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Inflammatory bowel disease (IBD) and rheumatoid arthritis (RA) are chronic inflammatory diseases that share immune dysregulation and mitochondrial dysfunction. Understanding the molecular mechanisms linking these diseases to mitochondrial dysfunction is crucial for developing novel diagnostic and therapeutic strategies. Datasets related to IBD and RA were obtained from the Gene Expression Omnibus database. Differentially expressed mitochondrial dysfunction-related genes (MDRGs) were identified using differential expression analysis. Weighted gene co-expression network analysis was performed to identify crosstalk genes (CGs). Logistic regression and support vector machine (SVM) models were constructed using least absolute shrinkage and selection operator regression to identify hub genes. Additionally, the differential expression and diagnostic value of the hub genes were verified using quantitative reverse transcriptase-polymerase chain reaction and validation sets. Finally, immune infiltration analysis was conducted to assess the role of immune cells in IBD and RA. A total of 87 CGs associated with mitochondrial dysfunction were identified between IBD and RA, among which Show less

Papillary thyroid carcinoma (PTC) is the most common form of thyroid cancer, with the majority of cases driven by genetic alterations that activate the MAPK signaling pathway. The BRAF V600E mutation is the most frequent alteration, while BRAF fusions are relatively rare but increasingly recognized as oncogenic drivers. These fusions typically involve the loss of BRAF's autoinhibitory N-terminal domain, leading to constitutive MAPK pathway activation. Here, we report a novel SORBS2::BRAF fusion in a case of PTC, further expanding the spectrum of BRAF alterations in thyroid cancer. A 32-year-old male was incidentally found to have a left thyroid nodule during a routine physical examination. Follow-up examinations revealed changes in the nodule's characteristics, prompting fine-needle aspiration biopsy, which identified atypical follicular epithelial cells suggestive of papillary thyroid carcinoma. Histopathological examination confirmed the diagnosis, and next-generation sequencing (NGS) revealed a novel in-frame fusion between SORBS2 exon 18 and BRAF exon 9. The resulting fusion protein retains the BRAF kinase domain while replacing its autoinhibitory domains with those of SORBS2. RT-PCR and Sanger sequencing confirmed the presence of the SORBS2::BRAF fusion. Quantitative PCR profiling of MAPK transcriptional output genes (DUSP6, CCND1, ETV4, c-Myc, and c-FOS) revealed marked upregulation in the tumor versus adjacent normal tissue, providing functional evidence for pathway activation. The SORBS2::BRAF fusion has not been previously reported in PTC or any other tumor type. Given the deletion of BRAF's inhibitory domain, this fusion likely acts as a tumor driver through constitutive activation of the MAPK pathway. This case underscores the importance of molecular diagnostics in identifying rare genetic alterations and highlights the need for further research into targeted therapies for BRAF fusion-driven cancers. The discovery of this novel fusion expands our understanding of the molecular landscape of PTC and provides a foundation for future therapeutic development. Show less

KRAS We studied short-term changes in signaling and mechanisms of primary resistance to AZD4625 in twelve KRAS Sustained tumor regression in four (33%) PDXs was observed while the remaining eight models were intrinsically resistant to AZD4625. Organoid responses to AZD4625 were concordant with their derived PDXs. Acute AZD4625 exposure significantly decreased gene expression of the ERK1/2 negative regulator, DUSP6, in all models while protein MAPK and AKT/mTOR signals were downregulated more frequently in the AZD4625-sensitive than AZD4625-resistant cohorts. Analyzing PDX transcriptomes and proteomes identified mTOR signaling as a putative mechanism of primary resistance to AZD4625. Our findings confirm AZD4625 as a highly active KRAS Show less

