Oncogenic BRAF mutations, including those in non-small cell lung cancer (NSCLC), are classified as Class I, II, or III. While approved therapies exist for BRAF Class I mutants, no approved therapies exist for Class II and III BRAF-mutated NSCLC. Analysis of a circulating tumor DNA database reveals Class II and III mutations comprise ~65% of BRAF-mutant NSCLC cases, with Class II patients showing worse outcomes than Class I. Exarafenib, a distinct pan-RAF inhibitor, demonstrates potent activity against BRAF Class II and III mutant preclinical models and initial clinical activity. Resistance studies reveal rewiring to an ARAF-mediated bypass pathway, characterized by RAS-mediated ARAF-KSR1 complexes maintaining MAPK signaling despite pan-RAF inhibitor treatment. RAS or MEK inhibition co-targeting is effective against this resistance mechanism. This study provides preclinical rationale for clinical testing of exarafenib in BRAF Class II/III cancers and unveils RAS-mediated ARAF-KSR1 complex formation as a resistance mechanism and rational co-therapy strategies.

Background: Bladder cancer (BCa) is a prevalent and aggressive malignancy characterized by high recurrence and metastasis rates. Despite advances in treatment, the prognosis for patients with advanced BCa remains poor. This study aimed to investigate the role of SAPCD2 in BCa progression and its potential as a therapeutic target. Methods: We performed a series of in vitro and in vivo experiments to assess the expression and function of SAPCD2 in BCa. The correlation between SAPCD2 expression and clinicopathological features was analyzed using tissue samples from BCa patients. Functional assays, including cell proliferation, migration, invasion, and metastasis tests, were conducted to evaluate the biological impact of SAPCD2. Mechanistic studies focused on the MAPK signaling pathway, TANK stabilization, and the interaction between SAPCD2 and the PLAGL2–CREB feedback loop. Results: Our results showed that SAPCD2 was significantly upregulated in BCa tissues and correlated with advanced clinicopathological features and poor prognosis. Overexpression of SAPCD2 promoted cell proliferation, migration, invasion, and metastasis, while its silencing led to the opposite effects. Mechanistically, SAPCD2 activated the MAPK signaling pathway by stabilizing TANK and preventing its degradation by SYVN1. Furthermore, we identified a positive feedback loop in which SAPCD2 enhanced PLAGL2 expression through CREB phosphorylation, further amplifying SAPCD2 expression and MAPK signaling. Conclusions: This study indicated that SAPCD2 could serve as a critical driver of BCa malignancy, emphasizing its role in sustaining oncogenic signaling through the SAPCD2–TANK–MAPK axis and the PLAGL2–SAPCD2–CREB feedback loop. Targeting this pathway may offer novel therapeutic strategies for treating aggressive BCa.

Root-knot nematode (RKN) infection poses a serious threat to the yield and quality of the perennial medicinal plant Trichosanthes kirilowii (T. kirilowii) in cultivation. However, its response mechanisms remain unclear. This study analyzed root growth and transcriptomic data at various root-knot nematode infection time points (0, 3, 6, 12, and 24 days post-infection, dpi) for T. kirilowii to reveal its specific response mechanisms. The results showed that RKN infection significantly affected the root growth and gene expression of T. kirilowii. At 24 dpi, individual plants formed an average of 69 galls, indicating the plant shows susceptibility. A total of 14,243 differentially expressed genes (DEGs) were identified, including 382 transcription factors. Weighted gene co-expression network analysis (WGCNA) of DEGs identified four key modules closely associated with RKN infection. GO and KEGG enrichment analyses indicated multiple metabolic pathways involved in the response process, including defense responses, hormone signaling, phenylpropanoid biosynthesis, and MAPK signaling pathways. Hub gene analysis of key modules identified 33 hub genes, including three critical transcription factors. This study demonstrates that T. kirilowii responds to RKN infection through coordinated regulation of multiple metabolic pathways and transcriptional regulatory networks. These findings enhance understanding of the molecular mechanisms underlying T. kirilowii–RKN interactions and provide critical insights for further research on resistance mechanisms and the identification of resistance genes in T. kirilowii.

