Unveiling the landscape of m5C RNA methylation in lung cancer: From molecular mechanisms to therapeutic opportunities.

Direct small-molecule inhibitors of the Keap1-Nrf2 protein-protein interaction: Scaffold evolution, PROTAC strategies, and therapeutic implications.

This study investigated the therapeutic potential of skin-derived precursor Schwann cells (SKP-SCs) for secondary brain injury following intracerebral hemorrhage (ICH) and its underlying mechanisms. An ICH model was established in mice via intrastriatal autologous blood injection. SKP-SCs were administered intranasally 24h post-ICH, with the AKT inhibitor GDC0068 used for intervention. Results demonstrated that transplanted SKP-SCs survived peri-hematomally, significantly improved short- and long-term neurological function, reduced brain tissue damage and neuronal apoptosis, preserved blood-brain barrier integrity, and suppressed microglial/macrophage activation and neutrophil infiltration. Mechanistically, SKP-SCs exerted neuroprotection by activating the PI3K/AKT/FOXO3a signaling pathway. In conclusion, intranasal SKP-SC transplantation alleviates ICH-induced deficits and secondary injury via this pathway, representing a promising therapeutic strategy during the acute phase following ICH.

This study aimed to combine network pharmacology with in vitro experiments to identify the key targets and potential mechanisms of salidroside (Sal) in the treatment of acute lung injury (ALI). Potential targets related to Sal and ALI were retrieved from the ChEMBL, SuperPRED, SwissTargetPrediction, GeneCards, OMIM, and CTD databases. Overlapping targets were imported into the STRING database and Cytoscape software to construct a protein-protein interaction (PPI) network and identify core targets. Functional enrichment analysis of these core genes, including GO and KEGG pathways, was performed using the DAVID database. Two genes, MAPK14 and GPX4, directly relevant to subsequent validation, were selected for molecular docking analysis. Furthermore, an in vitro model of ALI was established using LPS-induced alveolar type II epithelial cells to verify the protective mechanism of Sal. A total of 355 potential targets associated with Sal in ALI treatment were identified. In vitro experiments showed that, compared to the LPS group, the Sal group exhibited significantly reduced secretion of IL-6, ROS, p-MAPK, MDA, and Fe²⁺, along with increased GPX4 expression and attenuated lung injury. Integrated network pharmacology and experimental validation suggest that Sal pretreatment alleviates inflammatory response and oxidative stress, likely through regulation of the MAPK/GPX4 signaling pathway, thereby providing protection against lung tissue injury.

Inflammatory bowel disease (IBD), particularly ulcerative colitis, involves disruption of the intestinal mucosal barrier due to ecological and metabolic imbalances in the gut as its underlying pathology. Current therapies for Ulcerative colitis (UC) exhibit limited efficacy and adverse effects, necessitating the development of novel treatment strategies. Naringin and osthole are natural herbal compounds that show therapeutic potential in various inflammatory models due to their excellent anti-inflammatory activity. However, their combined therapeutic effects and precise mechanisms in UC remain unreported. This study aimed to explore the therapeutic effectiveness and mechanism of naringin combined with osthole in addressing dextran sodium sulfate (DSS)-induced colitis. The investigation centered on their impact on the disruption of the intestinal epithelial cell barrier, modulation of intestinal flora composition, alteration of metabolites, and inflammation model in vitro. Modal assessment encompassed body weight, disease activity index (DAI) score, colon length, and histopathological examination. Intestinal barrier integrity was evaluated through Quantitative Real-Time PCR, western blotting, and immunofluorescence staining. Microbiota abundance and metabolic levels wereassessed using 16S ribosomal RNA gene sequencing and metabolomics analysis. Protein expression levels ofpertinent pathways and associated receptors were testedthrough network pharmacology prediction and western blot analysis. Naringin and osthole synergistically relieved colitis symptoms in mice compared with either drug alone or 5-aminosalicylic acid, as evidenced by weight loss recovery, DAI scores, and colon length preservation. Mechanistically, naringin combined with osthole down-regulated the expression level of JNK/NF-κB signaling pathway related proteins and repaired intestinal barrier. Furthermore, the combination regulates the composition of the microflora and promotes the restoration of a steady state of the microflora.Metabolomicrevealed amino acid-tryptophan metabolism as a key metabolic pathway. It also reveals the microbiota-tryptophan pathway as a potential therapeutic strategy. Naringin combined with osthole can alleviate DSS-induced colitis more effectively by JNK/NF-κB signaling pathway, repairing barrier function and regulating intestinal microbiota and metabolites. These findings provide a theoretical basis for the combination therapy strategy to enhance the efficacy of potential functional food in treating ulcerative colitis.

