pathway as a critical mechanistic link between high sodium intake and vascular aging. KRN5 is a novel senolytic strategy that dismantles the Bcl-XL-dependent survival mechanism in senescent VSMCs.
CD36 exacerbates obesity-related vascular damage by promoting ER stress and endothelial insulin signaling impairment.
Xu Q, Gu Y, Zhuo K … +10 more , Sun Y, Ma Y, Zhang Y, Zhen Y, Li R, Zhang L, Yao Y, Jia H, Liu Y, Zhou MS
Cell Signal · 2026 Oct · PMID 42242575 · Publisher ↗
Obesity-associated elevated plasma free fatty acids (FFAs) levels contribute to vascular injury and insulin resistance, but the role of CD36 remains incompletely understood. This study investigated the role of CD36 in re...
Obesity-associated elevated plasma free fatty acids (FFAs) levels contribute to vascular injury and insulin resistance, but the role of CD36 remains incompletely understood. This study investigated the role of CD36 in regulating high-fat diet (HFD)-induced metabolic disturbances and vascular dysfunction and its downstream signaling. In HFD-fed mice, CD36 knockdown lowered body weight, abdominal fat accumulation, and serum lipid profile without affecting blood glucose. Moreover, CD36 knockdown reversed HFD-induced increases in aortic reactive oxygen species (ROS) generation, endoplasmic reticulum (ER) stress. It also attenuated aortic wall thickening, fibrosis, and impaired endothelial-dependent vasorelaxation to insulin. In palmitic acid (PA)-treated human umbilical vein endothelial cells, CD36 silencing similarly alleviated PA-induced ROS production, ER stress, and increased expression of pro-inflammatory proteins, while restoring impaired insulin-stimulated AKT/eNOS phosphorylation. Mechanistically, the mitochondrial-targeted antioxidant MitoTEMPO attenuated PA-induced ROS generation, ER stress, and rescued insulin signaling, indicating mitochondrial ROS as an upstream mediator. Conversely, CD36 overexpression exacerbated PA-induced ROS production, ER stress, and insulin signaling impairment, all of which were reversed by the antioxidant NAC or the ER stress inhibitor TUDCA. These gain- and loss-of-function experiments establish CD36 as a critical upstream regulator coupling PA stimulation to mitochondrial ROS and subsequent ER stress. Notably, as systemic CD36 knockdown was used in vivo, the potential contribution of vascular smooth muscle CD36 cannot be excluded. In conclusion, CD36 aggravates obesity-related vascular injury by promoting ROS-dependent ER stress, leading to endothelial insulin signaling impairment. Targeting CD36 or its downstream oxidative/ER stress pathways may represent a promising therapeutic strategy for obesity-associated vascular complications.
VDAC1 mediates LPS-induced T cell inflammation via mtDNA release and cGAS-STING activation.
Yuqian R, Guangyao Z, Yucai Z … +3 more , Yun C, Jie G, Yiping Z
Cell Signal · 2026 Oct · PMID 42242574 · Publisher ↗
Sepsis, a life-threatening condition characterized by dysregulated immune responses, leads to high mortality and morbidity. While splenic T cells are pivotal in systemic inflammation, their underlying mechanisms remain e...
Sepsis, a life-threatening condition characterized by dysregulated immune responses, leads to high mortality and morbidity. While splenic T cells are pivotal in systemic inflammation, their underlying mechanisms remain elusive. Here, we investigated the impact of bacterial endotoxin lipopolysaccharide (LPS) on mouse spleen tissue and primary T cells. LPS challenge provoked splenic inflammation, as evidenced by elevated levels of TNF-α, IFN-γ, IL-6, and IL-18 in whole spleen tissue. Transcriptomic profiling of whole spleen tissue implicated the cytosolic DNA-sensing pathway. Mechanistic studies in purified primary splenic CD3 T cells revealed that LPS triggered mitochondrial dysfunction, characterized by increased mitochondrial ROS (mtROS), Ca mobilization, and mitochondrial DNA (mtDNA) release into the cytosol, concurrent with VDAC1 oligomerization. Mechanistically, VDAC1 oligomerization was essential for LPS-induced mtDNA release and subsequent activation of the cGAS-STING-TBK1 axis. Notably, the VDAC1 oligomerization inhibitor VBIT-12 reversed cGAS-STING activation and cytokine expression. Collectively, our findings unveil a novel pathway wherein LPS induces VDAC1 oligomerization, leading to mtDNA leakage and activation of the cGAS-STING-TBK1 pathway in T cells, thereby fueling inflammation. This mechanism not only deepens our understanding of T cell-mediated immunopathology in endotoxemia but also highlights VDAC1 and associated mitochondrial function as potential therapeutic targets for sepsis and related inflammatory diseases.
