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Results for “MAP Kinase Signaling System”

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At least 19 recordsLinked to original sources

PubMed2026

Phosphoproteomics identification of ERK-dependent activation of Rps6kb1 in cardiac hypertrophy.

Cardiomyocyte growth is tightly controlled by multiple signaling pathways. Identification of master kinases in this process is essential in exploring potential targets for the treatment of pathological cardiac hypertrophy and heart failure. Here we identified the mTOR-independent activation of ribosomal protein S6 kinase b1 (Rps6kb1) during cardiomyocyte growth. By utilizing phosphoproteomics in primary neonatal rat ventricular myocytes, we revealed Rps6kb1 as one of most activated kinases under growth stimulation. We further demonstrated the role of Rps6kb1 phosphorylation in pathological cardiac hypertrophy and heart failure. We showed that the phosphorylation of multiple sites in Rps6kb1, including T367 in the kinase domain and S418/T421/S424 in the C-terminal domain, is not directly regulated by the activity of mTOR but coupled with the activation of the MEK1/ERK axis. In mice, cardiomyocyte-specific deletion of Rps6kb1 significantly inhibited both constitutively active ERK- and pressure overload-induced cardiac hypertrophy. In contrast, cardiomyocyte-specific overexpression of wild-type Rps6kb1, rather than the phosphorylation-defective mutant, elevated cardiac hypertrophy and augmented pressure overload-induced heart failure. In conclusion, our findings reveal that the MEK/ERK axis primes Rps6kb1 activation through phosphorylation of 2 separate domains of Rps6kb1, which may play an essential role in cardiac hypertrophy and heart failure under hemodynamic stress.

Animals↗

PubMed2025

Restraint of inflammasome-driven cytokine responses through the mRNA stability protein TTP.

Activation of the NLRP3 inflammasome causes extensive disturbance of cellular homeostasis, with Golgi disruption, mitochondrial dysfunction, and changes in intracellular ion concentration occurring rapidly upon stimulation. Given this, it would seem near certain that these changes might also globally affect cellular signaling pathways, yet few, if any, studies have explored this possibility. Here, we combine genomics and phosphoproteomics to identify inhibition of the ERK1/2 MAP kinase signaling cascade upon inflammasome stimulation. This loss of ERK1/2 activity results in rapid inactivation of the mRNA decay-promoting protein tristetraprolin (TTP), with loss of TTP promoting subsequent increased release of cytokines upon pyroptosis. Further, we observe significantly increased levels of TTP expression in patients with inflammatory bowel disease, a disease for which altered cytokine expression is a key driver of pathogenesis. Inflammasome activation thus rapidly inactivates a pathway designed to suppress cytokine release, potentially exacerbating hyperinflammatory states, including those involved in autoinflammatory disease.

Inflammasomes↗

PubMed2026

Phosphoproteomic analysis in a mouse model reveals ERK signaling as a key modulator of inflammatory response in nasal mucosa associated with childhood allergic rhinitis.

Childhood allergic rhinitis (AR) is a multifactorial condition arising from the interplay between genetic predisposition and environmental exposures. Although protein phosphorylation is widely recognized as a key regulator of gene expression across various physiological and pathological states, its global alterations in the nasal mucosa of pediatric patients with AR and their subsequent impact on mucosal function and inflammatory pathways remain incompletely characterized. Our study aimed to elucidate the molecular mechanisms underlying nasal mucosa dysfunction induced by pediatric AR. Our analysis revealed 3,861 proteins encompassing a total of 15,491 phosphorylation sites. Specifically, we detected 441 downregulated phosphorylation sites on 584 proteins and 531 upregulated phosphorylation sites on 722 proteins in the nasal mucosa of the AR group. Our proteomics findings suggest that the dysregulation of immune activation and metabolic regulation may contribute to AR pathophysiology. Through pathway analysis of the identified phosphorylation sites, we found Extracellular Signal-Regulated Kinase (ERK) signaling emerged as an important pathway; notably, upregulation of ERK1/2 phosphorylation was observed as a significant marker associated with AR. Importantly, targeting ERK inhibitors presents a potential therapeutic strategy for modulating key inflammatory response signaling pathways in the context of AR, although this finding is derived from preclinical mouse models and requires rigorous validation in human pediatric nasal mucosal tissues before any clinical translation can be considered. Collectively, these findings highlight that elucidating the molecular mechanisms underlying AR-induced nasal mucosal dysfunction in the mouse model may inform the novel therapeutic targets for pediatric allergy-related diseases. Overall, elucidating these mechanisms has substantial implications for developing targeted interventions aimed at mitigating inflammation associated with allergic rhinitis.