The placenta is known to be critical in the cause of preeclampsia. However, there is a subset of preeclampsia cases without identifiable placental pathology. We evaluated which clinical preeclampsia classification system best distinguishes preeclampsia with placental pathology from preeclampsia without placental pathology. We evaluated 5 placental pathological features in 197 placentas from patients with preeclampsia grouped by 3 clinical preeclampsia subclasses: (1) preeclampsia with calculated infant birthweight <10th percentile for gestational age (small for gestational age [SGA] preeclampsia) versus preeclampsia with birthweight ≥10th percentile for gestational age (not SGA preeclampsia); (2) preeclampsia with delivery before 34 weeks of gestation (early delivery preeclampsia) versus preeclampsia with delivery at or after 34 weeks of gestation (late delivery preeclampsia); and (3) preeclampsia with severe features versus preeclampsia without severe features. Clinical, histological and molecular findings in patients with preeclampsia were compared with normotensive patients, with and without SGA infants (N=1078 total). The SGA versus not small for gestational age preeclampsia classification system performed best (likelihood ratios [95% CI] for ≥3 of 5 placental pathological findings: 15.7 [6.5-38.1] in SGA preeclampsia versus not small for gestational age preeclampsia; 6.8 [4.3-10.8] in early delivery preeclampsia versus late delivery preeclampsia; and 5.2 [1.95-14.1] in preeclampsia with severe features versus preeclampsia without severe features; all P<0.0001). SGA preeclampsia and SGA normotensive placentas were abnormal and shared alterations in hypoxia, TNFα, glycolysis, unfolded protein response, estrogen response, UV response, p53, TGFβ, and mTORC1 signaling pathways. Classifying preeclampsia based on birthweight percentile for gestational age is the most useful system for consistently identifying preeclampsia associated with placental pathology.

Endothelial mechanosensing is essential for controlling vascular tone. LRRC8A (leucine-rich repeat-containing protein 8A) was previously identified as a core subunit of the mechanoresponsive LRRC8 complex, functionally encoding the endothelial volume regulatory anion channel and regulating vascular function. This study aims to identify the molecular identity of the endothelial LRRC8 complex and its function in vascular reactivity and blood pressure control. We generated germline epitope-tagged Lrrc8a-3xFlag knock-in mice and endothelium-specific Lrrc8a-3xFlag overexpression mice to permit LRRC8A and LRRC8C immunoprecipitation and define LRRC8 subunit interactions. We combined in vivo and in vitro loss-of-function models, electrophysiology, immunoblotting, and pressure myography of third-order mesenteric arteries to examine the contributions of individual LRRC8A/B/C subunits to vascular function and underlying signaling pathways. The contributions of LRRC8C to blood pressure control in vivo were further assessed using the angiotensin-induced hypertension model in Lrrc8c knockout mice. Although all LRRC8A-E subunits are expressed in endothelium, co-immunoprecipitation revealed enrichment of LRRC8A/B/C, suggesting the existence of an endothelial LRRC8A/B/C heteromer. Lrrc8a/b/c depletion studies showed codependent expression of LRRC8A/B/C, but not LRRC8D. Only LRRC8A and LRRC8C deficiency impaired AKT and endothelial NO synthase phosphorylation, increased myogenic tone (2.2- and 1.9-fold increase, respectively), and reduced endothelial NO synthase-dependent vasodilation (45% and 61% reduction, respectively). Global Lrrc8c knockout mice phenocopied Lrrc8a knockouts and exhibited exacerbated angiotensin-induced hypertension, as evidenced by 15% increase in mean arterial pressure. LRRC8A/B/C form the endothelial LRRC8 heteromeric complex. LRRC8C is nonredundant in supporting endothelial AKT-endothelial NO synthase signaling, vascular relaxation, and resistance to hypertension.