Notch2-expressing regulatory T cells attenuate allergic rhinitis by downregulating MHC class II expression on dendritic cells.
Zhou YT, Xi Y, Zhong D … +6 more , Xu S, Yang R, Qiao YL, Kong YG, Jiao WE, Chen SM
Cell Signal · 2026 Oct · PMID 42242573 · Publisher ↗
AIMS: To investigate the role of Notch2-expressing regulatory T cells (Notch2 Tregs) in modulating the function of dendritic cells (DCs) and their impact on the development of allergic rhinitis (AR). METHODS: Peripheral...
AIMS: To investigate the role of Notch2-expressing regulatory T cells (Notch2 Tregs) in modulating the function of dendritic cells (DCs) and their impact on the development of allergic rhinitis (AR). METHODS: Peripheral blood mononuclear cells (PBMC) from patients with allergic rhinitis (AR) and Control groups were analyzed by flow cytometry to quantify Notch2 Tregs. Murine T cells were isolated and transduced with a lentiviral vector overexpressing Notch2 to assess changes in the immunosuppressive function of Tregs. Scanning electron microscopy (SEM) was performed to visualize the morphological interactions between Tregs and Bone marrow-derived dendritic cells (BMDCs). BMDCs were cocultured with Notch2-overexpressing or control Tregs in direct-contact and Transwell coculture systems to evaluate changes in surface MHC class II (MHC II) expression. In vivo, Notch2-overexpressing Tregs were adoptively transferred into a conventional AR mouse model, after which the Treg and DC frequencies, surface MHC II expression, and allergic inflammatory responses were assessed. RESULTS: Patients with AR had a significantly lower frequency of peripheral Notch2 Tregs than controls (P < 0.01), and Notch2 Treg frequency was negatively correlated with allergen-specific IgE levels and TNSS (P < 0.01). In vitro, Notch2 enhanced the immunosuppressive function of Tregs, increased MHC II expression on Tregs, and decreased MHC II expression on DCs. In vivo, adoptive transfer of Notch2-overexpressing Tregs significantly alleviated allergic inflammation in AR mice by reducing MHC II expression on DCs (P < 0.05). CONCLUSION: Notch2 attenuates allergic inflammation in AR by enhancing Treg immunosuppressive function and downregulating MHC II expression on DCs. Notch2 in Tregs may represent a novel therapeutic target for allergic airway diseases.
Liver-brain axis mechanism underlying central immune remodeling triggered by peripheral hepatic damage.
Tian X, Ren Y, Chen Y … +2 more , Cheng X, Wei J
Cell Signal · 2026 Oct · PMID 42242572 · Publisher ↗
Liver dysfunction and various hepatic disorders cause neuropsychiatric abnormalities including depression, anxiety, cognitive impairment and personality changes through liver-brain axis imbalance, greatly worsening patie...
Liver dysfunction and various hepatic disorders cause neuropsychiatric abnormalities including depression, anxiety, cognitive impairment and personality changes through liver-brain axis imbalance, greatly worsening patient prognosis. The liver-brain axis acts as a bidirectional network via neural, humoral, immune and gut microbiota pathways, and its disruption dominates liver disease-related central nervous system (CNS) injury. Toxic metabolites such as bilirubin activate the transient receptor potential cation channel subfamily M member 2 (TRPM2)-spleen tyrosine kinase (SYK)-nuclear factor kappa-B (NF-κB) pathway in microglia, triggering excessive glutamatergic synapse phagocytosis in the anterior cingulate cortex (ACC) and sustained neuroinflammation with irreversible neural circuit damage. This review summarizes the pathogenesis of neuropsychiatric complications induced by liver dysfunction and liver transplantation, focusing on blood-brain barrier (BBB) disruption, systemic immune activation, neurotransmitter imbalance and resident immune cell phenotypic shifts. It clarifies four liver-brain axis regulatory pathways, highlights microglial central functions, and addresses gut-liver-brain axis crosstalk, meningeal immunity, choroid plexus barrier damage and circadian rhythm disturbance. It also concludes diagnostic biomarkers including bilirubin and fibroblast growth factor 21 (FGF21), alongside therapeutic targets covering the TRPM2-SYK-NF-κB pathway, microglial polarization and gut microbiota. This study provides a unified theoretical framework for clinical diagnosis, risk stratification and targeted treatment of liver disease-related neuropsychiatric complications, and explains CNS dysfunction mechanisms underlying metabolic dysfunction-associated steatotic liver disease (MASLD), liver cirrhosis and acute-on-chronic liver failure.