Animals↗

PubMed2026

The 9th International RASopathies Symposium.

The RASopathies are a group of congenital disorders with overlapping clinical manifestations that are caused by pathogenic germline or early somatic variants that result in the hyperactivation of the RAS/mitogen-activated protein kinase (MAPK) signaling pathway. Given the heterogeneous clinical presentations of these disorders that involve abnormalities across multiple organ systems, multidisciplinary clinical management and progress in scientific research are essential for optimal patient diagnosis and care. The 9th International RASopathies Symposium, a biennial meeting, was organized by the patient advocacy group RASopathies Network and showcased recent discoveries, case studies, and advances in preclinical research. Participants, who included scientists, clinicians, industry representatives, patients, and family advocates, explored knowledge gaps, innovative clinical approaches, and lived experiences of individuals with a RASopathy. Sessions centered around organ systems were introduced with a patient perspective to highlight the burden of disease, continued with presentations from established and early-career investigators. Overall, the RASopathies Symposia serve as a catalyst for sustained community collaboration focused on enhancing patient health and accelerating the translation of discoveries into effective treatments.

Humans↗

PubMed2010

MAP Kinase: SUMO pathway interactions.

The convergence and coordinated cross talk of different signalling pathways forms a regulatory network which determines the biological outcome to environmental cues. The MAPK pathways are one of the important routes by which extracellular signals are transduced into intracellular responses. Through protein phosphorylation mechanisms, they can play a pivotal role in regulating other posttranslational modifications such as protein acetylation and ubiquitination. In addition, protein sumoylation has emerged as an important pathway which also functions through post-translational modification. The SUMO pathway modulates a diverse range of cellular processes including signal transduction, chromosome integrity, and transcription. Interestingly, recent studies have provided links between the SUMO and MAPK signalling pathways which converge to modulate transcription factor activity. This was first demonstrated by the observation that the activation of the ERK pathway caused de-sumoylation of the transcription factor, Elk-1. Furthermore, a growing number of links are now being made between the MAPK pathway and protein sumoylation. Given the nature of protein sumoylation in diverse biological functions, it is not surprising that the effect of MAPK pathways on sumoylation varies between different proteins. Here, we describe protocols that can be used in studying the cross talk between the MAPK and SUMO pathways, particularly at the level of gene regulation.

Amino Acid Sequence↗

PubMed2026

Context-dependent effects of MIR100HG on tumorigenic phenotypes and p38/MAPK-AKT signaling in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide and is characterized by a hypoxic tumor microenvironment that promotes tumor progression, cellular adaptation, and therapeutic resistance. Increasing evidence indicates that long non-coding RNAs (lncRNAs) play critical roles in regulating tumor-associated signaling networks; however, the contribution of MIR100HG to hepatocellular carcinoma progression, particularly under hypoxic conditions, remains insufficiently understood. In this study, we investigated the expression pattern and functional significance of MIR100HG in hepatocellular carcinoma using epithelial-like Hep3B and mesenchymal-like SNU-398 cells, together with non-tumor hepatocytes (Clone-9). Gain- and loss-of-function approaches were employed to evaluate the impact of MIR100HG on tumor-associated cellular phenotypes under both normoxic and hypoxic conditions. Functional assays demonstrated that MIR100HG overexpression significantly enhanced cell proliferation, clonogenic potential, migration, and invasion, whereas MIR100HG silencing markedly suppressed these tumorigenic properties and increased apoptotic cell death. Mechanistic analyses revealed that MIR100HG promotes oncogenic signaling through the p38/MAPK and AKT pathways under normoxic conditions, whereas MIR100HG depletion reduced the phosphorylation of these key signaling proteins. Notably, additional pathway analyses under hypoxia-mimicking conditions revealed a distinct signaling response, in which the MIR100HG-associated activation of p38/MAPK and AKT observed under normoxia was not maintained. Moreover, the expression patterns of AKT-associated regulatory genes, including GAS6 and PTEN, were reversed under hypoxia-mimicking conditions. These findings suggest that the effects of MIR100HG on oncogenic signaling are highly dependent on the cellular oxygenation context and that hypoxia reshapes the downstream signaling consequences of MIR100HG expression in HCC cells. Collectively, our findings identify MIR100HG as a hypoxia-associated oncogenic regulator that enhances tumorigenic phenotypes and promotes survival signaling in hepatocellular carcinoma. These results highlight MIR100HG as a potential biomarker and therapeutic target in liver cancer and provide new insights into the molecular mechanisms underlying hypoxia-driven tumor progression.

