Cell. Signal. [JOURNAL]
Sun
200 papers
Lipid metabolic reprogramming of CD8 T cells in the tumor microenvironment.
Mao L, Zou J, Jin H … +3 more , Liao W, Li Y, Wu D
Cell Signal · 2026 Jul · PMID 41881092 · Publisher ↗
Metabolic reprogramming within the tumor microenvironment is a critical driver of CD8 T cell dysfunction that limits the efficacy of cancer immunotherapy. While glucose and amino acid deprivation are well-characterized,...
Metabolic reprogramming within the tumor microenvironment is a critical driver of CD8 T cell dysfunction that limits the efficacy of cancer immunotherapy. While glucose and amino acid deprivation are well-characterized, lipid metabolic rewiring has emerged as a fundamental determinant of T cell fate. This review systematically examines the mechanisms by which the tumor microenvironment disrupts CD8 T cell lipid metabolism to promote functional exhaustion and ferroptosis. We first discuss how local stressors such as hypoxia and acidosis alongside systemic host factors including obesity and hyperlipidemia synergistically impose a metabolic siege on infiltrating T cells. We then detail the molecular pathways of dysregulation revealed by recent lipidomic profiling, including CD36-mediated uptake of oxidized lipids that drives ferroptosis, as well as the dysregulation of cholesterol homeostasis that impairs TCR signaling and induces endoplasmic reticulum stress via the IRE1α-XBP1 axis, which directly drives the transcriptional expression of immune checkpoints. Finally, we evaluate therapeutic strategies such as pharmacological modulation of lipid transporters and metabolic engineering of CAR-T cells which hold promise for restoring metabolic fitness and reinvigorating antitumor immunity.
Mechanistic insights into sperm cyclic adenosine monophosphate (cAMP) signaling: Relevance for male infertility and contraceptive development.
Luque GM, Stival C, Oscoz-Susino N … +3 more , Krapf D, Buffone MG, Marín-Briggiler CI
Cell Signal · 2026 Jul · PMID 41881091 · Publisher ↗
Cyclic adenosine monophosphate (cAMP) signaling pathways play a pivotal role in mammalian sperm physiology, particularly in regulating capacitation, a complex series of biochemical events that enable sperm to acquire fer...
Cyclic adenosine monophosphate (cAMP) signaling pathways play a pivotal role in mammalian sperm physiology, particularly in regulating capacitation, a complex series of biochemical events that enable sperm to acquire fertilization competence. During the early stages of capacitation, an increase in cAMP concentration, driven by the activation of soluble adenylyl cyclase (sAC), activates different downstream effectors, including the protein kinase A (PKA). Activation of these pathways modulates the acquisition of hyperactivated motility in the flagellum and the occurrence of acrosomal exocytosis in the head. This review summarizes recent advances made in the last decade on this topic, with special emphasis on methodologies for analyzing cAMP dynamics and the regulation of cAMP production and its effects during capacitation. Special attention is given to the canonical mechanisms controlling sAC activity through bicarbonate and calcium, as well as emerging evidence for non-canonical modes of regulation. The complex and sometimes controversial interplay between the sAC/cAMP/PKA pathway and the calcium channel CatSper is discussed in depth, along with current knowledge in downstream cAMP effectors in sperm. Finally, the review highlights how modulation of the cAMP pathways may be exploited to either enhance sperm motility and function as a strategy to treat male infertility or, conversely, to inhibit sperm signaling as a potential non-hormonal contraceptive approach.
Potential of quercitrin in psoriasis intervention: Dual regulation of the oxidative stress-NF-κB axis and gut microbiota homeostasis.
Guo D, Wang R, Liu S … +2 more , Liu W, Wang X
Cell Signal · 2026 Aug · PMID 41881090 · Publisher ↗
BACKGROUND: Psoriasis, a chronic inflammatory skin disease, imposes a substantial clinical burden with limited long-term treatment efficacy. Quercitrin (QUE), a natural flavonoid possessing anti-inflammatory and antioxid...