PFKFB4 downregulation impairs decidualization via disturbing the glycolysis and GSK3β/β-catenin pathway and contributes to preeclampsia.
Li X, Zeng Y, Liu Y … +2 more , Xu Y, Zhang C
Cell Signal · 2026 Oct · PMID 42235627 · Publisher ↗
Preeclampsia (PE), a pregnancy-specific complication threatening maternal and fetal health, has an elusive pathogenesis. While placental dysplasia is a core driver, decidualization is essential for placentation. Our prio...
Preeclampsia (PE), a pregnancy-specific complication threatening maternal and fetal health, has an elusive pathogenesis. While placental dysplasia is a core driver, decidualization is essential for placentation. Our prior RNA sequencing identified significant downregulation of the key glycolytic enzyme PFKFB4 in decidual tissue from severe PE (sPE) patients. Here, we confirmed markedly lower PFKFB4 expression in sPE decidual tissue than in normal pregnant (NP) women. In in vitro artificial decidualization models, PFKFB4 expression increased significantly with decidualization progression, and siRNA-mediated PFKFB4 knockdown strongly impaired this process. Reducing glucose consumption, lactate production, cell proliferation, and migration. Co-immunoprecipitation (Co-IP) experiments showed that PFKFB4 interacts with GSK3β; PFKFB4 knockdown inhibited the GSK3β/β-catenin pathway, which, on the one hand, further suppressed glycolysis by downregulating LDHA and inducing cellular energy depletion, and on the other hand, decreased the expression of proliferation-related genes, thereby inhibiting cell proliferation and migration at energy metabolism and gene expression levels, and ultimately leading to decidualization defects. In summary, PFKFB4 is a dual regulator of aerobic glycolysis and the GSK3β/β-catenin pathway in decidualization; its downregulation in sPE impairs decidualization, potentially reducing trophoblast invasion and triggering placental dysplasia, highlighting PFKFB4 as a potential PE biomarker and therapeutic target.
IRF5 promotes the polarization of M1 macrophages and aggravates pulmonary inflammation in connective tissue disease-related interstitial lung disease (CTD-ILD) by regulating IFN-β.
Chen S, Ming Q, Yi L … +1 more , Wang X
Cell Signal · 2026 Oct · PMID 42235626 · Publisher ↗
BACKGROUND: Interferon regulatory factor 5 (IRF5) plays a vital role in proinflammatory M1 macrophages and is involved in their polarization. We aimed to explore the mechanism of action by which IRF5 participates in pulm...
BACKGROUND: Interferon regulatory factor 5 (IRF5) plays a vital role in proinflammatory M1 macrophages and is involved in their polarization. We aimed to explore the mechanism of action by which IRF5 participates in pulmonary inflammation in connective tissue disease-related interstitial lung disease (CTD-ILD). METHODS: mRNA and protein levels were determined by qRT-PCR and Western blotting. Chromatin immunoprecipitation (ChIP) assays were conducted to confirm the targeted relationship between IRF5 and interferon (IFN)-β. ELISA was performed to measure the levels of proinflammatory factors (interleukin (IL)-6, TNF-α, and IL-1β). IRF5 and CD86 expression levels were analyzed by flow cytometry. The nuclear location of IRF5 was detected by immunofluorescence. A double luciferase reporter assay was performed to confirm that IRF5 targets the IFN-β promoter. Hematoxylin and eosin (HE) staining was conducted to assess the histopathology of pulmonary. RESULTS: IRF5 and IFN-β levels in peripheral blood were increased in CTD-ILD patients. IRF5 enhanced IFN-β expression by directly binding to its promoter. IRF5 promoted the M1-type polarization of macrophages by activating IFN-β. MS19 suppressed IFN-β expression by inhibiting the activation of IRF5. MS19 repressed M1-type polarization of RAW264.7 cell induced by LPS- through regulating IRF5. MS19 improved pulmonary inflammation in CTD-ILD model mice by inhibiting the M1-type polarization of macrophages via the IRF5/IFN-β axis. CONCLUSION: IRF5 activated IFN-β transcription by targeting the IFN-β promoter, ultimately promoting the M1-type polarization of macrophages and aggravating inflammation in CTD-ILD, and the effects were alleviated by treated with MS19.
Role of homocysteine in renal tubular epithelial-mesenchymal transition: N-homocysteinylation of β-catenin impairs FUNDC1-dependent autophagy and mitochondrial quality control.