Schnitzler syndrome is a rare autoinflammatory syndrome caused by a dysregulation of the interleukin-1β signalling pathway. Symptoms tend to appear in middle age and include urticariform skin lesions, fever, bone pain, lymphadenopathy and IgM monoclonal gammopathy. Interleukin-1 (IL-1) targeted therapy constitutes the basis for treatment and can lead to complete resolution of symptoms. We report a case of Schnitzler syndrome in a 49-year-old man refractory to anakinra and subsequently treated successfully with canakinumab.

Gallbladder cancer (GBC) is a highly aggressive malignancy of the digestive system with a poor prognosis. Therefore, the development of effective targeted therapeutic strategies is critical for improving survival outcomes in patients with GBC. Erb-B2 receptor tyrosine kinase 2 (ERBB2) is a proto-oncogene whose overexpression or mutation has been closely linked to the initiation and progression of various cancers. Whole-exome sequencing (WES) was performed on tumor tissue from a patient with advanced GBC who underwent conversion surgery following combination therapy with the multi-targeted tyrosine kinase inhibitor anlotinib and the PD-1 immune checkpoint inhibitor camrelizumab, to identify potential genomic alterations associated with treatment response. Transcriptomic profiling was conducted in cell lines transfected with plasmids encoding either wild-type ERBB2 or the I655V mutant. Western blot analysis was used to assess activation of the downstream PI3K-AKT and MAPK-ERK signaling pathways and to measure PD-L1 expression levels. Bioinformatic analyses were employed to predict the structural and functional consequences of the ERBB2 I655V mutation. WES revealed that the ERBB2 I655V mutation may be associated with therapeutic response. Mechanistically, the I655V substitution resides within the GG4-like motif of the ERBB2 transmembrane domain and may alter the transmembrane dimerization interface, potentially promoting heterodimer formation with other ErbB family members and leading to enhanced downstream signaling. Transcriptome sequencing and in vitro experiments demonstrated that the ERBB2 I655V mutation constitutively activates ERBB2, resulting in sustained activation of the PI3K-AKT and MAPK-ERK pathways. This subsequently upregulates PD-L1 expression and contributes to an immunosuppressive tumor microenvironment, which may underline the observed clinical response to combined targeted and immunotherapy. The ERBB2 I655V mutation may be associated with improved treatment response to immunotherapy in gallbladder cancer.

Secondary metabolites (a.k.a. natural products) are believed to play beneficial roles for the producing organisms, such as coping with environmental stress or outcompeting other organisms. Some of them may function as signals. One such class of natural products is the cyclitol/aminocyclitol family of compounds, which includes myo-inositol and its derivatives, the aminoglycoside antibiotics, and the C7-cyclitols and C7N-aminocyclitols. While the function of inositol and its derivatives as intracellular signaling molecules has been well established, more recent studies have also demonstrated their important ecological roles. Studies have also shown that aminoglycoside antibiotics may function as signals that regulate biofilm formation in bacteria and secondary metabolite production in fungi. Several C7-cyclitols and C7N-aminocyclitols, e.g., acarbose, validamycin, and kirkamide, have been associated with gut microbiota modulation, gene regulation in fungi and insects, and/or plant-bacteria endosymbiosis. While mycosporine-like amino acids (MAAs) are well known for their UV-protective activities, studies with human cells and animals have shown intriguing biological activities involving gene regulation and activation of signaling pathways. This article reviews the roles of this family of natural products as signaling molecules involved in various biological events, including bacterial colonization and gene regulation, with physiological and ecological implications that may affect human health and other organisms.