BACKGROUND: Psoriasis, a chronic inflammatory skin disease, imposes a substantial clinical burden with limited long-term treatment efficacy. Quercitrin (QUE), a natural flavonoid possessing anti-inflammatory and antioxidant properties, exhibits therapeutic potential for psoriasis, yet its precise mechanism of action remains to be fully elucidated. METHODS: To evaluate the effects of QUE, LPS-stimulated HaCaT cells (modeling keratinocyte immune activation) and IMQ-induced psoriatic mice were employed. Skin pathology was assessed by PASI score and histopathological staining. Inflammatory cytokines and oxidative stress markers were measured both in vitro and in vivo using ELISA and commercial kits. NF-κB pathway expression was analyzed by Western blot (in vitro), IHC, and RT-qPCR (in vivo). Molecular docking predicted the binding of QUE to TLR4/MyD88, and 16S rRNA sequencing was used to analyze changes in gut microbiota composition. RESULTS: QUE effectively inhibited LPS-induced NF-κB activation and oxidative stress in HaCaT cells, leading to reduced release of pro-inflammatory cytokines. In IMQ-induced psoriatic mice, QUE treatment not only alleviated skin lesions and reduced splenomegaly, but also restored the structural integrity of dermal collagen and elastic fibers, thereby improving skin barrier function. Furthermore, QUE suppressed cutaneous NF-κB activation while ameliorating both systemic and local oxidative stress. Molecular docking analysis revealed that QUE directly binds to TLR4 and MyD88. Additionally, QUE restored gut microbiota homeostasis and enhanced intestinal barrier integrity. CONCLUSIONS: QUE alleviates psoriatic inflammation through synergistic regulation of the NF-κB pathway and gut microbiota homeostasis, exhibiting potential as a multi-target therapeutic agent.
Glut1-dependent lactylation drives VSMC senescence phenotype.
Tang Y, Ouyang J, Mo X … +10 more , Gan Y, Qin N, Huang M, Wu D, Wei S, Wu H, Huang Z, Qin J, Huang J, Wang H
Cell Signal · 2026 Jul · PMID 41876049 · Publisher ↗
Atherosclerosis (AS) is the leading cause of cardiovascular and cerebrovascular diseases. However, current clinical strategies to delay or treat AS are limited. Elucidating the underlying mechanisms of AS pathogenesis is...
Atherosclerosis (AS) is the leading cause of cardiovascular and cerebrovascular diseases. However, current clinical strategies to delay or treat AS are limited. Elucidating the underlying mechanisms of AS pathogenesis is critical for identifying novel therapeutic targets. Numerous studies have demonstrated that premature senescence of vascular smooth muscle cells (VSMCs) is a key contributor to AS progression, yet the molecular drivers of this process remain incompletely understood. This study reveals that membrane-bound glucose transporter 1 (Glut1), which mediates glucose uptake, is specifically upregulated in mouse aortic vascular smooth muscle cells (MOVAS) during the progression of AS. This phenomenon is accompanied by increased expression of senescence markers. In vitro experiments demonstrated that knockdown of Glut1 on MOVAS membranes significantly inhibited the senescence phenotype, whereas overexpression of Glut1 markedly exacerbated the senescence phenotype. Mechanistically, Glut1 promotes MOVAS senescence by activating the glycolysis-lactate-H3K18la signaling axis. Notably, reducing intracellular lactate levels, knocking out the lactylation writer P300, or overexpressing the lactylation eraser HDAC-1 all significantly improved the premature senescence phenotype of MOVAS. In summary, this study establishes a mechanistic link between the Glut1-lactate-H3K18la pathway and MOVAS senescence, providing a theoretical basis for understanding the metabolic-epigenetic mechanisms underlying VSMC senescence in atherosclerosis.
From palmitoylation to cholesterol metabolism: The hidden mechanism of lung tumorigenesis.
Shen L, Zhang H, Li Y … +12 more , Duan J, Zhang Y, Qu Y, Liu Y, Ye B, Zhou S, Zheng H, Luo C, Zeng K, Wang G, Dong X, Fang C
Cell Signal · 2026 Jul · PMID 41871748 · Publisher ↗
S-palmitoylation, a prevalent and reversible post-translational modification, is catalyzed by zinc finger DHHC-type palmitoyltransferases(ZDHHCs). Dysregulation of protein S-palmitoylation has been implicated in tumor de...
S-palmitoylation, a prevalent and reversible post-translational modification, is catalyzed by zinc finger DHHC-type palmitoyltransferases(ZDHHCs). Dysregulation of protein S-palmitoylation has been implicated in tumor development and progression; however, its specific role in lung adenocarcinoma (LUAD) remains largely undefined. In this study, bioinformatics tools and clinical specimens were employed to screen for crucial ZDHHCs associated with LUAD. In vitro assays (CCK-8, EDU, and colony formation) and in vivo experiments (subcutaneous xenograft tumor model) were conducted to assess the biological functions of ZDHHCs in LUAD. Mass spectrometry, co-immunoprecipitation, acyl-biotin exchange, and RNA sequencing technologies were applied to clarify the mechanisms by which ZDHHCs modulate LUAD growth. We confirmed that ZDHHC9 acted as a novel oncogene during LUAD development. Functional studies revealed that either silencing ZDHHC9 or administering a palmitoylation inhibitor could suppress LUAD cell proliferation. Mechanistic investigations showed that ZDHHC9 palmitoylated TRMT6 at cysteine 401, thereby stabilizing the TRMT6 protein. Subsequently, TRMT6 was found to upregulate SOAT1 expression in an mA methylation-dependent manner, thus increasing cholesterol esterification and promoting tumorigenesis. Moreover, the ZDHHC9-TRMT6-SOAT1 signaling axis facilitated tumor formation in nude mice by altering cholesterol metabolic homeostasis. Our results indicate that ZDHHC9-mediated S-palmitoylation serves as a bridge linking cholesterol metabolism to lung carcinogenesis. Targeting palmitoylation, along with its modifying enzymes, could be a promising strategy for treating LUAD.