Lei Y, Guo F, Sun H … +2 more , Huang J, Zhao Y
Cell Signal · 2026 Oct · PMID 42235625 · Publisher ↗
Given the nephrotoxicity of hyperhomocysteinemia and the key role of mitophagy in the homeostasis of kidney, this study investigated the β-catenin/FUNDC1/mitochondrial quality control axis to elucidate the mechanisms und...
Given the nephrotoxicity of hyperhomocysteinemia and the key role of mitophagy in the homeostasis of kidney, this study investigated the β-catenin/FUNDC1/mitochondrial quality control axis to elucidate the mechanisms underlying homocysteine-induced renal tubular fibrosis. A mouse model of hyperhomocysteinemia was established via continuous supplementation of homocysteine. Western blot quantified key proteins associated with autophagy (FUNDC1, LC3, p62), fibrosis (fibronectin, α-SMA, Snail1), β-catenin signaling, and kidney injury (KIM-1). Immunostaining assessed renal spatial distribution of β-catenin, FUNDC1, α-SMA, and fibronectin, while transmission electron microscopy visualized mitochondrial ultrastructural changes. ChIP and dual-luciferase reporter assays verified the transcriptional target. Meanwhile, IP combined with mass spectrometry (MS), molecular modeling, and site-directed mutagenesis identified the modification site. β-catenin signaling inhibition by homocysteine resulted in diminished FUNDC1 expression within renal tubular epithelial cells, simultaneously suppressing autophagy and facilitating renal tubular fibrosis. β-catenin overexpression enhanced FUNDC1 expression, thereby rescuing homocysteine-suppressed autophagy and effectively mitigating renal tubular epithelial-mesenchymal transition (EMT). FUNDC1 overexpression mitigated homocysteine-induced cellular stress, further enhanced autophagy and mitochondrial quality control, and alleviated renal tubular EMT. Further, dual-luciferase reporter assays and ChIP confirmed FUNDC1 as a β-catenin transcriptional target. IP combined with MS, molecular modeling, and site-directed mutagenesis experiments revealed that homocysteine induced N-homocysteinylation of β-catenin at Lys49, which remodeled β-catenin's local structure to promote Ser45 phosphorylation and subsequent β-catenin degradation. Conclusively, homocysteine induces N-homocysteinylation of β-catenin at Lys49 to promote its degradation, thereby inhibiting β-catenin-mediated transcriptional activation of FUNDC1, disrupting autophagy and mitochondrial quality control, and ultimately inducing renal tubular EMT.
UCA1 facilitates endometriosis progression through EIF4A3-mediated stabilization of E2F1 mRNA and enhanced glycolysis.
Cao Y, Wang H, Gou Y … +7 more , Zhang H, Liu J, Bai R, Liang Z, Zhao Y, Han X, Zhang Z
Cell Signal · 2026 Oct · PMID 42235624 · Publisher ↗
Long non-coding RNA Urothelial carcinoma-associated 1 (UCA1) is a pivotal regulator in the progression of endometriosis (EMs), yet its mechanistic role remains elusive. This study identified UCA1 as a factor promoting gl...
Long non-coding RNA Urothelial carcinoma-associated 1 (UCA1) is a pivotal regulator in the progression of endometriosis (EMs), yet its mechanistic role remains elusive. This study identified UCA1 as a factor promoting glycolysis through bioinformatic screening and functional validation. Ectopic endometrial lesions exhibited significant UCA1 upregulation compared to normal endometrial tissues. In ectopic endometrial stromal cells, UCA1 knockdown suppressed glycolytic activity, evidenced by diminished glucose uptake and lactate production, while rescue experiments demonstrated that overexpression of E2F Transcription Factor 1 (E2F1) reversed this metabolic suppression. Mechanistically, UCA1 recruited eukaryotic translation initiation factor 4A3 (EIF4A3) to stabilize E2F1 mRNA, establishing an RNA-protein complex confirmed by RNA immunoprecipitation, RNA pull-down, and fluorescence in situ hybridization assays. Further experiments have demonstrated that EIF4A3 directly targets the 3'-untranslated region (UTR) of E2F1. Chromatin immunoprecipitation assays demonstrated that E2F1 binds to the promoter of pyruvate kinase isozyme type M2 (PKM2), thereby activating its transcription and linking UCA1-mediated E2F1 regulation to glycolytic reprogramming. In vivo validation using a subcutaneous xenograft model indicated that silencing UCA1 significantly inhibited the growth of endometriotic lesions. These findings support a UCA1/EIF4A3/E2F1/PKM2 regulatory axis that drives EMs progression through metabolic alterations. This study provides evidence for UCA1 as both a disease-promoting effector and a valuable therapeutic target, with implications for developing diagnostic and treatment strategies that target lncRNA-mediated metabolic dysregulation in EMs.