Humans↗

PubMed2026

LncRNA H19 promotes vascular remodeling by inhibiting MFN2.

Neointimal hyperplasia, featuring excessive proliferation and migration of vascular smooth muscle cells (VSMCs), is crucial in vascular remodeling diseases. Long non-coding RNA (lncRNA) H19 promotes vascular remodeling, yet underlying mechanisms remain incompletely elucidated. Here, we investigated whether H19 acts via its derivative miR-675-5p. Bioinformatics found a conserved H19/miR-675-5p/MFN2 (mitofusin 2) axis. Cell assays were performed to evaluate the effects of H19 and miR-675-5p on VSMC proliferation and migration. The dual-luciferase reporter gene assay was used to assess the interaction between miR-675-5p and Mfn2 mRNA. The mouse model of common carotid artery ligation was used to evaluate the role of H19 in neointimal hyperplasia. Our data suggested that knockdown of H19 inhibited VSMC proliferation and migration, as well as neointimal hyperplasia. Mechanistically, H19 regulated MFN2 through miR-675-5p, leading to ERK1/2 (extracellular signal-regulated kinase 1/2) activation. In conclusion, we suggest that targeting the H19/miR-675-5p/MFN2/ERK1/2 axis may help to treat vascular remodeling diseases.

Animals↗

PubMed2026

FASN Promotes Malignant Progression of Bladder Cancer by Regulating Lipid Metabolism via the ERK/PPAR Pathway.

Among urological cancers, bladder cancer (BC) is one of the main causes of morbidity and death. Although the lipogenic enzyme fatty acid synthase (FASN) is known to aid in the growth of tumors, its precise role and mechanism in bladder cancer remain unclear. The effects and mechanisms of FASN in BC are examined in this study. Using information from The Cancer Genome Atlas (TCGA), the expression and prognostic significance of FASN were examined. Functional assays, including CCK-8, apoptosis, Transwell, and scratch-wound experiments, were conducted in BIU-87 and T24 cells after FASN knockdown and treatment with the ERK activator TBHQ. Western blot analysis assessed key proteins of the ERK/PPARγ pathway, such as PPARα, PPARγ, and p-ERK1/2, along with the lipid metabolism marker CD36. Metabolite levels, including free fatty acids, acyl-coenzyme A, and triglycerides, were quantified. Finally, an in vivo subcutaneous xenograft model was established to validate these findings. In BC tissues, FASN expression was markedly increased and associated with lower overall survival. FASN knockdown increased apoptosis while inhibiting BC cell motility, invasion, and proliferation. These phenotypic changes were associated with downregulation of the ERK/PPARγ pathway and reduced fatty acid uptake and metabolite levels. Both in vitro and in vivo, treatment with TBHQ effectively reversed the tumor-suppressive effects and metabolic alterations induced by FASN knockdown, confirming the involvement of ERK signaling. This study therefore demonstrates that FASN promotes BC progression by modulating the ERK/PPARγ pathway and lipid metabolism. Targeting FASN or its upstream activator ERK could thus provide a therapeutic strategy to inhibit BC growth.