TRIM69 potentiates the cGAS-STING signalling pathway by promoting STING ubiquitination.
Chen S, Yi L, Xue M … +1 more , Zheng C
Cell Signal · 2026 Jul · PMID 41865946 · Publisher ↗
The cytosolic sensor cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) is in charge of cytosolic DNA sensing and, as a result, the production of 2'3' cyclic GMP-AMP (cGAMP), which acts as a s...
The cytosolic sensor cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) is in charge of cytosolic DNA sensing and, as a result, the production of 2'3' cyclic GMP-AMP (cGAMP), which acts as a second messange molecule to activate the stimulator of interferon genes (STING) and the type I interferon (IFN-I) signalling pathway. We demonstrated that the E3 ubiquitin ligase enzyme TRIM69-induced ubiquitination of STING is necessary for cGAS-STING-mediated IFN-I production during antiviral innate immunity. A direct connection between TRIM69 and STING is essential for the ability of TRIM69 to activate the K63-linked ubiquitination of STING, which results in a significant increase in dimerization and downstream activation of TBK1. These findings suggest that TRIM69 is a novel, positive regulatory protein of the cytosolic DNA-sensing pathway, promoting the cGAS-STING signalling pathway.
PPT1 regulates mitochondrial redox by depalmitoylating PRDX3.
Zhu G, Jin L, Shen W … +4 more , Li X, Tian X, Zhang Y, Liu N
Cell Signal · 2026 Jul · PMID 41865945 · Publisher ↗
Multiple myeloma (MM) remains an incurable hematological cancer, with an enhanced antioxidant capacity that fuels disease progression. Peroxiredoxins (PRDXs), central players of redox homeostasis, are overexpressed in ca...
Multiple myeloma (MM) remains an incurable hematological cancer, with an enhanced antioxidant capacity that fuels disease progression. Peroxiredoxins (PRDXs), central players of redox homeostasis, are overexpressed in cancers including MM, and their high expression correlates with poor prognosis. However, the detailed mechanisms underlying how PRDXs are regulated in the context of redox homeostasis and MM pathogenesis remain unclear. In this study, we identify PPT1 as a promising therapeutic target that sustains PRDX3 antioxidant activity by catalyzing its depalmitoylation at the catalytic cysteine (C108). We demonstrated that genetic or chemical inhibition of PPT1 induced cytotoxicity in MM cells through a mechanism involving elevated mitochondrial reactive oxygen species (mtROS). Furthermore, PPT1 inhibition significantly suppressed the growth of xenograft tumors and increased the level of PRDX3 S-palmitoylation. Collectively, our study identifies PPT1 as the bona fide depalmitoylase of PRDX3 and establishes this axis as a promising therapeutic target in MM.
The lamin A/C-P4HB interaction axis regulates endoplasmic reticulum stress and apoptosis in myocardial ischemia-reperfusion injury via a calreticulin-associated mechanism.
Zhou J, Li X, Li N … +2 more , Wang M, Sun G
Cell Signal · 2026 Jul · PMID 41864485 · Publisher ↗
Endoplasmic reticulum stress (ERS) and apoptosis are hallmark pathological features of myocardial ischemia-reperfusion injury (MIRI). Lamin A/C, a nuclear lamina protein associated with cardiac disorders, has been implic...
Endoplasmic reticulum stress (ERS) and apoptosis are hallmark pathological features of myocardial ischemia-reperfusion injury (MIRI). Lamin A/C, a nuclear lamina protein associated with cardiac disorders, has been implicated in ERS and apoptosis regulation, yet its role in MIRI remains elusive. Meanwhile, P4HB, an ERS-associated chaperone, may interact with lamin A/C to modulate MIRI progression. We hypothesized that lamin A/C interacts with P4HB to modulate MIRI progression. We assessed the distribution of P4HB and lamin A/C in MIRI SD rat hearts and oxygen-glucose deprivation/reoxygenation (OGD/R)-treated primary neonatal rat cardiomyocytes (PNRCMs). By knocking down lamin A/C expression, we examined the impact of lamin A/C on P4HB distribution, ERS and apoptosis induced by OGD/R modeling. STRING network analysis and protein-protein docking were employed to predict the structural basis of lamin A/C/P4HB interaction. Our results demonstrated OGD/R treatment triggered P4HB nuclear envelope translocation, ERS activation, and apoptosis in PNRCMs, while those effects were attenuated by lamin A/C knockdown. The physical interaction between lamin A/C and P4HB in cardiac tissue was observed under both normal and MIRI conditions. The P4HB-lamin A/C interaction may be dynamically modulated by calreticulin. Collectively, our findings propose that lamin A/C regulates P4HB to mitigate OGD/R-induced ERS and apoptosis, potentially through a calreticulin-mediated dynamic mechanism.