Drug repurposing for pancreatic cancer: Lomitapide Mesylate as a potent HK2 inhibitor discovered via virtual screening.
Tan X, Zhang Y, Liu M … +11 more , Wang F, Huang B, Wang D, Wang Y, Gao J, Si Z, Yang X, Liu L, Li Z, Hu L, Wang P
Cell Signal · 2026 Oct · PMID 42235623 · Publisher ↗
Pancreatic cancer has an early diagnosis rate below 5% and is largely resistant to conventional chemotherapy. Aerobic glycolysis, a metabolic hallmark, drives Epithelial-Mesenchymal Transition (EMT) to promote tumor prog...
Pancreatic cancer has an early diagnosis rate below 5% and is largely resistant to conventional chemotherapy. Aerobic glycolysis, a metabolic hallmark, drives Epithelial-Mesenchymal Transition (EMT) to promote tumor progression and drug resistance. Hexokinase 2 (HK2) is the rate-limiting enzyme that initiates glycolysis. It is specifically overexpressed in pancreatic cancer cells and is a potential therapeutic target. To identify HK2 inhibitors, we performed structure-based virtual screening of over 70,000 compounds. The top candidate, Lomitapide Mesylate (LM), was validated through molecular docking, molecular dynamics simulations, Drug Affinity Responsive Target Stability (DARTS), and Cellular Thermal Shift Assay (CETSA), confirming direct HK2 binding. In vitro, LM inhibited HK2 activity, exerting anti-proliferative and pro-apoptotic effects. In a mouse organoid-derived xenograft model, LM monotherapy suppressed tumor growth. Importantly, LM combined with gemcitabine significantly enhanced anti-tumor efficacy, indicating potential to reverse gemcitabine resistance. Mechanistically, this synergy was linked to LM-mediated reversal of HK2-driven EMT. Thus, LM inhibits HK2 to block EMT and synergize with gemcitabine, offering a novel therapeutic strategy.
ELK1-YBX1 signaling promotes cisplatin resistance via ferroptosis adaptation in bladder cancer.
Luo Y, Ma J, Wang C … +10 more , Xiong W, Zhang X, Zhang B, Fu Y, Zhang X, Wang J, Zhang H, Zheng Y, Lu J, Shang P
Cell Signal · 2026 Oct · PMID 42229737 · Publisher ↗
Bladder cancer (BC) is one of the most common malignancies of the urinary system, and chemoresistance remains a major obstacle limiting the clinical efficacy of cisplatin-based chemotherapy. Elucidating the mechanisms un...
Bladder cancer (BC) is one of the most common malignancies of the urinary system, and chemoresistance remains a major obstacle limiting the clinical efficacy of cisplatin-based chemotherapy. Elucidating the mechanisms underlying cisplatin resistance may facilitate the identification of potential therapeutic targets and ultimately improve patient outcomes. In this study, we found that Y-box binding protein 1 (YBX1) was upregulated in bladder cancer tissues with poor chemotherapeutic response as well as in cisplatin-resistant bladder cancer cell lines, where it promoted tumor cell proliferation and invasion. Functional assays demonstrated that depletion of YBX1 significantly enhanced cisplatin sensitivity in both in vitro and in vivo. Mechanistically, elevated YBX1 expression was associated with reduced ferroptosis sensitivity in cisplatin-resistant cells. Although YBX1 induced autophagy and was accompanied by a reduction in glutathione peroxidase 4 (GPX4) protein levels, the overall enhancement of intracellular antioxidant capacity in resistant cells may partially offset the increased susceptibility to ferroptosis caused by GPX4 degradation. Furthermore, we identified the transcription factor ELK1 as an upstream regulator that transcriptionally upregulates YBX1, while YBX1 may contribute to the cisplatin-resistant phenotype through activation of the p62-NRF2-associated antioxidant pathway. Collectively, these findings highlight a critical role of YBX1 in cisplatin resistance and suggest that targeting YBX1 may represent a promising strategy for overcoming cisplatin-based chemoresistance in bladder cancer.
RING1 is an Integrin α5 E3 ubiquitin ligase and inhibits esophageal squamous cell carcinoma cell migration and metastasis.
Guo J, Zhao Y, Sun Y … +7 more , Zuo S, Li W, Yang Y, Wu C, Yong W, Zhao F, Hou S
Cell Signal · 2026 Oct · PMID 42229736 · Publisher ↗
Esophageal squamous cell carcinoma (ESCC) is an extremely aggressive malignancy associated with dismal prognosis and high mortality, primarily due to metastasis, with cell migration being a critical component of the meta...
