Clear cell renal cell carcinoma (ccRCC) is predominantly treated with anti-angiogenic therapies (AATs), such as sunitinib and axitinib. While these therapies initially improve outcomes, resistance frequently emerges, limiting long-term efficacy. Understanding the molecular mechanisms underlying AAT resistance is essential to optimize treatment strategies.

PD-L1 is one of the most critical immune checkpoint proteins, inhibiting T-cell immune responses by binding to PD-1. This study aims to validate that allicin can regulate PD-L1 expression through the IL-6/JAK2/STAT3 pathway, thereby inhibiting immune evasion in osteosarcoma.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing interstitial lung disease without any effective treatment. Berberine (BBR), a botanical alkaloid, possesses extensive biological activities and has significant therapeutic value in various diseases. However, the effect and potential mechanisms of BBR on pulmonary fibrosis remain elusive. In vivo, BBR was administered by gavage following intratracheal instillation of bleomycin (BLM) in a mouse model from Day 1 to Day 20. In vitro, Human Lung Fibroblast (HLF) and A549 cell lines were used to explore the effects of BBR on transforming growth factor β1 (TGF-β1) treated cells. Both cell lines were transfected with a lentivirus carrying TGF-β receptor 2 (TGFBR2) knockdown genes, and the autophagy inhibitor chloroquine (CQ) and PI3K inhibitor LY294002 were employed to investigate the underlying effects of BBR on TGF-β signaling and autophagy in pulmonary fibrosis. BBR administration attenuates pulmonary inflammation and fibrosis of BLM-induced mice in vivo. Analogously, BBR treatment significantly alleviates matrix collagen deposition and reduces the expression of fibrotic markers in TGF-β1-treated human lung fibroblasts (HLF) and alveolar epithelial cell (A549) in vitro. Mechanistically, we found that BBR downregulates the expression of TGFBR2 and suppresses TGF-β/Smad2/3 signaling in vivo and in vitro. Furthermore, BBR inhibits the activation of the PI3K/AKT/mTOR pathway and autophagy, then downregulates the expression of pro-fibrotic genes. The effect of BBR on pulmonary fibrosis was further verified using both TGF-β1-treated HLF and A549 cells with the addition of the inhibitors of PI3K, LY294002, and autophagy, CQ in vitro, respectively. Our study suggests that BBR can inhibit pulmonary fibrosis by down-regulating the expression of TGFBR2, attenuating TGF-β/Smad2/3 signal, and activating autophagy through phosphorylation of PI3K/AKT/mTOR.

Vibrio alginolyticus is a widespread marine pathogen responsible for major disease outbreaks in aquaculture and zoonotic infections in humans. Its pathogenicity is tightly regulated by quorum sensing and driven by biofilm formation, motility, and multiple virulence factors. The organism's high adaptability and virulence complicate traditional antibiotic treatments, especially amid rising antibiotic resistance. Although thymol, a natural monoterpenoid, is known for its broad-spectrum bactericidal activity, its effects on the survival and virulence of V. alginolyticus have not been previously investigated. In this study, we evaluated the inhibitory potential of thymol against V. alginolyticus. Experimental results demonstrated that thymol significantly reduced the survival of both planktonic and mature biofilm cells, induced reactive oxygen species generation, and disrupted membrane integrity. Furthermore, thymol at sub-inhibitory concentrations markedly impaired quorum sensing regulated biofilm formation and motility. Global transcriptomic analysis revealed that thymol exerts a multifaceted inhibitory mechanism by downregulating key genes involved in antioxidant defense, membrane biosynthesis, energy metabolism, ABC transporter function, quorum sensing, biofilm formation, and motility. In addition, computational studies revealed strong binding affinities between thymol and the upstream key quorum sensing regulators LuxS and LuxU, with hydrogen bonds formed at key active site residues, further supporting its anti-virulence potential. To our knowledge, this is the first study demonstrating that thymol acts as a potent inhibitor of V. alginolyticus survival and virulence. These findings highlight thymol as a promising natural agent for managing V. alginolyticus associated infections in aquaculture systems.