circFAM53B-1 and circFAM53B-2 drive VSMC phenotypic modulation via ISG15-mediated suppression of SRF.
Zhao L, Li Y, Bi R … +8 more , Shen J, Gao Y, Song J, Zhen Z, Zheng B, Lian H, Wen J, Zhang X
Cell Signal · 2026 Jul · PMID 41861925 · Publisher ↗
Although circRNAs have been widely studied in various disease contexts, their roles in vascular smooth muscle cells (VSMCs) phenotypic modulation remain incompletely understood. This study aims to investigate the regulat...
Although circRNAs have been widely studied in various disease contexts, their roles in vascular smooth muscle cells (VSMCs) phenotypic modulation remain incompletely understood. This study aims to investigate the regulatory functions and molecular mechanisms of two newly identified circRNAs, circFAM53B-1 and circFAM53B-2, in VSMCs phenotypic switching. Here, we show that both circFAM53B-1 and circFAM53B-2 were upregulated by PDGF-BB in a KLF4-dependent manner. They decreased VSMCs contractile markers α-SMA and SM22α levels by suppressing the expression of serum response factor (SRF). Mechanistically, the PDGF-BB-KLF4-circFAM53B1/2 axis enhanced ISG15 expression, which in turn promoted SRF degradation via the ubiquitin-proteasome pathway, subsequently facilitating VSMCs phenotype switching. This study identifies circFAM53B-1 and circFAM53B-2 as key regulators of VSMCs phenotypic switching via the ISG15-SRF pathway. These findings provide new insights into the molecular mechanisms underlying vascular remodeling and suggest potential therapeutic targets for related diseases. Further research is needed to clarify the precise regulation of ISG15 by circFAM53B-1/2 and to evaluate their in vivo therapeutic potential.
PRELID2 promotes the progression of nasopharyngeal carcinoma by positively regulating the TXNDC12-GSH-GPX4 axis and inhibiting ferroptosis.
Liang T, Liu X, You X … +2 more , Xu G, Chen L
Cell Signal · 2026 Jul · PMID 41861924 · Publisher ↗
BACKGROUND: Nasopharyngeal carcinoma (NPC) treatment is challenged by advanced metastasis, high recurrence rates, and resistance to both radiotherapy and chemotherapy. PRELI domain-containing protein 2 (PRELID2) is overe...
BACKGROUND: Nasopharyngeal carcinoma (NPC) treatment is challenged by advanced metastasis, high recurrence rates, and resistance to both radiotherapy and chemotherapy. PRELI domain-containing protein 2 (PRELID2) is overexpressed in cancers and linked to poor prognosis, but its role in NPC remains unclear. METHODS: We utilized public datasets to analyze the expression characteristics and clinical prognostic significance of PRELID2 in NPC. The expression of PRELID2 in NPC cell lines was validated through Western blotting and quantitative reverse transcription PCR (qRT-PCR). The effects of PRELID2 on NPC cell proliferation, migration, and invasion were assessed using in vitro functional assays, such as CCK-8, colony formation, Transwell, wound healing assays, and an in vivo subcutaneous xenograft tumor model in nude mice. Downstream mechanisms were investigated through RNA-seq and rescue experiments. RESULTS: Both mRNA and protein levels of PRELID2 were elevated in NPC cells, and associated with poorer survival. In vitro experiments demonstrated that overexpression of PRELID2 significantly enhanced NPC cell proliferation, migration, and invasion. In vivo experiments confirmed that silencing PRELID2 markedly suppressed the growth of subcutaneous xenograft tumors in nude mice. RNA-seq and functional rescue validation revealed that PRELID2 positively regulates the expression of thioredoxin domain-containing protein 12 (TXNDC12), increasing intracellular GSH levels. The accumulation of GSH enhances GPX4 activity, effectively inhibiting ferroptosis in NPC cells and ultimately promoting tumor progression. CONCLUSION: PRELID2 promotes NPC by upregulating TXNDC12 to sustain GSH levels, thereby enhancing GPX4 activity, inhibiting ferroptosis, and driving tumor growth. Suggest PRELID2 as a potential prognostic biomarker and therapeutic target for NPC.