Hepatocellular carcinoma (HCC) is treated with sorafenib as a first-line treatment; however, resistance reduces its clinical effectiveness. It has been demonstrated that CCDC137 influences cell survival and proliferation. However, in HCC, its role in sorafenib resistance has not been thoroughly investigated. This study examined how CCDC137 makes HCC cells resistant to sorafenib, with a focus on the Akt/mTOR signaling pathway. HCC cell lines resistant to sorafenib (Huh7/sora) were generated by gradually increasing sorafenib concentrations in Huh7 cells. Bioinformatics analysis was performed on the Cancer Genome Atlas (TCGA)-hepatocellular carcinoma (LIHC) dataset and the GSE29721 dataset. The prognostic significance of CCDC137 was verified using Kaplan-Meier survival curves. Using the in vitro cell assays, the consequences of CCDC137 for the migration, apoptosis, invasion, and proliferation of parental HCC cells and sorafenib-resistant cells were assessed. The changes were analyzed using the Western blot test in the AKT/mTOR signaling pathway in resistant cells after CCDC137 knockdown or overexpression. CCDC137 was significantly elevated in Huh7/sora cells resistant to sorafenib and was linked to a poor outcome for individuals with HCC. CCDC137 knockdown reduced cell viability, induced apoptosis and inhibited migration and invasion in Huh7/sora cells. Conversely, CCDC137 overexpression in Huh7 cells enhanced sorafenib resistance. Mechanistically, CCDC137 activated the Akt/mTOR signaling pathway, AKT inhibition with MK2206 reversed opposition and increased apoptosis in resistant cells. Through triggering the Akt/mTOR signaling pathway, CCDC137 encourages sorafenib resistance in HCC cells, potentially offering a treatment approach to combat sorafenib resistance in HCC cells.

This study aimed to elucidate the role of neuronaI precursor cell-expressed developmentally down-regulated 4-like (NEDD4L), a developmentally downregulated E3 ubiquitin ligase, in rheumatoid arthritis (RA). Serum NEDD4L levels in RA patients (during both stable and active disease stages) and healthy controls were measured by enzyme-linked immunosorbent assay (ELISA). Immunohistochemistry (IHC) was used to analyze NEDD4L expression in synovial tissues from RA patients compared to traumatic control subjects. In animal experiments, the proteasome inhibitor MG-132 was administered to inhibit NEDD4L degradation, and its effects on joint inflammation and bone erosion were evaluated in a collagen-induced arthritis (CIA) rat model. At the cellular level, NEDD4L overexpression and knockdown models were constructed in rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs). The effects of NEDD4L on RA-FLS proliferation, migration, and invasion were assessed using CCK-8, wound healing and Transwell assays, respectively. Transcriptome analysis of the NEDD4L-knockdown model provided further insights into the associated diseases and pathways. Finally, the impact of NEDD4L on key proteins of the Wnt/β-catenin signaling pathway (DVL2, GSK3β, p-GSK3β, β-catenin) was examined via Western blotting and immunofluorescence, systematically investigating the mechanism of NEDD4L in RA pathogenesis both in vivo and in vitro. NEDD4L expression was downregulated in the serum and synovial tissues of RA patients. Functional assays demonstrated that NEDD4L knockdown enhanced the proliferative, migratory, and invasive capacities of RA-FLSs and promoted the secretion of the pro-inflammatory cytokines IL-6 and TNF-α, whereas NEDD4L overexpression exerted opposite effects. In CIA rats, MG-132 intervention alleviated joint inflammation and bone destruction, concomitant with restored synovial NEDD4L expression. Mechanistic studies further revealed that NEDD4L influences the biological behavior of RA-FLSs by regulating key components of the Wnt/β-catenin signaling pathway. NEDD4L modulates the migration, invasion, and pro-inflammatory cytokine secretion of RA-FLSs via the Wnt/β-catenin signaling pathway, suggesting its potential as a therapeutic target for RA. Key Points • NEDD4L knockdown activates Wnt/β-catenin pathway (DVL2, GSK3β, β-catenin). • Promotes IL-6/TNF-α secretion and cell invasiveness. • NEDD4L overexpression shows opposite effects. • Potential therapeutic target for RA.

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.