Humans↗

PubMed2026

METTL14-mediated m6A modification of CCNE1 accelerates progression of myelodysplastic syndromes via MAPK-ERK and PI3K-AKT signaling pathways.

BACKGROUND: N6-methyladenosine (m6A) is the most common RNA modification and plays a key role in the initiation, progression, and relapse of multiple cancers, including hematologic malignancies. However, the role of m6A and m6A regulatory genes in myelodysplastic syndromes (MDS) remains unclear. This study aims to elucidate the function and molecular mechanism of methyltransferase METTL14 in MDS. METHODS: RT-qPCR was used to assess the expression of multiple m6A regulators, focusing on METTL14 in MDS patients and cell lines. METTL14 overexpressing and knockdown cell lines were established, and CCK-8, EdU, and flow cytometry assays were performed to explore the biological functions of METTL14.Dot blot, MeRIP-Seq, MeRIP-qPCR, RT-qPCR, and Western blot were employed to investigate the underlying molecular mechanism. RESULTS: Dysregulation of multiple m6A regulators was observed in MDS, among which METTL14 was upregulated. Elevated METTL14 expression increases MDS risk and adverse prognosis, emerging as a biomarker for poor prognosis. METTL14 promoted proliferation and cell-cycle progression of MDS cells while inhibiting apoptosis; corresponding changes were observed in cell cycle and apoptosis markers. METTL14 regulated cellular m6A levels. Downstream targets of METTL14 were enriched in cell cycle-related pathways, with CCNE1 identified as a critical target. Knockdown of METTL14, actinomycin D, or S-adenosylhomocysteine treatment reduced CCNE1 mRNA and protein levels. Furthermore, METTL14 activated MAPK-ERK and PI3K-AKT signaling via CCNE1 in an m6A-dependent manner, thereby promoting proliferative MDS cells' capacity. CONCLUSIONS: This study delineates a METTL14/m6A/CCNE1 signaling axis in MDS progression and suggests that METTL14-mediated m6A modification may be a potential therapeutic target for MDS.

Humans↗

PubMed2026

CTSG Suppresses Breast Cancer Progression by Inhibiting the EGFR/ERK Signaling Pathway and Enhancing CD8⁺ T Cell Activation.

BACKGROUND: Breast cancer (BC), the most common female malignancy, has metastasis as its main cause of mortality. Cathepsin G (CTSG) is involved in tumorigenesis and immunity. This study explores the role of CTSG in BC progression and CD8 + T cell regulation. METHODS: Differentially expressed genes and proteins (DEGs/DEPs) were analyzed using Limma, and core genes were screened using Random Forest (RF) and Least absolute shrinkage and selection operator (LASSO). CTSG expression was analyzed using GSE36295, the Cancer Genome Atlas (TCGA), reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and western blot. Cell viability, proliferation, cell cycle, migration, and invasion were detected using Cell Counting Kit-8 (CCK8), 5‑Ethynyl‑2'‑deoxyuridine (EdU), flow cytometry, and Transwell assays, respectively. Sphere diameter was analyzed via sphere formation assay. Downstream mechanisms were examined using western blot, CCK8, flow cytometry, and Transwell assays. CD8 + T cell activity was examined using EdU, western blot, and flow cytometry. RESULTS: A total of 177 genes overlapped between GSE36295 DEGs and PDC000173 DEPs. CTSG was the hub gene identified by RF and LASSO. CTSG expression was significantly reduced in BC (P < 0.01). CTSG overexpression suppressed cell viability, proliferation, migration, invasion, sphere formation, and CD44 and CD133 expression (P < 0.01). CTSG up-regulation inhibited epidermal growth factor receptor (EGFR)/extracellular signal-regulated kinase (ERK) signaling axis and reduced cancer cell malignancy (P < 0.01). CTSG overexpression activated CD8 + T cells via EGFR/ERK inhibition, enhancing their cytotoxic effect on cancer cells (P < 0.01). CONCLUSION: CTSG inhibits BC malignancy and enhances CD8 + T cell function via EGFR/ERK inhibition.