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and the leading cause of cancer-related deaths. Immune checkpoint inhibitors (ICIs) of programmed death-1 (PD-1)/programmed death ligand-1 signaling induce tumor regression in some patients with NSCLC, but most patients with NSCLC exhibit resistance to ICIs therapy. NSCLC shapes the potent tumor immunosuppressive microenvironment (TIME) that underlies tumor immune tolerance and acquired resistance. Therefore, elucidating the cellular and molecular mechanisms by which NSCLC establishes and sustains the TIME is essential for developing novel strategies to overcome immune resistance and enhance the clinical benefit of ICIs. The correlation between sterile alpha motif domain and histidine-aspartate domain-containing protein 1 (SAMHD1) expression and ICIs was analyzed via immunohistochemistry. Cell migration assay was performed to assess the effect of SAMHD1 on macrophage recruitment. Multicolor flow cytometry was performed to analyze the effect of SAMHD1 knockdown on the tumor microenvironment. SAMHD1 regulation of the dual specificity phosphatase 6-extracellular regulated protein kinases 1/2 (DUSP6-ERK1/2) pathway was verified by RNA sequencing and western blotting. Here, we identify the SAMHD1 as a potential therapeutic target and a major determinant of poor response to ICIs in patients with NSCLC. Tumors with high SAMHD1 expression show resistance to anti-PD-1 antibody (αPD-1) treatment, whereas tumors with low SAMHD1 expression are highly sensitive. SAMHD1-dependent resistance to αPD-1 is characterized by increased tumor-associated macrophages (TAMs) infiltration and reduced CD8+T cell numbers. Mechanistically, SAMHD1 regulates the expression of macrophage-associated chemokines by influencing the activation of the DUSP6-ERK1/2 pathway, which contributes to TAMs aggregation within NSCLC tumors to shape an immunosuppressive microenvironment. The HIV accessory protein viral protein-x (VPX) specifically degrades SAMHD1 to promote HIV replication. Similarly, the vpx-engineered oncolytic adenovirus (oAd-vpx) targets SAMDH1 degradation to enhance oncolytic adenovirus replication and weaken the hostile immune microenvironment shaped by TAMs, thereby triggering a CD8+T-cell-dependent antitumor immune response. The combination of oAd-vpx and αPD-1 inhibits tumor growth and enhances sensitivity to ICIs in both mouse and human NSCLC. This research identifies a key mechanism of SAMHD1-driven immunosuppression and highlights its important role in oncolytic adenovirus therapy. This study provides a theoretical basis for targeting SAMHD1 as a drug therapy strategy in patients with NSCLC. Show less

DUSP6, a dual-specificity phosphatase, has become a focal point in understanding the pathogenesis of various liver disorders. This study aims to investigate the role of DUSP6 in liver fibrosis and explore the underlying mechanism. Using a CCL4-induced mouse model, the consistent upregulation of DUSP6 expression was observed. Notably, when Dusp6 was knocked down, liver fibrosis showed significant improvement, revealing a protective effect intricately linked to the ERK pathway. This was accompanied by an increase in ferroptosis-related proteins SLC7A11 and GPX4, underscoring the role of ferroptosis, an iron-dependent form of regulated cell death, in this process. Transcriptomic analysis further revealed a crucial downregulation of Cyp2e1 following Dusp6 knockdown. In vitro, DUSP6 knockdown not only promoted ERK phosphorylation but also suppressed CYP2E1 expression, enhancing cell proliferation, bolstering hepatocyte resistance to ferroptosis, and alleviating hepatocyte injury. Importantly, inhibiting CYP2E1 in mouse models of liver fibrosis effectively slowed the progression. These findings illuminate a critical regulatory mechanism that DUSP6 regulates liver fibrosis via targeting ferroptosis, offering new a direction for therapeutic strategies in liver disease. Show less

Artificial sweeteners (ASs) are widely used sugar substitutes, but chronic exposure is linked to male infertility. We integrated computational prediction, network analysis, and wet-lab validation to explore mechanisms. Seven ASs were screened in AdmetSAR 3.0; high-confidence positives were prioritized. Targets were predicted by SwissTargetPrediction, SEA, and TargetNet, and intersected with the top 50 % GeneCards testicular-injury genes to define candidate targets. STRING PPI and enrichment analyses were performed, followed by machine-learning feature selection and independent dataset validation. Ligand-target binding was evaluated by molecular docking and 100-ns molecular dynamics (MD) simulations. Single-cell RNA-seq (Male Health Atlas) mapped core-gene expression across testicular clusters. TM3 Leydig cells were exposed to aspartame (0.5-2 mM) for 48 h and analyzed by RT-qPCR. Aspartame, neotame, and sucralose showed high-confidence reproductive-toxicity signals. Ninety-one candidate targets were identified, and FGFR1 emerged as the core gene with good discrimination in two datasets. Docking and MD supported stable AS-FGFR1 binding, especially for aspartame. FGFR1 was enriched in Leydig and vascular-associated cells. Aspartame upregulated FGFR1, DUSP6, and SPRY2 and downregulated STAR. FGFR1-associated signaling may link AS exposure to impaired male reproductive function, warranting in vivo and protein-level validation. Show less