Upon RNA virus infection, nuclear translocation of activated transcriptional factors via the RNA-sensing signal pathway is a key event in the interferon (IFN)-mediated antiviral response, and a specific target of viral immune evasion. Foot-and-mouth disease virus (FMDV) causes an acute vesicular disease in cloven-hoofed animals and poses a serious economic risk to the dairy industry. FMDV VP4, one of the structural proteins, is an internal protein of the viral capsid and is known to play an important role in cell entry. Here, we demonstrate a novel molecular mechanism by which VP4 inhibits karyopherin (KPNA)-mediated antiviral immune responses. VP4 and IRF3 specifically interacted with the nuclear localization signal (NLS) binding site on the KPNA4 molecule, and VP4 inhibited the interaction between KPNA4 and IRF3 via competitive binding with higher affinity. Thus, VP4 inhibited nuclear translocation of IRF3 without affecting dimerization and phosphorylation of IRF3. Consequently, VP4 significantly enhanced the replication of RNA and DNA viruses by suppressing IFN production through inhibition of the IRF3-mediated type I IFN signaling pathway. Taken together, these results suggest that VP4 negatively regulates host type I IFN signaling by inhibiting the nuclear translocation of IRF3 and provide a critical implication for better understanding the pathogenesis of FMDV.

African swine fever virus (ASFV) employs sophisticated regulatory strategies to manipulate host cell apoptosis, a process critical for its pathogenesis and immune evasion; however, the mechanisms underlying this process remain incompletely understood. Here, we report a novel mechanism by which the ASFV-encoded envelope protein CD2v suppresses apoptosis by activating the TPL2 (tumor progression locus 2)-MEK (mitogen-activated protein kinase kinase)-ERK (extracellular signal-regulated kinase) signaling axis, leading to proteasomal degradation of the pro-apoptotic protein BimEL in primary porcine alveolar macrophages and wild boar lung (WSL) cells. We further demonstrated that ASFV infection triggers ERK1/2-dependent phosphorylation and degradation of BimEL, a process independent of viral replication and mediated by viral structural components. A targeted screen identified CD2v as the key viral protein driving this pathway. Both the purified extracellular domain of CD2v (Asp17-Tyr206) and virion-associated CD2v activated TPL2-MEK-ERK signaling without requiring internalization into cells, resulting in BimEL downregulation and subsequent suppression of apoptosis. Crucially, CRISPR-Cas9-mediated knockout of CD2v abolished ASFV-induced ERK1/2 activation and consequential BimEL degradation. Furthermore, we discovered that soluble CD2v released from ASFV-infected cells can activate this signaling axis in uninfected bystander cells, thereby inhibiting apoptosis distantly. This paracrine function, alongside its intrinsic role in directly infected cells, enables CD2v to establish a pro-survival microenvironment conducive to viral propagation. Our findings uncover a multifaceted anti-apoptotic mechanism employed by ASFV, expanding the functional repertoire of CD2v and providing new insights into ASFV pathogenesis with potential therapeutic implications.IMPORTANCEThis study elucidates a distinct mechanism of apoptosis inhibition by African swine fever virus (ASFV), a pathogen that causes a devastating disease in swine. We identify the ASFV CD2v protein as a key suppressor of cell death that operates by hijacking the host TPL2-MEK-ERK signaling pathway to degrade the pro-apoptotic protein BimEL. Importantly, CD2v mediates this effect not only within infected cells but also, in a soluble form, on surrounding uninfected bystander cells. This dual action helps create a protective, pro-survival cellular environment that facilitates viral spread and persistence. Understanding this novel apoptotic suppression mechanism advances our knowledge of ASFV-host interactions and highlights potential new avenues for therapeutic intervention.