Molecular mechanism of S100P promotes hepatocellular carcinoma by regulating MYBL2-mediated transcription of AURKB.
Zhu L, Li G, Wang C … +3 more , Bu L, Wu X, Chen X
Cell Signal · 2026 Jul · PMID 41856224 · Publisher ↗
Hepatocellular carcinoma (HCC) progression involves the synergistic roles of S100P and AURKB. Using bioinformatics, molecular assays, and in vitro/vivo models, we show that S100P activates the RAGE/Ras/p-p38/NFκB pathway...
Hepatocellular carcinoma (HCC) progression involves the synergistic roles of S100P and AURKB. Using bioinformatics, molecular assays, and in vitro/vivo models, we show that S100P activates the RAGE/Ras/p-p38/NFκB pathway, upregulating MYBL2, which directly enhances AURKB transcription. Clinically, S100P correlates positively with AURKB expression and tumor immune suppression. HCC cells with low S100P expression showed significantly greater sensitivity to the AURKB inhibitor AZD1152-HQPA than control cells, with a 61% decrease in IC₅₀. This study reveals the S100P/MYBL2/AURKB axis as a key driver of HCC and a predictor of targeted therapy response, supporting precision treatment strategies.
Extracellular matrix stiffness drives cutaneous squamous cell carcinoma malignant progression via YAP-dependent glycolysis.
Feng Y, Zhou T, Yan C … +5 more , Wang X, Li B, Wang L, Li Y, Geng S
Cell Signal · 2026 Jul · PMID 41850468 · Publisher ↗
The extracellular matrix (ECM) stiffness is significantly elevated in cutaneous squamous cell carcinoma (cSCC) and positively correlates with Clark level, tumor thickness and poor disease-free survival, implicating ECM s...
The extracellular matrix (ECM) stiffness is significantly elevated in cutaneous squamous cell carcinoma (cSCC) and positively correlates with Clark level, tumor thickness and poor disease-free survival, implicating ECM stiffness as a driver of cSCC malignant progression. Using clinical samples, hydrogels of different stiffness, and a mouse xenograft model, we demonstrated that ECM stiffening activates the integrin-FAK-YAP mechanotransduction pathway. This activation promotes YAP nuclear translocation and YAP-TEAD1 complex formation, which in turn enhances the transcription of the glycolytic enzyme PKM2. Consequently, PKM2 upregulation drives aerobic glycolysis in cSCC cells, leading to increased proliferation, migration, apoptosis resistance, and EMT progression. Therapeutic inhibition of ECM stiffness, YAP transcriptional activity or glycolysis markedly reduces tumor growth and malignant behaviors in vivo. These findings identify a critical mechano-metabolic signaling cascade driving cSCC malignant progression, providing novel targets for therapeutic intervention against cancers associated with fibrosis and mechanical stress.
Paeoniflorin suppresses the phenotypic transformation of vascular smooth muscle cells during atherosclerosis by regulating the MAPK/NF-κB pathways and ABCA1 expression.
Zhang Y, Sun L, Li F … +2 more , Li Y, Zhou Q
Cell Signal · 2026 Jul · PMID 41850467 · Publisher ↗
BACKGROUND: The pathological environment of atherosclerosis (AS) is characterized by hyperlipidemia and chronic inflammation, which cause increased heterogeneity among vascular smooth muscle cells (VSMCs). Owing to its l...
BACKGROUND: The pathological environment of atherosclerosis (AS) is characterized by hyperlipidemia and chronic inflammation, which cause increased heterogeneity among vascular smooth muscle cells (VSMCs). Owing to its lipid-regulating and anti-inflammatory effects, paeoniflorin (Pae) inhibits VSMC phenotypic transformation, making it a promising candidate for AS treatment. METHODS: Mouse aortic VSMCs were treated with oxidized low-density lipoprotein (ox-LDL) and Pae, and the effects on cell phenotype were examined. An AS model was established by feeding ApoE mice a high-fat diet. Serum and tissue samples were collected for analysis after treatment with or without Pae oral administration. RESULTS: Pae reversed weight gain and elevated TG levels in the AS model. Oil Red O staining showed that Pae inhibited VSMC-derived foam cell formation in vitro and reduced aortic sinus plaque area, aortic wall lipid deposition, and hepatic steatosis in the AS model. Immunofluorescence staining of the aortic sinus revealed that Pae mitigated α-SMA overexpression and reversed ATP-binding cassette transporter A1 (ABCA1) downregulation. Western blotting analysis revealed that Pae inhibited ERK1/2 and p65 phosphorylation, curbed MMP2 overexpression, and restored downregulated ABCA1 expression. Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine staining, and wound healing assays demonstrated that Pae inhibited ox-LDL-induced VSMC proliferation and migration. Additionally, Pae significantly inhibited the expression of the inflammatory factors IL-6 and MCP-1 both in vivo and in vitro. CONCLUSIONS: Pae may treat AS by inhibiting VSMC phenotypic transformation.