The maternal environment during gestation influences fetal development, with long-lasting effects on postnatal health and productivity. This study evaluated the effect of prenatal heat stress (PNHS) on blood DNA methylation of dairy calves immediately after birth and whether such modifications persist into early life. Holstein calves were born to dams exposed to either PNHS (n = 36, temperature-humidity index >68, access to shade of a freestall barn) or prenatal cooling (PNTN; n = 37, access to shade and evaporative cooling) during the last 54 ± 5 d of gestation. Whole-genome enzymatic DNA methyl sequencing was performed on blood samples collected at birth (d 0; n = 3 PNHS, n = 5 PNTN) and 1 wk post-weaning (d 63 of age; n = 8 PNHS, n = 8 PNTN). From birth onward, all calves were actively cooled and managed under the same conditions. At birth, 682,898 differentially methylated cytosines (DMC) were identified genome-wide. Principal component analysis using 55,304 DMC located in genes expressed in blood cells revealed a clear clustering by prenatal treatment. However, at weaning, clear clustering by treatment was no longer observed using 23,977 treatment-associated DMC in blood-expressed genes, despite 97,289 DMC persisting genome-wide from birth to weaning. Immune cell deconvolution showed only minor differences in granulocytes (d 0) and CD4/CD8 Show less

Nasopharyngeal carcinoma (NPC) is a complicated pathological cancer, which has a close association with pyroptosis and abnormal alternative splicing (AS). However, the molecular changes and functions of AS-mediated pyroptosis in cisplatin-resistant NPC cells remain poorly understood. The expression patterns of different splicing isomers of dual-specificity phosphatase 6 (DUSP6) were evaluated by semi-quantitative PCR. The effects of DUSP6 knockdown on cisplatin sensitivity and pyroptosis in NPC were examined by CCK-8 assay, immunofluorescence and ELISA. The occurrence mechanism of DUSP6 AS was explored by RNA pull down, mass spectrometry and MeRIP-PCR. DUSP6 underwent AS, among which the intron retention isoform DUSp6-IR1 increased in expression dependent on the dose and time of cisplatin. Knockdown of DUSP6-IR1 significantly suppressed viability and cisplatin resistance and promoted apoptosis of C666-1 cells upon cisplatin treatment. In vivo, sh-DUSP6-IR1 reduced the weight and volume of tumors. While DUSP6-IR1 knockdown in C666-1 cells enhanced pyroptosis (evidenced by elevated LDH release, Gasdermin D (GSDMD)/NOD-like receptor thermal protein domain associated protein 3 (NLRP3) expression, and IL-18/IL-1β levels, along with reduced cell viability), these effects were reversed by a pyroptosis inhibitor. The m6A reader protein insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) enhanced the splicing generation of the DUSP6-IR1 isoform through its KH3-4 domains, thereby suppressing pyroptosis in NPC cells and ultimately conferring cisplatin resistance. These findings revealed a promising novel direction to investigate cisplatin resistance and suggested potential therapeutic target for overcoming chemotherapy resistance in NPC. The online version contains supplementary material available at 10.1186/s12885-025-15337-9. Show less

There is a close connection between aging and osteoarthritis (OA), but the specific mechanisms are still unclear. This study aims to explore the potential connections and molecular mechanisms between OA and aging through multi-omics and genetics methods. Integrating single-cell RNA sequencing (scRNA-seq), bulk RNA-seq data, Mendelian randomization (MR), colocalization analysis, and cell function analysis, this study explores the correlation between OA and aging. Furthermore, it investigates the potential causal relationship between key marker genes and OA. Integrating and analyzing scRNA-seq data from OA, aging, and control groups revealed a significant increase in the proportion of the classical monocyte core subgroup. Differential expression analysis yielded 77 marker genes, and further MR analysis identified four key marker genes (DUSP6, CSTA, CD300E, and GPX1) as causally related to OA, which was confirmed in an independent validation cohort. Reverse MR and Steiger filtering indicated no evidence of reverse causality. DUSP6- and CSTA-classical monocytes may interact with other cell subgroups through the MIF-(CD74 + CD44) signaling pathway. This study revealed the heterogeneity of monocyte subgroups in OA and aging patients, identifying key marker genes with a causal relationship to OA through an integrated multi-omics approach, providing potential molecular targets for the diagnosis and treatment of OA from an aging perspective. Show less