In tomato, the 25 AHL family members were classifi ed into three subfamilies. SlAHL5 and SlAHL25 belonged to CladeB, interacted and enhanced salt and osmotic stress tolerence of transgenic Arabidopsis. AT-hook motif nuclear-localized (AHL) proteins participate in plant growth, development, and response to abiotic stress. Their functions in the resistance to salt and osmotic stresses are largely unknown in tomato. Here, a total of 25 AHL genes in the tomato (Solanum lycopersicum) genome were identified. Phylogenetic and gene structure analyses indicated that they were classified into two clades and three subfamilies. Synteny relationship analysis demonstrated that all paralogous SlAHL pairs evolved under purifying selection. Promoter structure analysis revealed that many stress-related and phytohormone-related cis-acting elements existed. Gene expression pattern assays indicated that they had significantly different expressions in various organs, and most of them were up-regulated by high salinity and/or osmotic stress. Yeast two-hybrid (Y2H) assays demonstrated that SlAHL5 and SlAHL25, two nucleus-localized members in Clade B, interacted with each other to form a heterodimer, with SlAHL5 having self-activation activity, which is absent in SlAHL25. Constitutive expression of either SlAHL5 or SlAHL25 increased the resistance of transgenic plants to both salt and osmotic stresses, as revealed by the promoted primary root growth and biomass production, the relatively higher chlorophyll and proline content, and the enhanced catalase (CAT) and peroxide dismutase (POD) activity under both stress conditions. Our study on SlAHL genes under different stress conditions reported here provides a basis for further functional analysis of SlAHL genes, as well as for the development of new breeding strategies to improve resistance to multiple abiotic stresses in tomato.

Cardiac arrest (CA) remains a major public health challenge with high incidence and mortality. Post-cardiac arrest brain injury (PCABI) is the primary determinant of poor neurological outcomes and survival. Although curcumin (Cur) exhibits neuroprotective effects in multiple cerebral injury models, its precise pharmacological mechanisms in PCABI remain incompletely understood.

Hepatocellular carcinoma (HCC) is a primary malignant tumour that impacts patients' quality of life. Currently, clinical experience from The First Affiliated Hospital of Guangzhou University of Chinese Medicine suggests that Jianpi Jiedu Xiaozheng Fang (JPJDXZF) demonstrates promising efficacy in the treatment of HCC. We aimed to explore the mechanisms of JPJDXZF in HCC based on network pharmacology. The components and their relevant targets of JPJDXZF were identified using databases such as SymMap, TCMID, TCMSP, and TCM-ID. Following ADME screening, 1443 active components of JPJDXZF were identified, and 435 corresponding drug targets were predicted using the SwissTargetPrediction database. Subsequently, prognosis-related differentially expressed genes (DEGs) associated with HCC were analyzed using TCGA and GTEx datasets, and a gene expression matrix was derived. Key genes involved in HCC regulation were identified, and functional analyses were performed. Furthermore, we explored the regulatory effects of JPJDXZF at the cellular, organoid, and animal levels. We identified 18 intersecting genes between HCC prognosis-related genes and JPJDXZF-target genes. Venn diagram analysis successfully identified BIRC5 and CYP2E1 as two potential targets for JPJDXZF in treating HCC. Pathway enrichment analysis indicated that the core targets of JPJDXZF were enriched in multiple signalling pathways, including the Hippo pathway, in which BIRC5 is involved as a downstream regulatory gene. In in vitro experiments, JPJDXZF-containing serum significantly reduced the viability and migration of HepG2 and MHCC97-H cells, leading to a decrease in organoid diameter and ATP activity in HCC organoids. In in vivo experiments, tumours in nude mice treated with JPJDXZF exhibited reduced volume and weight, along with decreased expression of BIRC5 and Hippo pathway effectors YAP and TAZ. At the mechanistic level, JPJDXZF treatment was associated with altered Hippo pathway-related signalling, accompanied by reduced YAP/TAZ activity and changes in BIRC5 expression, together with effects on HCC cell proliferation and apoptosis. In addition, siMST1/2 interference and EMT inhibitor-1 treatment partially attenuated the effects of JPJDXZF on cell viability, migration, and apoptosis. JPJDXZF regulates BIRC5 expression in association with Hippo pathway activity in HCC. In vitro, in vivo, and molecular mechanism analyses support JPJDXZF as a potential therapeutic strategy for HCC by modulating key proteins in the Hippo pathway, thus affecting HCC cell proliferation, apoptosis, and migration.