Dimethyl fumarate alleviated DSS-induced colitis by regulating Th17/Treg balance via suppressing JAK2/STAT3 and NF-κB signaling.
Jin L, Guo F, Liang J … +8 more , Dai A, Wang Y, Yang P, Du B, Wang X, Lin D, Xi X, Guo Y
Cell Signal · 2026 Jul · PMID 41839286 · Publisher ↗
Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by immune dysregulation. Restoring Th17/Treg balance represents a promising therapeutic strategy for UC. Gut metabolism has been reported to c...
Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by immune dysregulation. Restoring Th17/Treg balance represents a promising therapeutic strategy for UC. Gut metabolism has been reported to critically regulates Th17 and Treg cell homeostasis. However, the role of fumarate in the pathogenesis of UC and the immunoregulatory effect of Dimethyl fumarate (DMF) in the treatment of UC remain unclear. Herein, results demonstrated decreased fumarate levels in colonic tissues of DSS-induced colitis mice, whereas DMF administration elevated colonic fumarate concentrations and relieved DSS-induced colitis by suppressing the inflammatory response and pro-inflammatory cytokines in vivo. Moreover, DMF treatment significantly decreased the frequency of Th17 cells, increased the frequency of Treg cells, thus improved Th17/Treg balance in vitro. Mechanistically, DMF significantly inhibited Th17 cell differentiation via interrupting JAK2/STAT3 and NF-κB signaling. Taken together, these results indicated that DMF alleviated DSS-induced UC by suppressing JAK2/STAT3 and NF-κB signaling to restore Th17/Treg balance. Furthermore, these findings preliminary demonstrate a role for fumarate in the pathogenesis of UC and suggest that DMF treatment leading to fumarate accumulation is a potential metabolic mechanism for colitis mitigation. Collectively, DMF-mediated immunometabolic reprogramming constitutes a novel strategy for UC immunotherapy.
Exosomal miRNA let-7i-5p alleviates asthma triggered by RSV-induced exosomes by regulating dendritic cell autophagy via the MITF/DAP1/P70S6K pathway.
Liu J, Yao B, Wang S … +8 more , Deng Y, Xie J, Jiao L, Hu Y, Zhou Z, Ding Y, Luo Y, Wang M
Cell Signal · 2026 Jul · PMID 41839285 · Publisher ↗
BACKGROUND: Asthma is a chronic airway inflammatory disease, with respiratory syncytial virus (RSV) infection being a significant trigger. Studies have demonstrated the potential therapeutic effects of exosomes derived f...
BACKGROUND: Asthma is a chronic airway inflammatory disease, with respiratory syncytial virus (RSV) infection being a significant trigger. Studies have demonstrated the potential therapeutic effects of exosomes derived from bone marrow mesenchymal stem cells (BMSCs) on asthma. However, our preliminary research revealed that exosomes from BMSCs induced by RSV (Exos-RSV) can induce asthma, and among the exosomes, the miRNA let-7i-5p exhibits low expression. The role of miRNA let-7i-5p in asthma mediated by Exos-RSV remains to be further elucidated. METHODS: In order to elucidate the role of miRNA let-7i-5p in Exos-RSV induced asthma, based on previous research, we obtained Exos-RSV with different miRNA let-7i-5p contents through plasmid transfection technology, and used these Exos-RSV to intervene in mice and dendritic cells (DCs) to construct animal and cell models for comparison. ELISA was used to evaluate changes in inflammatory factors in animal serum. Histological staining was used to evaluate lung tissue lesions. CCK-8 was used to evaluate cell viability, and flow cytometry was used to evaluate cell cycle and apoptosis. RT-qPCR and western blotting was used to evaluate the expression of autophagy and related molecules in animal lung tissue and DCs in vitro. RESULTS: We observed that when Exos-RSV lacked miRNA let-7i-5p, asthmatic mice exhibited elevated serum levels of IL-5, IL-13, and IL-33, along with pulmonary tissue infiltration of inflammatory cells, goblet cell hyperplasia, increased collagen deposition, and enhanced expression of ET-1, collagen1, and Fibronectin proteins. Conversely, overexpression of miRNA let-7i-5p in exosomes alleviated these manifestations. In vitro experiments showed that Exos-RSV, which were deficient in miRNA let-7i-5p, increased the proportions of both early and late apoptotic DCs, elevated G1-phase cell ratios, and reduced S-phase cell proportions. When exosomes overexpressed miRNA let-7i-5p, the number of early apoptotic DCs decreased, while cell proportions across phases remained stable. Mechanistic studies revealed that Exos-RSV lacking miRNA let-7i-5p enhanced DCs autophagy and inhibited the MITF/DAP1/P70S6K signaling pathway in both in vivo and in vitro models. Conversely, overexpression of miRNA let-7i-5p partially reversed these changes. CONCLUSIONS: The lack of miRNA let-7i-5p in Exos-RSV is a key mechanism underlying asthma induction. Exosomal miRNA let-7i-5p acts as an autophagy inhibitor by targeting and regulating autophagy-related signaling pathways, thereby alleviating airway inflammation and remodeling in asthma, providing a promising therapeutic strategy.