Esophageal squamous cell carcinoma (ESCC) is an extremely aggressive malignancy associated with dismal prognosis and high mortality, primarily due to metastasis, with cell migration being a critical component of the metastatic process. Ring finger protein 1 (RING1), an E3 ubiquitin ligase, has been reported as an important regulator in tumorigenesis. However, its specific functions and substrates in ESCC remain to be elucidated. Here, we found that RING1 acted in a catalytic domain-dependent manner to inhibit ESCC cell migration, but had no effect on cell proliferation. Interestingly, we confirmed that RING1 inhibited cell adhesion, spreading, and migration by regulating Integrin α5/FAK pathway in ESCC. Mechanistically, we identified Integrin α5 as a new substrate of RING1. RING1 could bind and destabilize Integrin α5 via K11-linked ubiquitination. Overexpression of RING1 resulted in the degradation of Integrin α5 and suppressed cell migration in ESCC cells, especially under fibronectin-coated condition. Re-expression of Integrin α5 rescued RING1-mediated suppression of ESCC cell adhesion, spreading, and migration. Knockdown of Integrin α5 could abrogate RING1-mediated inhibitory effects on cell adhesion, spreading, migration, and tumor metastasis. Altogether, our findings provide new mechanistic insights into RING1-mediated inhibition of tumor metastasis via binding to Integrin α5, highlighting the RING1/Integrin α5/FAK axis as a promising target for the treatment of metastatic ESCC.
STC2 mediates hypoxia-induced immunosuppression and tumorigenesis in hepatocellular carcinoma.
Li X, Pan Z, Ma Y … +6 more , Wang B, Liu W, Chen Y, Yang Y, Yang Y, Tian X
Cell Signal · 2026 Oct · PMID 42217552 · Publisher ↗
BACKGROUND: Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with a poor prognosis and limited therapeutic options. There is a pressing need to identify novel prognostic biomarkers and therapeutic targets...
BACKGROUND: Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with a poor prognosis and limited therapeutic options. There is a pressing need to identify novel prognostic biomarkers and therapeutic targets, particularly among secreted proteins which play critical roles in tumor progression and the tumor microenvironment. METHODS: We conducted an integrated bioinformatic analysis of transcriptomic data from TCGA-LIHC and GEO datasets to identify dysregulated secretory proteins and construct a prognostic model. The top candidate, STC2, was selected for functional validation. Immune cell infiltration was analyzed using ESTIMATE and CIBERSORT algorithms. The functional role of STC2 was investigated through in vitro assays including siRNA knockdown, overexpression, cell proliferation, colony formation, and wound healing. Mechanisms of transcriptional regulation were assessed by chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays. RESULTS: We established a robust risk-scoring model based on a signature of secretory proteins, which identified STC2 as a key prognostic determinant. High STC2 expression was linked to an immunosuppressive tumor microenvironment characterized by enriched macrophage infiltration. Furthermore, STC2 expression was significantly upregulated in HCC tissues and strongly associated with advanced tumor stage, metastasis, and reduced patient survival. Mechanistically, we demonstrated that the transcription factor HIF-1α directly binds to the STC2 promoter and activates its transcription. Functional studies confirmed that STC2 drives HCC cell proliferation, clonogenicity, and migration. Transcriptomic profiling further indicated that STC2 is involved in activating the PI3K-Akt and HIF-1α signaling pathways. Moreover, STC2 is highly expressed in tumor regions and is associated with M2-type macrophage polarization in TME. CONCLUSION: Our study unveils STC2 as a pivotal hypoxia-induced oncogene in HCC, directly transcriptionally activated by HIF-1α. STC2 fosters tumor progression by enhancing malignant phenotypes and sculpting an immune-suppressive microenvironment, positioning it as a promising prognostic biomarker and an attractive therapeutic target for HCC.
OVOL1 targets YAP to suppress esophageal squamous cell carcinoma progression.
Yan Z, Li Y, Li J … +6 more , Huang S, Lan H, Hu G, Xie C, Qi G, Gan J
Cell Signal · 2026 Oct · PMID 42217551 · Publisher ↗
BACKGROUND: Abnormal regulation of OVO-like proteins (OVOLs) has been recognized as an important contributor to cancer development. Ovo like transcriptional repressor 1 (OVOL1), a member of the OVOL family, has been repo...