Chronic inflammation constitutes a well-established driver of colorectal carcinogenesis, yet the molecular circuitry linking inflammatory receptor signalling to tumour cell survival remains incompletely delineated. Here we demonstrate that the HMG-CoA reductase inhibitors atorvastatin and rosuvastatin modulate inflammatory survival pathways in colorectal cancer cells in a manner consistent with targeted interference with the protease-activated receptor 2 (PAR-2)-extracellular signal-regulated kinase (ERK)-tumour necrosis factor-α (TNF-α) signalling axis. Using lipopolysaccharide-stimulated HT-29 and Caco-2 cells as complementary models of inflammatory colorectal malignancy, we show that both statins selectively attenuate PAR-2 expression at the protein and transcript levels while leaving structurally related PAR-1 unaffected. This pattern of receptor modulation is accompanied by suppression of total ERK1/2 expression, ERK1/2 phosphorylation, and the transcriptional target DUSP6, together with attenuation of TNF-α secretion. Importantly, these signaling shifts are associated with dual apoptotic programs; the extrinsic pathway, reflected by transcriptional upregulation and proteolytic activation of caspase-8; and the intrinsic mitochondrial pathway, evidenced by reciprocal modulation of Bcl-2 family proteins favoring Bax over Bcl-2. Both pathways converge upon activation of executioner caspase-3 and an increase in Annexin V-defined apoptotic fractions, indicating re-engagement of programmed cell death under inflammatory stress. Notably, rosuvastatin consistently demonstrates superior potency across signaling endpoints, achieving comparable biological effects at lower concentrations than atorvastatin. Collectively, these data indicate that clinically deployed statins target the PAR-2-ERK axis and are associated with re-activation of apoptotic pathways in inflammatory colorectal cancer models, while leaving open the possibility that additional statin-responsive networks contribute to their pro-apoptotic effects. This mechanistic framework provides biological plausibility for epidemiologic observations linking statin use with reduced colorectal cancer risk and improved outcomes, and supports further translational evaluation of PAR-2-directed statin strategies in colorectal malignancy. Show less

Important pathophysiological characteristics of human tumors are the presence of hypoxia and of an extracellular acidosis. Both metabolic parameters can affect the malignant behavior of tumors but also the response to treatments. Here the modulation of the ERK1/2 signaling plays a relevant role. ERK1/2 activation is controlled by the dual-specificity phosphatase 6 (Dusp6) and by this modulates cellular processes. For this reason, the study analyzed the impact of hypoxia and/or extracellular acidosis on the expression of Dusp6. Several tumor cell lines were exposed to control conditions (room air, pH = 7.4), hypoxia (pO Show less

Dual-specificity phosphatase 6 (DUSP6) is a phosphatase specific for extracellular signal-regulated kinase (ERK). Dusp6-knockout mice are resistant to diet-induced hepatic steatosis, which appears to be linked to the downregulation of cytochrome P450 4 A (CYP4A); however, its mechanism remains unclear. This study aimed to elucidate how DUSP6 regulates CYP4A11 in human hepatocyte-lineage cells by focusing on forkhead box O1 (FOXO1). HepG2 and HuH-7 cells were challenged with palmitic acid and oleic acid to induce lipid accumulation while manipulating the expression of DUSP6, FOXO1, CYP4A11, ERK, and/or AKT. Lipid accumulation was reduced by DUSP6 knockdown, resulting in decreased CYP4A11 expression despite elevated phosphorylated ERK, AKT, and FOXO1. Inhibition of ERK increased lipid accumulation, while simultaneous inhibition of ERK and AKT decreased it. Knockdown of FOXO1 or induced expression of DUSP6 increased CYP4A11 expression and lipid accumulation, whereas induced expression of FOXO1 decreased them. Chromatin-immunoprecipitation showed that FOXO1 bound to CYP4A11 promoter. Immunoprecipitations revealed that DUSP6 bound to and anchored FOXO1 in the cytoplasm. These results indicate that DUSP6 interferes with FOXO1's repressive activity towards CYP4A11 by sequestering it in the cytoplasm and preventing its nuclear translocation, which ultimately unleashes CYP4A11 and promotes lipid accumulation. Show less