Humans↗

PubMed2026

Eucalyptol mitigates isoproterenol-induced myocardial injury in rats via activation of p38 MAPK/JNK signaling, suppression of ER stress, and modulation of apoptotic pathway.

BACKGROUND: Myocardial injury (MI), a subset of cardiovascular diseases, remains a leading cause of deaths globally, driven by pathological inflammation, oxidative stress, and apoptosis. Despite advances in interventional cardiology, high relapse rates and therapeutic limitations underscore the urgent need for novel pharmacological agents. Phytochemicals, with their multi-target approach and favorable safety profiles, offer promising alternatives for mitigating ischemic injury. METHODS: The cardioprotective effects of 1,8-cineole, a monoterpene derived from Eucalyptus species, was investigated in a rat model of isoproterenol-induced myocardial injury. Serum levels of cardiac enzymes (creatine kinase (CK), lactate dehydrogenase (LDH)) and pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) were quantified. Preliminary histopathological analysis was performed to assess the extent of myocardial damage. Key molecular mechanisms were evaluated via western blotting and immunohistochemistry, examining pathways related to inflammation (NF-κB), apoptosis (Bcl-2/Bax, caspase-3), endoplasmic reticulum (ER) stress (GRP78, CHOP, PERK-eIF2α), and antioxidant defense (GSH, SOD, CAT). RESULTS: Our results demonstrate that 1,8-cineole significantly reduced the levels of serum cardiac enzymes (CK-MB, LDH), and histopathological damage. Mechanistically, 1,8-cineole also suppressed pro-inflammatory cytokine release (TNF-α, IL-6, and IL-1β) via inhibition of the NF-κB pathway. Furthermore, it attenuated cardiomyocyte apoptosis by modulating Bcl-2/Bax expression and inhibiting caspase-3 activation. Additionally, 1,8-cineole alleviated ER stress by downregulating GRP78, CHOP, and PERK-eIF2α signaling. Importantly, we identified enhanced Nrf2 nuclear translocation and subsequent upregulation of antioxidant enzymes (GSH, SOD, CAT) as key contributors to its cytoprotective effects. CONCLUSIONS: 1,8-Cineole exhibits potent cardio-protection in experimental myocardial injury by targetinginflammation, apoptosis, ER stress, and oxidative stress through modulation of p38 MAPK/JNK, suppression of inflammatory markers (TNF-α, IL-6, IL-1β) and apoptotic markers (Bax, p53). Its natural origin, bioavailability, and multi-mechanistic effectiveness make it a promising candidate for translational development as an adjunct therapy for myocardial injury.

Animals↗

PubMed2026

Development of receptor and oncogene-responsive luciferase reporter vectors that are activated via kinase signaling to AP-1.

This study aimed to generate lentiviral vectors carrying an array of AP-1 motifs driving luciferase gene expression as reporters of mitogen-activated protein kinase (MAPK) activity. We created a series of vectors based on LeGO-iG that were used to generate stably transduced leukemia cell lines. A vector termed LEGO-AP1×6-GM55 containing an array of 6 AP-1 sites linked to the minimal CSF2 promoter was sufficient to support high levels of MAPK-inducible luciferase activity in leukemic cell lines that was suppressed by MAPK inhibitors. The inclusion of a putative chromatin priming element encompassing RUNX and ETS motifs increased the activity of these vectors. The additional inclusion of the full-length mouse CSF2 promoter, or the human DUSP5 promoter further increased the MAPK-dependent activity of these vectors in leukemic cells. These vectors support moderate levels of constitutive activity in cells carrying mutations that activate the RAS/RAF/MEK MAPK signaling pathway, and high-level activity after direct activation of MAPK signaling. They also respond to T-cell receptor activation via MAPK and Ca2+ signaling pathways. This resource will now make it easier to track receptor or oncogene-inducible MAPK activity in cultured cells, and potentially in tumors, close to real-time.

Humans↗

PubMed2025

Glutamate molecular structure and protein affect the inhibition of breast cancer cell metastasis: Cell-derived exosomes inhibitory effects through the MAPK signaling pathway.