Spinocerebellar ataxia type 3 (SCA3) is a progressive inherited neurodegenerative disorder characterized by impaired coordination and balance due to cerebellar ataxia. Currently, there are no Food and Drug Administration (FDA)-approved drugs or curative treatments for SCA3. This study aimed to uncover the potential therapeutic mechanism of natural products (NP or NPs) against SCA3 using an integrative computational strategy combining network pharmacology, molecular docking, molecular dynamics (MD) simulation, principal component analysis (PCA), free energy landscape (FEL), dynamic cross-correlation matrix (DCCM), and Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) calculations. A total of 4,986 SCA3-related targets were retrieved from the GeneCards database, and 696 unique NP-related targets were obtained from SwissTargetPrediction and SuperPred databases. Protein-protein interaction (PPI) network analysis revealed 239 overlapping targets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis identified the MAPK signaling pathway (hsa04010) as a key mechanism involving 33 critical proteins, including AKT1, TP53, TNF, EGFR, RELA, and MAPK1. Among the screened compounds, crocin exhibited the highest binding affinities with AKT1 (- 9.5kcal/mol) and TP53 (- 6.6kcal/mol) in docking studies. Further validation through MD simulation, PCA, FEL, DCCM, and MM/PBSA analysis confirmed the stability and strong interaction of crocin with these targets. This study highlights crocin as a promising candidate for SCA3 therapy and provides a foundation for future experimental validation.

Berberrubine protects against noise-induced cochlear damage and hearing loss by inhibiting the p38 MAPK signaling pathway.

Background Exposure to fine particulate matter (PM 2.5 ) increases asthma severity and reduces glucocorticoid responsiveness in children, yet the molecular mechanisms underlying PM 2.5 sensitivity remain unclear. We previously identified a PM 2.5 -sensitive asthma phenotype and developed a PM 2.5 sensitivity polygenic risk score (sPRS) correlated with asthma exacerbations and lung function decline. Research question We sought to determine whether genetic variants contributing to PM 2.5 sensitivity converge on specific biological pathways or transcriptional regulators, and whether children with a high sPRS exhibit immune transcriptional signatures consistent with heightened PM 2.5 susceptibility. Methods Genes implicated by sPRS variants were mapped using regulatory annotation tools and evaluated for pathway and transcription factor target enrichment. Peripheral blood mononuclear cells (PBMCs) from high- and low-sPRS children matched on long-term ambient PM 2.5 exposure were profiled using single-cell RNA sequencing. Donor-level pseudobulk differential expression was performed using a paired quasi-likelihood negative binomial framework, followed by exploratory pathway enrichment and perturbagen signature analyses. Results sPRS-implicated genes were enriched for transcriptional regulators linked to SMAD2/3- and MAPK-associated signaling, suggesting TGF-β1-related pathway involvement. No genes reached false-discovery-rate-adjusted significance at the donor level in this small, matched cohort. However, secondary pathway-level analyses demonstrated concordant enrichment across multiple immune populations in inflammatory and stress-response signaling programs previously linked to PM 2.5 exposure. Perturbagen signature analyses likewise highlighted small-molecule regulators of TGF-β1-associated pathways. Interpretation These integrative genomic and transcriptomic analyses nominate TGF-β1-SMAD/MAPK signaling as a biologically plausible axis of genetic susceptibility to PM 2.5 in pediatric asthma. Given the modest sample size and indirect nature of enrichment-based inference, these findings should be considered hypothesis-generating and motivate targeted functional validation.