Histone lactylation: A sensor of epigenetic reprogramming mediated by cellular metabolism.
Wang L, Song S, Yao S … +10 more , Wang Z, Li Q, Ma Z, Li J, Li Y, Yang M, Zhang K, Han Y, Xu D, Zhao Z
Cell Signal · 2026 Jul · PMID 41833774 · Publisher ↗
Epigenetic reprogramming plays a critical role in connecting genotype to phenotype, providing the flexibility that allows organisms to adapt to developmental needs, environmental shifts, and disease challenges through th...
Epigenetic reprogramming plays a critical role in connecting genotype to phenotype, providing the flexibility that allows organisms to adapt to developmental needs, environmental shifts, and disease challenges through the flexible regulation of gene expression. Histone lactylation, a recent modification in the field of epigenetic regulation, directly associates metabolic products-lactate-with chromatin modifications, revealing how cellular metabolism regulates the epigenetic landscape. In this review, we discuss the effects of histone lactylation on transcription and its metabolic regulatory mechanisms, explore the interplay between subnuclear metabolic microdomains and histone acetylation, and highlight the specific 'writing,' 'erasing,' and 'reading' enzymes involved in histone lactylation. Additionally, we discuss the physiological functions and recent advancements in the understanding of histone lactylation in disease progression, emphasizing its scientific significance for future research.
KNDC1 attenuates fibrosis in nonalcoholic fatty liver disease by inhibiting glycolysis in hepatic stellate cells.
Li J, Ni Y, Huang R … +5 more , Zhang Y, Wang J, Hu H, Li M, Liu H
Cell Signal · 2026 Jul · PMID 41833773 · Publisher ↗
BACKGROUND: Metabolic disruptions in non-alcoholic fatty liver disease (NAFLD) contribute to the progression of liver fibrosis. Kinase non-catalytic c-lobe domain containing 1 (KNDC1) is associated with intracellular sig...
BACKGROUND: Metabolic disruptions in non-alcoholic fatty liver disease (NAFLD) contribute to the progression of liver fibrosis. Kinase non-catalytic c-lobe domain containing 1 (KNDC1) is associated with intracellular signaling pathways. We investigated how KNDC1 regulates glycolysis and hepatic fibrosis. METHODS: Hepatic stellate cells (HSCs) stimulated with transforming growth factor-β1 (TGF-β1) and mice fed with high-fat and fructose diet were used as models for hepatic fibrosis. The impact of KNDC1 on glycolysis was assessed using Seahorse metabolic analyzer. And glucose uptake of HSCs was measured and visualized. Western blot and histological analysis were employed to examine the activity levels of hepatic fibrosis. Furthermore, proximity ligation assays, GST pull-down, and molecular docking were employed to identify the interaction between KRAS and glucose transporter 2 (GLUT2). RESULTS: KNDC1 inhibits glycolysis, blunts HSCs, thus alleviating hepatic fibrosis. In vitro, KNDC1 activates KRAS. Mechanistically, KRAS binds to GLUT2, preventing its membrane translocation, reducing glucose uptake, thereby inhibiting glycolysis. CONCLUSIONS: We revealed a new molecular mechanism linking KNDC1 and GLUT2. Our research offers novel insights into the potential therapeutic applications of KNDC1 and glycolysis in the management of hepatic fibrosis in NAFLD.
ADP-heptose/ALPK1 signaling pathway: Function, regulation, and involvement in diseases.
Li M, Zou X, Zhai S … +5 more , Wu M, Zheng Z, Wu Y, Duan W, Du J
Cell Signal · 2026 Jul · PMID 41833772 · Publisher ↗
Innate immunity serves as the first line of natural defense against pathogenic microbial infections in the host. During this process, pathogen-associated molecular patterns (PAMPs) are responsible to initiate the innate...