Psoriasis is a chronic inflammatory skin disease characterised by keratinocyte hyperproliferation and immune cell infiltration driven by cytokines such as IL-17A. The dual-specificity phosphatase 6 (DUSP6) is a negative regulator of MAPK signalling and was previously reported to be a key mediator of arthritis severity. Here, we examine the role of DUSP6 in a mouse model of psoriasis. Psoriasis was studied in the imiquimod-induced model (IMQ). The skin of DUSP6+/+ and DUSP6-/- mice was treated with IMQ cream. Disease severity was assessed using well-established clinical and histologic systems. Skin inflammatory genes were quantified by qPCR.DUSP6-/- mice exhibited significantly reduced skin inflammation with lower PASI clinical scores (mean DUSP6-/- 1.8 and DUSP6+/+ 8.4; p < 0.0001). Histologic scores for epidermal thickening, parakeratosis and immune cell infiltration were decreased in the DUSP6-/- mice (p < 0.0005), and mRNA levels of IL1β, IL17A and STAT3 were lower in DUSP6-/- skin (p ≤ 0.05) compared with DUSP6+/+. In conclusion, DUSP6 is required for the development of psoriasis-like skin inflammation in mice. In the absence of DUSP6, mice were protected and had significantly lower levels of pathogenic genes, suggesting a new and central role for DUSP6 in skin inflammation and a potential therapeutic target in psoriasis. Show less

Myocardial infarction (MI) is the most severe clinical manifestation of coronary artery diseases (CVD) and serves as a critical driver of sudden cardiac death and heart failure (HF). Its pathophysiology begins with the abrupt cessation of coronary blood flow, leading to severe ischemia and subsequent cardiomyocyte necrosis. This study aimed to investigate the molecular mechanisms by which METTL14 regulates the progression of MI in mice via the OTUD1/DUSP6 signaling axis. An MI mouse model was established by ligating the left anterior descending (LAD) coronary artery. The progression of MI was evaluated through echocardiography, HE staining, Masson's trichrome staining, TUNEL assay, and assessment of inflammatory cytokines. Mechanistically, Me-RIP, PAR-CLIP Co-IP, and protein stability assays were performed to dissect the interactions within the METTL14/OTUD1/DUSP6 axis. Our results demonstrated that METTL14 was highly expressed in the MI mouse model. Silencing METTL14 significantly reduced the left Ventricular Internal Diameter at end-diastole (LVIDd) and left Ventricular Internal Diameter at end-systole (LVIDs), increased ejection fraction (EF) and fractional shortening (FS), and attenuated histopathological damage, apoptosis, and the levels of inflammatory cytokines (TNF-α and IL-β). Further analysis revealed that METTL14 promotes OTUD1 mRNA stability and expression by modulating its m Show less

Of all the skin malignancies, melanoma is the most invasive and challenging to treat. Melanoma patients have a poor prognosis and a high recurrence rate despite advancements in treatment. There is substantial evidence that plant-derived bioactives prevent and treat melanoma effectively. The naturally occurring bioactive compound dalbergin, found in certain species of the The online version contains supplementary material available at 10.1007/s40203-026-00604-9. Show less

Apoptosis plays a significant role in osteoporosis (OP), yet a causal relationship between apoptosis gene expressions and OP remains unexplored. This study applies an integrated multi-omics analysis to establish causality between them, offering clinical treatment and prediction insights. Apoptosis-related genes are sourced from GeneCards, and 6 transcriptomic datasets from the cells in the circulation are obtained from GEO. Meta-analysis integrated differentially expressed apoptosis-related genes (DEGs) from the above 6 datasets. Causality between gene expressions, epigenetic changes, and OP is examined using OP genome-wide association study (GWAS), plasma expression quantitative trait loci (eQTL), and methylation quantitative trait loci (mQTL) data, while analysis of skeletal muscle eQTL and OP GWAS data is conducted. External validation is performed with the UK Biobank datasets. Meta-analysis of 6 GEO datasets identified 384 DEGs, including 78 apoptosis-related genes. The three-step analysis indicates 8 candidate causal genes in blood, including MAP3K3, DPP8, RPL3, PPP2CA, CD86, LRRFIP1, TRAP1, and DUSP6, with LRRFIP1 influenced by four methylation sites. Analysis of skeletal muscle data reveals 4 causal genes, including SIPA1L3, PDLIM7, CTNNB1, and DPP8. Among apoptosis-related genes causally linked to OP in both circulation and skeletal muscle, LRRFIP1 was validated based on methylation-associated regulation and demonstrated consistent, reproducible expression patterns. This study uses a multi-omics strategy to clarify the roles of apoptosis-related gene expressions and their corresponding methylation in OP, providing targets and a basis for early diagnosis, personalized treatment, and monitoring of OP. Show less