The aim of this study was to investigate the inhibitory effect of glutamate molecular structure and protein on breast cancer cell metastasis and the potential inhibitory mechanism of cell-derived exosomes via MAPK signaling pathway. Breast cancer cell lines with high metastatic potential were selected by in vitro cell culture technique. The effects of specific inhibitors of glutamic acid on the proliferation and metastasis of breast cancer cells were studied. Changes in protein expression profiles were analyzed by proteomics techniques to identify key proteins associated with breast cancer metastasis. Breast cancer cells were treated with inhibitors of the MAPK signaling pathway to evaluate their effect on cell metastasis and compare with exosome treatment. The results showed that the specific inhibitors of glutamate molecular structure could significantly inhibit the proliferation and metastasis of breast cancer cells. Proteomic analysis revealed several down-regulated proteins that are closely related to breast cancer metastasis.

Humans↗

PubMed2024

Molecular Characterization of Juxtaglomerular Cell Tumors: Evidence of Alterations in MAPK-RAS Pathway.

Juxtaglomerular cell tumor (JGCT) is a rare neoplasm, part of the family of mesenchymal tumors of the kidney. Although the pathophysiological and clinical correlates of JGCT are well known, as these tumors are an important cause of early-onset arterial hypertension refractory to medical treatment, their molecular background is unknown, with only few small studies investigating their karyotype. Herein we describe a multi-institutional cohort of JGCTs diagnosed by experienced genitourinary pathologists, evaluating clinical presentation and outcome, morphologic diversity, and, importantly, the molecular features. Ten JGCTs were collected from 9 institutions, studied by immunohistochemistry, and submitted to whole exome sequencing. Our findings highlight the morphologic heterogeneity of JGCT, which can mimic several kidney tumor entities. Three cases showed concerning histologic features, but the patient course was unremarkable, which suggests that morphologic evaluation alone cannot reliably predict the clinical behavior. Gain-of-function variants in RAS GTPases were detected in JGCTs, with no evidence of additional recurrent genomic alterations. In conclusion, we present the largest series of JGCT characterized by whole exome sequencing, highlighting the putative role of the MAPK-RAS pathway.

Humans↗

PubMed2025

Rv2741 Promotes Mycobacterium Survival by Modulating Macrophage Function via the IL-1α-MAPK Axis.

One of the primary healthcare problems in the world today is tuberculosis (TB), a chronic infectious illness brought on by Mycobacterium tuberculosis (M. tuberculosis). A distinct family of PE_PGRS proteins, encoded by the M. tuberculosis genome, has attracted more attention because of their involvement in immune evasion and bacterial pathogenicity. Nevertheless, the specific functions and mechanisms of action for the majority of PE_PGRS proteins remain largely unexplored. This study focuses on the Rv2741 (PE_PGRS47) gene, which is exclusively present in pathogenic mycobacteria. To examine the function of Rv2741 in host-pathogen interactions, we created recombinant strains of Mycobacterium smegmatis (M. smegmatis) that expressed the M. tuberculosis Rv2741 gene. IL-1α was found to be a key mediator of host response modulation by Rv2741. Rv2741 downregulates the secretion of IL-1α and inhibits the MAPK signaling pathway, particularly the p38 and ERK1/2 pathways, thereby cooperatively inhibiting macrophage autophagy and apoptosis. Meanwhile, the decrease in IL-1α secretion directly leads to changes in the cytokine secretion pattern and a reduction in nitric oxide (NO) production. This multifaceted regulatory mechanism ultimately favors the survival of M. smegmatis in macrophages. This research significantly expands our understanding of Rv2741 function, revealing its crucial role as a multifunctional virulence factor in the immune evasion of M. tuberculosis.

Interleukin-1alpha↗

PubMed2026

MM-derived exosomes promote M2 macrophage polarization and immunosuppressive microenvironment: therapeutic opportunities.