BACKGROUND: Abnormal regulation of OVO-like proteins (OVOLs) has been recognized as an important contributor to cancer development. Ovo like transcriptional repressor 1 (OVOL1), a member of the OVOL family, has been reported to function either as a tumor suppressor or as an oncogene in different cancer types; however, its role in esophageal squamous cell carcinoma (ESCC) has not been clearly defined. METHODS: The expression of OVOL1 in ESCC was examined using multiple independent patient cohorts, and its clinical significance was further evaluated. The functional role of OVOL1 in ESCC cells was determined through both in vitro and in vivo experiments. To elucidate the underlying mechanisms, RNA-seq, luciferase reporter, co-immunoprecipitation, and chromatin immunoprecipitation (ChIP) assays were performed. RESULTS: Reduced OVOL1 expression was frequently observed across multiple ESCC cohorts and was associated with poor clinical outcomes. Both in vitro and in vivo experiments showed that enforced OVOL1 expression suppresses ESCC cell proliferation, stemness-associated traits, and lung metastasis caused by tail vein injection of ESCC cells in mice, whereas OVOL1 knockdown enhances these malignant behaviors. Mechanistically, OVOL1 represses Yes1-associated transcriptional regulator (YAP) transcription, which is likely achieved through a histone deacetylase (HDAC)-dependent mechanism, thereby limiting ESCC progression. CONCLUSION: OVOL1 acts as a tumor suppressor in ESCC, in part by suppressing YAP.
miR-494-3p/G6PC/FOXO1 signaling axis drives autophagy-mediated breast cancer progression and predicts poor prognosis.
Zhu K, Du P, Li W … +3 more , Feng X, Han A, Chen L
Cell Signal · 2026 Sep · PMID 42217550 · Publisher ↗
The role of the glucose-6-phosphatase catalytic subunit (G6PC) in breast cancer (BC) remains poorly understood. In this study, we aimed to investigate the expression and prognosis of G6PC in BC and to elucidate the molec...
The role of the glucose-6-phosphatase catalytic subunit (G6PC) in breast cancer (BC) remains poorly understood. In this study, we aimed to investigate the expression and prognosis of G6PC in BC and to elucidate the molecular mechanisms by which G6PC regulates the malignant progression of BC. G6PC was markedly upregulated in BC tissues and cells, and elevated G6PC expression was associated with poor patient prognosis. Functional assays showed that G6PC promoted BC cell proliferation, migration, invasion, epithelial-mesenchymal transition, and cell cycle progression, while enhancing autophagy. G6PC accelerates tumor growth and lung metastasis in vivo. Mechanistically, miR-494-3p was found to directly target G6PC and was downregulated in BC; the loss of miR-494-3p led to the upregulation of G6PC expression. Further analyses showed that G6PC interacts with FOXO1 to regulate autophagy, and rescue experiments demonstrated that the miR-494-3p/G6PC/FOXO1 axis is essential for the pro-malignant effects of G6PC in BC. Collectively, these findings identified G6PC as an adverse prognostic factor and uncovered a novel miR-494-3p/G6PC/FOXO1 signaling axis that drives BC progression by modulating autophagy, highlighting a potential target for therapeutic intervention.
Immune cells in chronic prostatitis/chronic pelvic pain syndrome: From pathological mechanisms to therapeutic opportunities.
Li Z, Yan R, Lao Y … +6 more , Guan X, Xiao X, He H, Li R, Tao Y, Dong Z
Cell Signal · 2026 Sep · PMID 42208635 · Publisher ↗
Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common urological disorder characterized by persistent pelvic pain or discomfort as its core symptom. It is frequently accompanied by lower urinary tract sy...
Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common urological disorder characterized by persistent pelvic pain or discomfort as its core symptom. It is frequently accompanied by lower urinary tract symptoms and significant psychological burden, severely impacting patients' quality of life. The etiology of this condition is complex, and treatment is challenging. Increasing basic and clinical research indicates that abnormal immune system activation and its mediated chronic inflammatory response are central mechanisms in the onset, maintenance, and chronicity of CP/CPPS symptoms. This systematic review examines the roles of key immune cells in the CP/CPPS pathophysiological process, focusing on the phenotypic characteristics and functional states of T lymphocytes (particularly Th1, Th17, and Treg cells), macrophages (M1 and M2 types), neutrophils, and mast cells, as well as their contributions to disease initiation, progression, and chronicity. These immune cells do not function in isolation but collectively construct a dynamic, self-amplifying immunological inflammatory microenvironment through cytokine networks, chemokine gradients, and intercellular interactions. Integrating existing literature evidence, this review mechanistically outlines the abnormal characteristics of major immune cells in CP/CPPS and their roles in inflammation maintenance, pain generation, and tissue remodeling. It emphasizes the mechanisms of Th1/Th17-Treg imbalance, macrophage M1/M2 polarization abnormalities, and the bridging role of neutrophils and mast cells in the immune-neural axis. Furthermore, it summarizes potential therapeutic strategies targeting immune cells and their key signaling pathways, aiming to provide a systematic theoretical basis for CP/CPPS pathogenesis research and precision interventions.