Mitogen-activated protein kinase (MAPK) phosphatases [MKPs, also known as dual-specificity phosphatases (DUSPs)] regulate MAPKs -key mediators of cellular processes such as proliferation, differentiation, and survival- by dephosphorylating the threonine and tyrosine residues required for MAPK activation. MKP-3/DUSP6 is an ERK-selective phosphatase that has also been reported to regulate the transcription factor FOXO1. The full-length MKP-3 transcript has been shown to encode the MKP-3L protein, whereas alternative splicing gives rise to the shorter isoform MKP-3S. However, the available information regarding the functional differences between these variants is limited. By combining biochemical and bioinformatic approaches, we demonstrate that these isoforms differ significantly in subcellular localization and enzymatic activity. Structural analysis and molecular docking reveal that while MKP-3S retains functional binding domains and recognizes ERK2 similarly to the full-length isoform. However, the absence of critical catalytic motifs in MKP-3S leads to a structural uncoupling where the protein retains its ability to bind ERK2 but fails to induce dephosphorylation, suggesting a non-canonical role as a molecular scaffold. The results obtained demonstrate significant variations in subcellular localization, enzymatic activity, and the capacity to modulate FOXO1 transcriptional activity. This, in turn, affects the expression of genes such as p21. In conclusion, the findings indicate that MKP-3 variants exhibit distinct functional behaviours, which may result in differential regulation of a wide range of cellular processes. Show less

Primary resistance to chimeric antigen receptor (CAR) T-cell therapies has limited their widespread application. Our prior genome-wide CRISPR/Cas9 screening revealed that the loss of CD58, a crucial intrinsic resistance factor in tumors, resulted in insufficient immune synapse formation and impaired CAR T-cell activation and cytotoxicity. However, the specific signaling pathway and transcriptional changes associated with CAR T-cell dysfunction have not been addressed. Here, we revealed that AP-1-mediated activation was attenuated in CAR T cells impaired by tumor CD58 loss, driving a decrease in mitochondrial biogenesis, metabolic kinetic impairment, mitochondrial membrane potential loss and ROS accumulation. Moreover, this AP-1 attenuation triggered death receptor-independent apoptosis through the intrinsic mitochondrial pathway. In seeking therapeutic strategies, we pharmacologically and genetically blocked three distinct inhibitory phosphatases positioned upstream of AP-1 signaling. Multifaceted validation has demonstrated that dual specificity phosphatase 6 (DUSP6) blockade is an effective approach to supplement AP-1 signaling while notably reducing CAR T-apoptosis and enhancing mitochondrial fitness, proliferation and long-term cytotoxicity. The transcriptomic profiles of DUSP6-ablated CAR T cells revealed markedly upregulated T-cell activation signatures and enriched metabolic pathways. Clinically, bulk and single-cell RNA-seq analyses revealed that DUSP6 was downregulated in patients who responded to T-cell-based immunotherapy, implying its relevance to patient outcomes. Our findings repositioned CD58 not merely as an immune synapse component but also a metabolic checkpoint in CAR T-cell biology, the loss of which triggers AP-1-dependent mitochondrial derangement and creates a permissive landscape for intrinsic apoptosis, which can be ameliorated by ablation of the inhibitory phosphatase DUSP6. Crucially, DUSP6 ablation represents a promising engineering target to potentiate CAR T-cell efficacy in broader applications. Show less