Multiple myeloma (MM) progression involves extensive immunosuppressive remodeling of the bone marrow microenvironment. In this study, we performed a comprehensive mass spectrometry-based proteomic analysis of exosomes derived from MM cells (MM-Exos), revealing that these exosomal proteins are predominantly enriched in pathways associated with immune regulation. We demonstrated that MM-Exos effectively drive macrophage polarization toward the M2 phenotype, thereby facilitating the establishment and maintenance of an immunosuppressive tumor microenvironment. Mechanistically, we identified the ERK1/2 signaling pathway as a critical mediator of MM-Exo-induced macrophage polarization. Importantly, we found that simvastatin, a widely used inhibitor of cholesterol biosynthesis, effectively impaired exosome secretion from MM cells and subsequently reduced M2 macrophage polarization. Collectively, our study reveals a novel mechanism of immune evasion in MM, in which MM-Exos promote the polarization of macrophages toward the M2 phenotype via ERK1/2 pathway activation. These findings underscore the therapeutic potential of targeting exosome-mediated intercellular communication within the MM bone marrow microenvironment to improve clinical outcomes.

Exosomes↗

PubMed2026

Tranexamic acid protects human dermal fibroblasts from D-galactose-induced senescence via the GPR30/MAPK pathway.

BACKGROUND: Tranexamic acid (TXA) is widely used for pigmentary disorders, but its anti-ageing potential remains unclear. This study aimed to evaluate whether topical 3% TXA improves early periorbital wrinkles in women with facial melasma and to investigate whether TXA protects human dermal fibroblasts from D-galactose-induced senescence via the GPR30/MAPK pathway. METHODS: Fifty women with melasma were randomized to 3% TXA serum plus moisturizer or moisturizer alone for 8 weeks, with follow-up to week 12. Periorbital wrinkles were graded using a modified Fitzpatrick Wrinkle Scale (MFWS). Separately, D-gal-induced senescence in HDFs was assessed via viability, SA-β-gal activity, senescence markers, ROS, antioxidant enzymes, SASP/ECM gene expression, and MAPK activation. GPR30 involvement was examined using antagonist G15, shRNA knockdown, and molecular docking. RESULTS: Topical TXA produced significantly greater MFWS reductions versus moisturizer alone at weeks 4, 8, and 12, with benefit persisting post-treatment. In HDFs, TXA preserved viability, reduced SA-β-gal positivity, attenuated p21/p16, restored Lamin B1, decreased ROS, and rescued antioxidant activities. TXA downregulated IL-6, IL-8, MMP1, and MMP3, and suppressed D-gal-induced ERK, JNK, and p38 phosphorylation. These effects were weakened by G15 or GPR30 knockdown; docking supported a stable TXA-GPR30 interaction. CONCLUSIONS: TXA showed clinical anti-wrinkle activity in melasma patients and protected HDFs from D-gal-induced senescence, partly via GPR30-dependent modulation of oxidative stress, SASP/ECM expression, and MAPK signalling. TXA is a promising candidate for skin ageing intervention.

Humans↗

PubMed2025

The proxiome of a plant viral protein with dual targeting to mitochondria and chloroplasts revealed MAPK cascade and splicing components as proviral factors.

The coat protein (CP) of the melon necrotic spot virus (MNSV) is a multifunctional factor localized in the chloroplast, mitochondria, and cytoplasm, playing a critical role in overcoming plant defenses such as RNA silencing (RNAi) and the necrotic hypersensitive response. However, the molecular mechanisms through which CP interferes with plant defenses remain unclear. Identifying viral-host interactors can reveal how viruses exploit fundamental cellular processes and help elucidate viral survival strategies. Here, we employed a TurboID-based proximity labeling approach to identify interactors of both the wild-type MNSV CP and a cytoplasmic CP mutant lacking the dual transit peptide (ΔNtCP). Of the interactors, eight were selected for silencing. Notably, silencing MAP4K SIK1 and NbMAP3Kε1 kinases, and a splicing factor homolog NbSMU2 significantly reduced MNSV accumulation, suggesting a proviral role for these proteins in plants. Yeast two-hybrid and bimolecular fluorescence complementation assays confirmed the CP and ΔNtCP interaction with NbSMU2 and NbMAP3Kε1 but not with NbSIK1, which interacted with NbMAP3Kε1. These findings open up new possibilities for exploring how MNSV CP might modulate gene expression and MAPK, thereby facilitating MNSV infection.

Chloroplasts↗