DMBX1 is a transcription factor that plays important roles in various biological processes. However, systematic research on DMBX1 in colon cancer remains limited. This study aimed to investigate the expression characteristics of DMBX1 in colon cancer and its impact on prognosis and the immune microenvironment. Gene expression and clinical data for colon cancer were downloaded from The Cancer Genome Atlas (TCGA) database. Analyses performed included differential gene expression analysis, mutation analysis, prognosis analysis, tumor microenvironment (TME) analysis (including immune cell infiltration, immune checkpoints, DNA repair genes, and methyltransferase correlation analysis), and functional enrichment analysis. Furthermore, the function of DMBX1 was validated through Western blot, Transwell, and cell scratch assays, including knockdown and overexpression of DMBX1. Differential expression analysis revealed that DMBX1 expression was significantly higher in colon cancer tissues compared to normal tissues. Its high expression was significantly associated with poorer patient survival (p < 0.05). Mutation analysis found that the DMBX1 gene has a relatively high mutation frequency in colon cancer, and different mutation types significantly affected its gene expression levels. Tumor microenvironment analysis indicated that DMBX1 gene expression was significantly correlated with the infiltration levels of various immune cells and the expression of immune checkpoint genes. Enrichment analysis results showed that DMBX1 is involved in multiple key biological processes and signaling pathways, particularly participating in the process of cell adhesion. After knocking down the DMBX1 gene, the expression of ZO-1 and E-cadherin increased, while the expression of Vimentin and Slug decreased, suggesting that DMBX1 may affect the invasion and metastasis of colon cancer by regulating the epithelial-mesenchymal transition (EMT) process. Conversely, overexpression of DMBX1 led to decreased expression of ZO-1 and E-cadherin and increased expression of Vimentin and Slug. Transwell and cell scratch assay results further validated that high expression of DMBX1 significantly increased the invasion and migration capabilities of colon cancer cells, while knocking down DMBX1 inhibited these capabilities. Our findings suggest that DMBX1 may have potential as a prognostic biomarker for prognostic assessment in colon cancer and is associated with alterations in the tumor immune microenvironment.Mechanistically, DMBX1 likely primarily influences the occurrence and development of colon cancer by promoting the invasion and migration of colon cancer cells.

Regulatory T (Treg) cells perform immunosuppressive functions in rapid response to genetic and environmental stress for maintaining the immune balance, which play a physiological role in preventing autoimmune and inflammatory diseases. Given the highly dynamic and reversible nature of small ubiquitin-like modifier (SUMO) modification, along with the predominant nuclear localization of SUMO paralogs and their associated enzymes, SUMOylation is essential for the flexible regulation of key nuclear processes in Treg cells, such as membraneless organelle formation, genome integrity, and cell cycle progression. Notably, SUMO:SUMO-interacting motif (SIM) interactions facilitate the formation of regulatory complexes that govern cellular processes, and enable crosstalk with other post-translational modifications (PTMs), particularly ubiquitination, phosphorylation, acetylation, and methylation, which are globally harnessed by Treg cells in various contexts to regulate key processes of protein stability, signaling pathways, transcriptional reprogramming, and epigenetic modifications, thereby fine-tuning their immune-regulatory responses. This review explores the multifaceted roles of SUMOylation in Treg cell biology, emphasizing its influence on differentiation, maturation, transcriptional and epigenetic regulation, and metabolic reprogramming. By delineating these pathways, we aim to uncover how dysregulation of SUMOylation may be destined to Treg cells mediated immune disorders, providing a foundation for therapeutic interventions.

Postoperative cognitive dysfunction (POCD) is a common and serious complication in older adult patients. While the tyrosine kinase ABL1 has been implicated in neurodegenerative diseases, its specific role in POCD remains unexplored. This study aims to investigate whether ABL1 influences POCD in aged mice by regulating microglial autophagy and neuroinflammation via the mTOR/ULK1 pathway. An aged mouse model of POCD was established, and ABL1 silencing and 3-Methyladenine (3-MA) were used to intervene in mice. The Novel Object Recognition Test (NORT) assessment and water maze experiment were conducted. qRT-PCR quantified the mRNA levels of inflammatory cytokines, hippocampal damage was assessed by immunofluorescence, and western blot analyzed the protein expression of autophagy-related genes and the mTOR/ULK1 pathway. Co-Immunoprecipitation (CO-IP) was used to detect the binding of ABL1 to mTOR. In vitro experiments used microglial cells, where ABL1 silencing and rapamycin (Rapa) were used to construct a cellular model and conduct relevant cell experiments. ABL1 silencing or 3-MA rescued cognitive deficits in aged POCD mice, concurrently mitigating neuroinflammation, microglial activation, and aberrant autophagy in the hippocampus. We established ABL1 as a direct binding partner of mTOR. Silencing ABL1 activated the mTOR pathway, leading to ULK1 inhibition and suppression of autophagic activity. Consistent with these in vivo results, ABL1 knockdown in microglia attenuated pro-inflammatory responses, inhibited autophagy, and conferred protection against neuronal damage. ABL1 exacerbates POCD in aged mice by promoting microglial autophagy and neuroinflammation through the mTOR/ULK1 signaling pathway. Targeted inhibition of ABL1 may represent a novel therapeutic strategy for preventing or treating POCD.