Pharmacological preconditioning of mesenchymal stem cells (MSCs) is a promising strategy to enhance their therapeutic efficacy for end-stage liver disease; however, maximizing this benefit remains a major clinical challenge. Senkyunolide H (SNH), a small-molecule compound derived from Angelica sinensis, exhibits anti-inflammatory, antioxidant, and anti-apoptotic properties. Nevertheless, its capacity to optimize MSCs-based therapy for liver disease has not been fully elucidated. Here, we demonstrate that SNH preconditioning significantly enhances the therapeutic efficacy of bone marrow mesenchymal stem cells (BMSCs) in a murine model of liver cirrhosis. Specifically, SNH-pretreated BMSCs markedly alleviated hepatocellular injury, promoted hepatocyte proliferation, and attenuated collagen deposition. Mechanistically, SNH augments the therapeutic potency of BMSCs by partly binding to macrophage erythroblast attacher (MAEA), a subunit of the E3 ubiquitin ligase complex. This interaction stabilizes MAEA, which in turn facilitates the ubiquitination and proteasomal degradation of dual specificity phosphatase 6 (DUSP6), thereby activating ERK/STAT3 signaling and upregulating the secretion of hepatocyte growth factor (HGF). Collectively, our findings highlight SNH preconditioning as a robust approach to enhance the paracrine function and therapeutic potential of BMSCs, and identify MAEA as a novel therapeutic target for BMSCs-based interventions in liver cirrhosis. Show less

This study aims to investigate the role of DUSP6 in thyroid cancer metastasis and elucidate its underlying molecular mechanisms. Immunohistochemistry were performed to explore the expression of DUSP6, IL-8 and PAD4 in papillary thyroid carcinoma (PTC) tissues and adjacent non-cancerous thyroid tissues. Effects of DUSP6 on the proliferation, apoptosis, migration, and invasion of thyroid cancer cell lines TPC-1 and IHH4 were performed through in vitro experiments. A rescue experiment was performed to verified DUSP6 regulated the migration and invasion of thyroid cancer cells TPC-1 and IHH4 through IL-8 and neutrophil extracellular traps (NETs) formation. In addition, in vitro cell experiments were conducted to analyze the regulation of NETs formation by DUSP6 through IL-8. Finally, the effect of sh-DUSP6 on the growth of thyroid cancer tumors in mice were conducted through in vivo experiments. DUSP6 expression was significantly upregulated in PTC tissues. Moreover, the expression of DUSP6 in tumor tissues of TPC patients is positively correlated with the expression of IL-8 and PAD4. Overexpression of DUSP6 promotes the proliferation, migration, and invasion of thyroid cancer cells (TPC-1 and IHH4) while inhibiting apoptosis. Conversely, silencing DUSP6 exerts opposing effects. Knockdown of IL-8 reverses the enhanced migratory and invasive capabilities induced by DUSP6 overexpression in these cell lines. NETs treatment enhances the migration and invasion of TPC-1 and IHH4 cells, whereas the application of sh-DUSP6 or sh-IL-8 counteracts this NETs-mediated promotion. Furthermore, DUSP6 overexpression facilitates NETs formation by upregulating IL-8 expression. In vivo experiments demonstrate that sh-DUSP6 suppresses thyroid cancer tumor growth in mouse models. Conclusion: DUSP6 promotes the metastasis of thyroid cancer by facilitating the formation of neutrophil extracellular traps via IL-8. Show less

Bladder cancer (BC) is one of the most prevalent urinary malignant tumors that is intricately regulated by molecular pathways. Multiple studies have demonstrated a clear association between DUSP6 and malignant tumor progression; however, its role and underlying mechanisms in BC remain unclear. Here, we found that DUSP6 exhibits significantly elevated expression in BC tissues compared with normal tissues and is strongly associated with poor overall survival. Transcriptomic analysis revealed a robust correlation between DUSP6 expression and mitophagy, a selective form of autophagy crucial for maintaining mitochondrial integrity. Show less

Dual specific phosphatases (DUSPs) are a family of phosphatases, including DUSP4, DUSP5, and DUSP6, that function as negative regulators of the RAF/MEK/ERK pathway. These DUSPs have been extensively studied in various human cancers, particularly those with KRAS mutations. Our previous research indicated that these DUSPs are downregulated by KRAS knockdown in KRAS mutant lung cancer cell lines and upregulated in an hTERT/Cdk4-immortalized normal human bronchial cell line HBEC3-KT expressing mutant KRAS Show less