Histone deacetylase 6 (HDAC6) has emerged as a promising therapeutic target in cancer due to its immunomodulatory effects. While its prognostic significance remains debated, we demonstrate that HDAC6 loss significantly impairs myeloid leukemia progression in vivo, despite having no functional impact on leukemia cell proliferation in vitro. Global proteome and secretome profiling of HDAC6-knockout (KO) cells revealed upregulation of several immune-related modulators, including RNase T2, a tumor suppressor known to modulate the tumor microenvironment. Notably, RNase T2 upregulation upon HDAC6 loss was observed in myeloid leukemia cells but not in lymphoblastic leukemia cells. Moreover, pharmacological inhibition of HDAC6 recapitulated this phenotype, leading to RNase T2 upregulation in myeloid leukemia cells. ATAC-seq revealed increased chromatin accessibility of RNase T2 following HDAC6 loss, highlighting a functionally epigenetic regulatory contribution. Further functional assays conducted in an immunocompetent setting, both ex vivo and in vivo, demonstrated that HDAC6 inhibition sensitized murine myeloid leukemia cells to broad CD8+ T cell activation as evidenced by increased TNFα and CD107a expression. Consistently, in a syngeneic murine model, HDAC6 inhibition restricted the growth of myeloid leukemia cells. Moreover, an extended drug screening analysis identified Cytarabine and Clofarabine as significantly synergizing with HDAC6 inhibitor (Ricolinostat) in myeloid leukemia cell lines and in patient-derived xenograft (PDX) cells, while showing limited synergy in lymphoid leukemia cell lines, PDX, or healthy control cells. These findings suggest that HDAC6 represents a promising therapeutic target in myeloid lineage-derived leukemia cells by simultaneously enhancing immune activation and increasing chemosensitivity.

Silicosis remains a critical occupational health concern worldwide, lacking effective treatments due to unclear mechanisms. In this study, we investigated the citrullinated proteomic profile and its effects in mice exposed to silica. Our findings demonstrated elevated levels of citrullinated peptides and citrullinated vimentin (Cit-Vim) in silicotic mice and silica-treated macrophages, regulated by peptidylarginine deiminase (PADI2). Unlike vimentin, Cit-Vim amplified the production of tumor necrosis factor-α (TNF-α), Interleukin-6 (IL-6), and IL-1β in silica-treated macrophages through interaction with Toll-like receptor 4 (TLR4) signaling. RNA sequencing revealed that early growth response protein 1 (EGR1) is a target of PADI2, with Cit-Vim inducing lung inflammation via EGR1 signaling. Pharmacological inhibition or genetic knockout of Padi2 attenuated silica-induced lung inflammation and fibrosis. These findings suggest that targeting PADI2 may represent a novel therapeutic strategy of silicosis.

The aim of the present research is to deeply investigate the cytotoxic and immunomodulatory activities of the mucin extracted from Ereminia desertorum snails´ mucus against two tumor cell lines; human hepatocellular carcinoma (HepG-2) and human colon adenocarcinoma (CACO-2) cells. Both cell lines were treated with Ereminia desertorum snails´ mucin and the anti-cancer potential of the mucin was evaluated by the crystal violet assay test and gene expression analysis using reverse transcription- polymerase chain reaction (RT-PCR).

von Hippel-Lindau (VHL) is a tumor suppressor frequently inactivated in renal cell carcinoma (RCC), and its loss is associated with aberrant DNA methylation. Here we demonstrate that VHL-deficient RCC cells are highly vulnerable to DNA methyltransferase (DNMT) inhibitors. US Food and Drug Administration-approved DNMT inhibitors, such as decitabine and azacitidine, and investigational agents including RX-3117 and SGI-1027 selectively suppressed the growth of VHL-deficient RCC cells. Mechanistically, VHL loss leads to HIF-2α-dependent transcriptional upregulation of DNMT1, resulting in widespread CpG hypermethylation. Transcriptomic profiling and an RNA interference-based rescue screen identified KCNK3, a putative tumor suppressor, as a key mediator of DNMT inhibitor-induced synthetic lethality in VHL-deficient RCC. The KCNK3 promoter is hypermethylated and transcriptionally repressed in VHL-deficient RCC, where treatment with DNMT inhibitors reverses this methylation, restoring KCNK3 expression and resulting in cell growth inhibition. Silencing KCNK3 significantly attenuated the antitumor effects of DNMT inhibitors both in vitro and in vivo. Further mechanistic analysis showed that KCNK3 reactivation triggers TNF-α, MAPK and apoptotic signaling pathways, contributing to the observed synthetic lethality. Collectively, these findings establish DNMT inhibition as a synthetic lethal strategy in VHL-deficient RCC and highlight a potential therapeutic vulnerability for personalized treatment approaches.