Drought, intensified by climate change, poses a mounting threat to global food security by severely constraining crop productivity. While microbial inoculants offer promise for drought tolerance, their poor adaptability remains insufficient for extremely water-deficient environments. Desert plants host unique drought-adapted microbiomes that remain largely unexplored for agricultural applications. Here, we investigated the microbial community of the desert shrub Caragana korshinskii and identified a core set of drought-responsive strains. A synthetic microbial community (SynCom) derived from these strains significantly improved wheat growth under drought stress. Metagenomic analyses revealed that microbial functions related to biofilm formation, quorum sensing, and carbon metabolism were enriched, with Pseudomonas identified as a key functional taxon. Guided by inter-strain interactions in biofilm assembly, we streamlined the consortium into a five-member synthetic community, where quorum-sensing signals promoted community-wide biofilm formation. Community biofilm production improved strain colonization and conferred greater drought tolerance compared to monocultures. In plants, mechanistic investigations indicated that the simplified SynCom inoculation universally upregulated MAPK and jasmonic acid signaling pathways. Furthermore, carbohydrate metabolic pathways such as starch and sucrose metabolism were specifically activated, suggesting a multi-level mechanism underlying SynCom-mediated drought tolerance. These findings demonstrate that SynCom constructed on the endophytic flora of desert plants can significantly enhance crop drought tolerance. Our work highlights the pivotal role of community biofilm synthesis in facilitating root colonization and activating a multidimensional drought tolerance network in plants. This study not only gives an ecological perspective on desert microbiome adaptations but also offers a strategic framework for developing effective microbial inoculants for arid-region agriculture. Video Abstract.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that lacks effective targeted therapies. The interleukin-18 (IL-18) signaling pathway contributes to cancer progression and poor survival outcomes in several tumor types, including TNBC. IL-18 receptor accessory protein chain (IL-18RAcP), binding to the IL18/IL18Rα complex, plays a critical role in initiating and transducing IL-18 signaling. Targeting IL-18RAcP with human antibodies may offer a promising therapeutic strategy for TNBC. Human single-chain variable fragment (scFv) antibodies targeting IL-18RAcP were screened via phage display and characterized using ELISA, SPR, and crystallography. The functional assays that were used included qRT-PCR, MTT, Western blotting, flow cytometry, and xenograft models. Binding interactions were further validated through yeast two-hybrid assays and structural analysis. We found that elevated IL-18RAcP expression in TNBC is associated with poor recurrence-free survival (RFS), suggesting its potential as both a clinical marker and a therapeutic target. Using combinatorial scFv antibody phage display libraries, we identified a human monoclonal antibody, scFvAPC10, which binds IL-18RAcP with high affinity. scFvAPC10 significantly inhibits TNBC cell proliferation in vitro and reduces tumor growth in vivo by inducing apoptosis. Mechanistic studies reveal that scFvAPC10 impairs both NF-κB and MAPK signaling pathways. Structural analysis shows that scFvAPC10 interacts with the D1-D2 domains of IL-18RAcP through three hydrogen bonds, confirming the specificity of the interaction. Our findings highlight the therapeutic potential of targeting IL-18RAcP in TNBC through modulation of IL-18/IL-18R-mediated signaling pathways. The development of scFvAPC10 offers a promising approach for novel antibody-based therapies in the treatment of TNBC.

Design and optimization of N-(3-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)amide derivatives as potent anti-inflammatory agents against LPS-induced acute lung injury.

Calcium-sensing receptor (CaSR)-targeting agonist peptides play a crucial role in maintaining intestinal homeostasis. In this study, we integrated deep learning, virtual screening, and molecular simulation to develop Peptide_MDI, an intelligent screening platform built on Nextflow. From 2798 candidate peptides derived from wheat gliadin, we identified RLSYQFPFYP (designated CaSR_TP_1) as the lead peptide, which binds CaSR with a dissociation constant Kd = 74.4 nM. Functionally, CaSR_TP_1 upregulates tight junction proteins, promotes cell proliferation, enhances antioxidant defenses, and reduces the transcriptional levels of TNF-α, IL-8, and IL-6. Mechanistically, it attenuates H2O2 induced oxidative stress by activating the CaSR/PLCγ1/Rac1/MAPK signaling cascade. In conclusion, the CaSR-targeting peptide RLSYQFPFYP was identified with high affinity (nanomolar range) using Peptide_MDI, establishing a scalable technological framework for discovering bioactive peptides that promote gut homeostasis and for designing next-generation smart peptide therapeutics.

Chemical basis for the antioxidant activity of Piper nigrum: integrative profiling of volatile components from multi-origin black and white pepper.