Squamous cell carcinomas arising in patients with recessive dystrophic epidermolysis bullosa are highly aggressive and often cause premature death. Current treatment options are limited, highlighting the need for innovative drug development concepts. Through transcriptome-guided computational drug screening, we identified selumetinib, a MAPK/extracellular signal-regulated kinase inhibitor, as a candidate drug for recessive dystrophic epidermolysis bullosa-associated squamous cell carcinomas. To verify the therapeutic potential of selumetinib against recessive dystrophic epidermolysis bullosa-associated squamous cell carcinomas, we assessed its efficacy in vitro and in vivo. In vitro, selumetinib decreased tumor cell viability, significantly reduced phosphorylation of extracellular signal-regulated kinase, and induced a mesenchymal-to-epithelial phenotypic shift, as indicated by increased E-cadherin and decreased vimentin expression. Functionally, it impaired tumor cell motility and invasion. Moreover, selumetinib significantly decreased PD-L1 and increased major histocompatibility complex class I levels and modulated the expression of immune-related cytokines. In vivo, selumetinib significantly suppressed tumor growth and reduced phosphorylated extracellular signal-regulated kinase levels in xenograft tumors. RNA sequencing identified EGR1 (early growth response protein 1), FOS (fos proto-oncogene), and DUSP6 (dual-specificity phosphatase 6) as candidate biomarkers of treatment response. Selumetinib, identified by computational drug screening, demonstrates efficacy against recessive dystrophic epidermolysis bullosa-associated squamous cell carcinomas in vitro and in vivo, suggesting its potential for clinical use. Show less

Several KRASG12D inhibitors (KRASG12Di) are under clinical evaluation for pancreatic ductal adenocarcinoma (PDAC). However, as seen with other first generation KRAS inhibitors, resistance may limit their long-term efficacy, necessitating combination strategies to enhance therapeutic outcomes. Exportin 1 (XPO1), a nuclear transport protein overexpressed in PDAC, represents a therapeutic vulnerability in KRAS-mutant cancers. Here, we demonstrate that the second-generation XPO1 inhibitor Eltanexor synergizes with MRTX1133 to enhance its efficacy in multiple PDAC models. We generated KRASG12Di-resistant PDAC cells and assessed their response to Eltanexor. The antiproliferative effects of MRTX1133 and Eltanexor combinations were evaluated in 2D and 3D Eltanexor sensitized MRTX1133-resistant PDAC cells to growth inhibition. In both 2D and 3D culture models, the combination of Eltanexor and MRTX1133 significantly reduced cell viability. Mechanistically, the combination treatment suppressed key KRAS downstream signaling molecules, including p-ERK, mTOR, p-4EBP1, DUSP6, and cyclin D1. Kinome analysis further revealed reduced MAPK-related kinase activity. Combining subtherapeutic doses of Eltanexor and MRTX1133 resulted in significant tumor regression and prolonged survival in PDAC xenograft and immunocompetent orthotopic allograft models. Moreover, maintenance therapy with Eltanexor prevented tumor relapse, yielding a durable antitumor response. This study demonstrates that Eltanexor overcomes resistance to MRTX1133 and enhances its efficacy in PDAC. The combination regimen may provide a durable therapeutic response while reducing the required dose of KRASG12D inhibitors, potentially delaying resistance and improving patient outcomes. Show less

The Saccharomyces cerevisiae Cell Wall Integrity (CWI) pathway responds to cell wall stress and is composed of MAP3K Bck1, MAP2Ks Mkk1 and Mkk2 and MAPK Slt2. Although human ERK5 has been considered the functional orthologue of Slt2, our results indicate that human ERK1 and ERK2 exhibit a much greater ability than ERK5 to replace Slt2 under various cell wall stresses. ERK5 is only able to slightly complement an slt2Δ mutant phenotype in the presence of tunicamycin, and the constitutively active truncated version ERK5ΔCt did not improve this complementation ability. Like Slt2, ERK1, ERK2 and ERK5ΔCt are concentrated in the nucleus, and show higher phosphorylation than ERK5 upon CWI pathway stimulation. Expression of a hyperactive version of the human MAP2K MEK5 leads to specific ERK5 and ERK5ΔCt phosphorylation, leading to a partial replacement of the Mkk1/2-Slt2 function under cell wall stress. Expressed in yeast, the human Dual Specificity Phosphatases DUSP3 and DUSP6 reduce the level of ERK5 phosphorylation to a similar extent, whereas DUSP6 shows higher activity than DUSP3 on ERK1 or ERK2. Our results show the different degree of integration of human ERKs and DUSPs into the yeast CWI signalling circuit, which can be exploited for functional analysis or pharmacological screenings. Show less