Innate immunity serves as the first line of natural defense against pathogenic microbial infections in the host. During this process, pathogen-associated molecular patterns (PAMPs) are responsible to initiate the innate immune response and trigger the subsequent adaptive immune response through activating pattern recognition receptors expressed by host cells. Adenosine diphosphate-heptose (ADP-heptose) is a core heptose metabolite involved in bacterial lipopolysaccharide biosynthesis. Recent studies have revealed that ADP-heptose, as a novel PAMP, specifically binds to alpha-protein kinase 1 (ALPK1) in host cells and activates the inflammatory signaling pathway. This mechanism plays a critical role in the development of various inflammatory diseases. This review introduced the recent advances on the ADP-heptose/ALPK1 signaling pathway and its relevance to various diseases.
Geniposide enhances cisplatin sensitivity in non-small cell lung cancer through PUMA-mediated apoptotic pathway.
Sun J, Han Y, Wang C … +5 more , Wang T, Hu W, Yu M, Wang Y, Han W
Cell Signal · 2026 Jul · PMID 41833771 · Publisher ↗
BACKGROUND: Cisplatin-based chemotherapy remains the standard treatment for advanced non-small cell lung cancer (NSCLC); however, its efficacy is constrained by acquired drug resistance and dose-limiting toxicity. Dysreg...
BACKGROUND: Cisplatin-based chemotherapy remains the standard treatment for advanced non-small cell lung cancer (NSCLC); however, its efficacy is constrained by acquired drug resistance and dose-limiting toxicity. Dysregulated apoptosis is recognized as a key mechanism contributing to cisplatin resistance in NSCLC. Geniposide, an active component of traditional Chinese medicine, has demonstrated broad-spectrum antitumor activity; however, its role in cisplatin resistance remains unclear. METHODS: Network pharmacology was employed to identify potential targets. The platinum-resistant A549/DDP cell line and its parental A549 line were used as in vitro models. Functional assays were performed to evaluate proliferation, apoptosis, migration, and mitochondrial membrane potential. RNA sequencing and gene knockdown/overexpression approaches were performed to investigate the underlying molecular mechanisms. An A549/DDP xenograft model was used to assess in vivo therapeutic efficacy. RESULTS: Network pharmacology analysis identified 125 common targets enriched in apoptosis and p53 signaling pathways. Geniposide significantly enhanced cisplatin sensitivity in A549/DDP cells by inhibiting proliferation and migration while promoting apoptosis and inducing mitochondrial membrane potential dissipation. RNA-seq identified PUMA as a key pro-apoptotic mediator. Combined treatment markedly upregulated PUMA expression, accompanied by activation of p53 signaling. Silencing of PUMA or p53 attenuated the chemosensitizing and pro-apoptotic effects, whereas PUMA overexpression independently reduced cisplatin IC₅₀ values. In vivo, geniposide combined with low-dose cisplatin achieved tumor suppression comparable to high-dose cisplatin without inducing systemic toxicity. CONCLUSION: These findings demonstrate that geniposide enhances cisplatin sensitivity in NSCLC by activating the p53-PUMA-mediated mitochondrial apoptotic pathway, thereby providing a potential strategy for overcoming chemotherapy resistance with improved safety.
The deubiquitinase USP28 promotes esophageal squamous cell carcinoma proliferation by stabilizing ΔNp63 protein.
Cai C, Cheng N, Luo H … +5 more , Guan H, Peng J, Zhang P, Chen X, Fang Y
Cell Signal · 2026 Jul · PMID 41833770 · Publisher ↗
Esophageal squamous cell carcinoma (ESCC) remains a lethal malignancy with limited therapeutic options. The deubiquitinase USP28 has emerged as a key stabilizer of the oncogenic transcription factor ΔNp63 in squamous can...
Esophageal squamous cell carcinoma (ESCC) remains a lethal malignancy with limited therapeutic options. The deubiquitinase USP28 has emerged as a key stabilizer of the oncogenic transcription factor ΔNp63 in squamous cancers, yet its functional significance and therapeutic potential in ESCC are unexplored. Here, we elucidate that USP28 is essential for ESCC proliferation. Genetic ablation of USP28 induced profound G2/M cell cycle arrest and apoptosis, phenotypes mechanistically linked to the destabilization of ΔNp63. We further establish that USP28 directly binds to and deubiquitinates ΔNp63, thereby controlling its protein stability. Crucially, targeting this axis with CT1113, a novel and potent USP28 inhibitor, recapitulated the anti-tumor effects of genetic knockdown, triggering ΔNp63 degradation, cell cycle arrest, and apoptosis in ESCC cells. Importantly, CT1113 administration significantly suppressed tumor growth in ESCC xenograft models. Our study not only defines the USP28/ΔNp63 axis as a critical driver of ESCC but also validates the therapeutic strategy of pharmacologically inhibiting USP28 for the treatment of this aggressive cancer.
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