miR-4458 is linked to cancer, and PRTG, an AS-related RA pathway gene, is a predicted target. This study clarifies miR-4458's role in AS and whether it modulates VSMC behaviors via PRTG and the RA pathway. Vascular smooth muscle cells (VSMCs) were treated with oxidized low-density lipoprotein (ox-LDL) to establish AS models, and RT-qPCR was applied to detect expression levels of miR-4458, PRTG, α-SMA, SM22α, vimentin, osteopontin, CRABP2, and RARRES1. Cell viability and migration ability were assessed via Cell Counting Kit-8 (CCK-8) and Transwell assay. Targeting between miR-4458 and PRTG was verified via dual-luciferase reporter gene assay (DLR assay).ox-LDL treatment upregulated miR-4458, downregulated PRTG, and enhanced cell viability and migration. miR-4458 overexpression promoted ox-LDL-mediated cell viability and migration, and facilitated VSMC phenotypic transformation. In contrast, miR-4458 knockdown counteracted the aforementioned ox-LDL effects. PRTG was confirmed as a target of miR-4458 via DLR assay, and its knockdown significantly enhanced the stimulatory effect of miR-4458 knockdown on cell viability and migration. miR-4458 is highly expressed in AS, which can promote the transformation of smooth muscle cells (SMCs) to smooth muscle cells (SEMs), as well as the proliferation and migration of SMCs, thereby accelerating the progression of AS. Interaction between the miR-4458/PRTG axis and retinoic acid (RA) signaling pathway could be harnessed therapeutically to modulate VSMC phenotype in ox-LDL-induced AS.

The fall armyworm (FAW), as a destructive invasive pest, poses a serious threat not only to maize production, but also to rice yield in Asia. Understanding plant-mediated impacts of native insects on invasive counterparts is important to assess the consequences of biological invasions. Yet it remains unclear whether infestation by native pests such as the rice leaf folder (RLF) can enhance rice resistance, thereby limiting the FAW's capacity to invade paddies and preventing it from becoming a serious rice pest. Here, we found that pre-infestation by either the native RLF or FAW itself induces defenses and significantly reduces the performance of subsequently feeding FAW larvae. Transcriptomic analysis revealed that both herbivores activate the jasmonic acid (JA) signaling pathway. Consistently, exogenous methyl jasmonate (MeJA) application enhanced rice resistance to FAW, whereas inhibition of JA biosynthesis attenuated RLF-induced resistance. Metabolomic profiling showed that herbivory induced the tryptophan metabolic pathway, leading to the accumulation of defensive tryptophan-derived metabolites. Feeding assays confirmed that these metabolites, particularly tryptamine and 5-methoxyindoleacetate, significantly suppressed FAW larval growth in a concentration-dependent manner. The key role of JA-tryptophan defense was further validated by exogenous application of MeJA, which upregulated the tryptophan pathway and increased defense metabolite accumulation. Our findings reveal a potential mechanism whereby native herbivore attack induces the jasmonate and tryptophan metabolic pathways, thereby enhancing rice resistance to the invasive FAW. This provides mechanistic evidence for plant-mediated biotic resistance and identifies the JA pathway and tryptophan-derived metabolites as targets for sustainable pest management. © 2026 Society of Chemical Industry.