The lactate-GPR81-AMIGO2 axis promotes pancreatic ductal adenocarcinoma progression and predicts poor prognosis.
Zhang Q, Wang L, Yu Z … +4 more , Xu T, Tang J, Zhu Z, Zhou J
Cell Signal · 2026 Oct · PMID 42208634 · Publisher ↗
Pancreatic ductal adenocarcinoma (PDAC) carries an extremely poor prognosis. Excessive lactate accumulation occurs in the hypoxic tumor microenvironment, yet the roles of lactate receptor GPR81 and adhesion molecule AMIG...
Pancreatic ductal adenocarcinoma (PDAC) carries an extremely poor prognosis. Excessive lactate accumulation occurs in the hypoxic tumor microenvironment, yet the roles of lactate receptor GPR81 and adhesion molecule AMIGO2 and their crosstalk in PDAC remain unclear. This study applied PDAC data from TCGA/GTEx databases, 83 clinical samples from Zhongda Hospital, CFPAC1/CAPAN2/CAPAN1 cell lines, and BALB/c-nu nude mouse models. Lactate levels were detected; Expression of GPR81, AMIGO2 and related molecules were measured by qPCR, IHC and Western Blot. GPR81/AMIGO2 were regulated via lentivirus, siRNA or plasmid transfection. Cell functions and tumorigenesis were evaluated by CCK-8, wound-healing, Transwell and in vivo assays. RNA-seq and enrichment analyses screened differential genes; Cox regression and nomogram assessed the prognostic value of AMIGO2. Lactate concentration and GPR81 expression were significantly increased in PDAC and correlated with poor prognosis. High-lactate conditions upregulated GPR81 expression under both energy deficiency and normal energy supply conditions. GPR81 knockdown inhibited PDAC cell proliferation, migration and tumorigenicity, whereas overexpression showed the opposite effects independently of lactylation. GPR81 activated the TGFβ2-pSMAD2/3-ZEB1 pathway by upregulating AMIGO2, and AMIGO2 rescued the inhibitory effects caused by GPR81 knockdown. AMIGO2 was highly expressed in PDAC and acted as an independent prognostic factor. The prognostic model combining AMIGO2 and TNM staging system showed superior predictive accuracy. Our results elucidate that AMIGO2 mediates lactate-GPR81-driven PDAC progression through the TGFβ2-pSMAD2/3-ZEB1 signaling cascade. AMIGO2 is an independent prognostic factor for PDAC, and its integration with the TNM staging system yields a preliminary prognostic model with improved predictive performance in our single-center cohort.
OSBPL2 deficiency impaired autophagy and induced apoptosis in auditory cells via AMPK-TFEB signalling pathway.
Wang X, Li T, Jiang J … +7 more , Lu Y, Chen Z, Pang X, Xing G, Cao X, Wei Q, Yao J
Cell Signal · 2026 Sep · PMID 42191057 · Publisher ↗
OSBPL2 was identified as a causal gene responsible for autosomal dominant non-syndromic hearing loss. Previous study revealed that OSBPL2-mediated AMPK signalling was crucial for cholesterol-homeostasis in inner ear. AMP...
OSBPL2 was identified as a causal gene responsible for autosomal dominant non-syndromic hearing loss. Previous study revealed that OSBPL2-mediated AMPK signalling was crucial for cholesterol-homeostasis in inner ear. AMPK is the downstream component of a kinase cascade as the key regulator of autophagy, metabolism, cell growth and apoptosis, etc. In addition, OSBPL2 deficiency could lead to autophagy impairment in auditory cells, indicating the potential role of OSBPL2-mediated AMPK signalling in autophagy. In the present study, autophagy function was characterized in hair cells (HCs) of Osbpl2-knockout mice and in Osbpl2-knockdown HEI-OC1 cells. The results showed that OSBPL2 deficiency impaired autophagy by inhibiting AMPK-TFEB signalling, resulting in aberrant accumulation of lipid droplets and apoptosis in auditory cells, which could be partially reversed by trehalose treatment. This study revealed the implications of OSBPL2 for autophagy in auditory cell and contributed to elucidating the pathogenesis of OSBPL2 mutations in hearing loss.
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