ERK-dependent astrocytic PAI-1 induction by influenza A virus disrupts the neurochemical balance of the PAI-1/tPA axis.

UPP1 as a potential target for astilbin in ameliorating high-fat diet-induced bone loss via MAPK signaling: a study incorporating gut microbiota and metabolomics.

This study explores the molecular mechanisms underlying cold stress tolerance in the contrasting strawberry cultivars Queen Elisa (highly cold tolerant) and Camarosa (cold sensitive). Various physiological parameters were measured in these cultivars under cold stress and non-stress conditions. RNA-Seq was used to identify differentially expressed genes and enriched pathways involved in the plant response to cold stress. Biochemical data revealed that the cold-tolerant cultivar under cold stress had higher levels of soluble carbohydrates and proline compared to the cold-sensitive cultivar. Gene expression data demonstrated that cold-tolerance and cold-sensitive cultivars under cold stress modulated genes mainly involved in carbohydrate metabolism, hormone signaling, and secondary metabolism. GO and KEGG pathway enrichment data showed that cofactor biosynthesis, hormone signaling, and MAPK signaling were the most significantly enriched pathways in both cultivars. The transcription factors NAC, C2H2, ERF, MYB, WRKY, bHLH, DREB, CONSTANS-like, MADS, CCCH, and HY5, and several other key genes have been identified as closely associated with plant tolerance to cold stress. In particular, both contrasting cultivars respond similarly to cold stress, but the cold-tolerant cultivar exhibited a broader modulation of stress-related transcription factors and hormone signaling pathways, which were interpreted as a stronger molecular and biochemical response compared to the cold-sensitive cultivar. Furthermore, several key genes are suggested to be associated with plant tolerance and are proposed as potential targets for the development of biotechnological tools based on transgenesis and genome editing in strawberries. Therefore, this research provides new insights into the genetic and molecular basis of strawberry tolerance to cold stress.

Despite widespread human exposure to tin, its health effects remain poorly understood. This study examined the role of tin in neural tube defects (NTDs) through a case-control study and animal experiments. Tin levels in maternal serum and placentas were analyzed in 200 NTD cases and 400 controls to explore potential associations. Elevated tin concentrations in maternal serum were associated with an increased risk of NTDs, with an odds ratio of 2.31 (95% CI, 1.13-4.75), with similar associations found for placental tin and tributyltin (TBT) exposure. In animal experiments, pregnant mice exposed to 10-40 mg/kg TBT exhibited a 25.5%-27.6% incidence of fetal NTDs. Maternal TBT exposure increased oxidative stress and apoptosis in embryonic neural tissues. Antibody microarray analysis prioritized MAPK signaling as the dominant perturbed pathway. Subsequent western blot and RT-qPCR analysis convergently validated TBT-induced MAPK hyperactivation. Vitamin E supplementation had antagonistic effects, reducing these harmful outcomes. These findings suggest that prenatal tin exposure is a significant risk factor for NTDs. The teratogenic effect of TBT appears to be mediated by enhanced oxidative stress, activation of MAPK signaling, and apoptosis in the developing neural tube, processes that can be mitigated by Vitamin E supplementation. Thus, tin exposure during pregnancy is associated with an increased risk of fetal NTDs, and animal models demonstrate that TBT can induce these defects through specific biological pathways. This research highlights the need for further investigation into tin exposure and its potential health impacts on fetal development.

Surface-layer proteins of Enterococcus faecium WEFA23 inhibit Listeria monocytogenes-induced inflammation via TLR2-mediated NF-κB and MAPK signalling in RAW 264.7 cells.

IgG from anti-MDA5⁺ CADM patients impairs NK cell function via CD16 in RP-ILD.

Novel heterosteroids induce anabolic effects in human skeletal muscle cells: An integrated analysis of anabolic and catabolic signaling pathways.

DHCR24 knockdown-induced cellular cholesterol deficiency triggers tau hyperphosphorylation at Thr181, Ser199 and Ser202/Thr205 via p38 MAPK/JNK signaling.

Diazepam exerts immunosuppressive effects on macrophages isolated from the head kidney of catfish (Silurus asotus).