Endothelin-1 (ET-1) is a critical mediator of airway remodeling and subepithelial fibrosis in patients with asthma. However, the roles of casein kinase 2 (CK2), p300, and STAT3 signaling pathways in ET-1-induced connective tissue growth factor (CTGF) expression remain poorly understood. In WI-38 cells (human lung fibroblasts), pharmacological inhibitors of CK2 (apigenin and 4, 5, 6, 7-tetrabromobenzotriazole (TBB)) markedly attenuated ET-1-induced CTGF expression, and ET-1 promoted nuclear translocation of CK2. Transfection with CK2α' siRNA, but not CK2α siRNA, inhibited ET-1-induced CTGF expression, and ET-1 induced tyrosine phosphorylation of CK2α'. ET-1-induced CTGF expression was attenuated by a STAT3 dominant-negative mutant, STAT3 siRNA, or p300 inhibitor (C646). In addition, CK2α' silencing suppressed ET-1-induced phosphorylations of p300 and STAT3. ET-1-mediated STAT3 acetylation and STAT3 transcriptional activity were inhibited by transfection with p300 or CK2α' siRNA. ET-1 also induced assembly of a CK2α'/p300/STAT3/c-Jun/HDAC7 complex and its recruitment to the CTGF promoter. However, CK2α was dispensable for these CK2α'-mediated downstream signaling events. Furthermore, CK2α' knockdown attenuated ET-1-induced fibronectin, collagen I, and α-smooth muscle actin expression. Together, these findings identify CK2α' as a key regulator of ET-1-driven transcriptional complex formation that promotes profibrotic protein expressions in human lung fibroblasts.

Staphylococcus aureus forms biofilms in the context many infections, including endocarditis, lung infection, and the colonization of implants. How antimicrobials specifically affect S. aureus biofilms as opposed to planktonic S. aureus is an important consideration in the development of treatments of these infections. It is well known that bacteria in biofilms are more resistant to antimicrobials, and the degree and nature of the responses is crucial to understanding the basis of this resistance. While certain antimicrobials such as antibiotics have specific mechanisms that induce pathways related to those mechanisms, and others such as hypochlorite are highly toxic, a wide variety of compounds exhibit intermediate effects that affect multiple systems. Responses to these substances are important to understand if new therapeutics are to be designed. Here, we investigated antibacterial and antibiofilm effects of cinnamaldehyde (CmAl), an antibacterial agent commonly used in foods. CmAl affects multiple bacterial systems, providing a model for the characterization of these intermediate responses. We measured CmAl activity on established biofilm and planktonic bacteria using recombinant bioluminescent S. aureus and performed RNA-seq on CmAl-treated biofilms and planktonic bacteria. RNA-seq results revealed response pathways that differ between these states, including phosphate uptake. The results of this study demonstrate how CmAl differentially affects S. aureus biofilms compared to planktonic forms.

Organic anion transporting polypeptide (OATP) 1B3 plays a clinically significant role in hepatic drug disposition. Lysine acetylation, a key post-translational modification, has not been investigated for OATP1B3. This study determined the lysine acetylation status of OATP1B3 by proteomics and assessed the impact of inhibition of lysine deacetylase (KDAC) 6, a major cytosolic KDAC, on OATP1B3 acetylation and transport function. Proteomics revealed 7 acetylation sites, including 5 with additional ubiquitin-like modifications, and 4 phosphorylation sites (T10, S293, S295, S683). In human embryonic kidney 293 (HEK293)-Myc-FLAG-OATP1B3 cells, preincubation with the selective KDAC6 inhibitor tubacin (TBC) (5 μM, 24 hours), markedly reduced OATP1B3-mediated transport of [3H]cholecystokinin-8 (CCK-8), a specific substrate, and [3H]estradiol-17β-D-glucuronide to 0.15 ± 0.03-fold and 0.19 ± 0.01-fold of the control, respectively, without affecting OATP1B3 mRNA, protein levels, or membrane localization determined by real-time reverse transcription polymerase chain reaction, immunoblotting, and confocal microscopy. TBC treatment increased K664 acetylation to 2.12 ± 1.03-fold of the control (P < .05). Consistently, the acetylation-mimetic K664Q variant exhibited reduced transport compared with the acetylation-null K664R variant (P < .05). Treatment with a second KDAC6 selective inhibitor, WT-161 (3 μM, 5 hours), similarly reduced OATP1B3-mediated [3H]CCK-8 transport. In cultured primary human hepatocytes, TBC treatment for 4, 8, and 24 hours decreased [3H]CCK-8 transport to 0.34 ± 0.02-fold, 0.27 ± 0.03-fold, and 0.37 ± 0.03-fold of the control, respectively (all P < .05). The study reveals a novel post-translational modification of OATP1B3 by lysine acetylation and demonstrates impaired transporter function following KDAC6 inhibition, likely involving increased acetylation at K664, thereby providing new insight into OATP1B3-mediated drug-drug interactions driven by KDAC6 activity. SIGNIFICANCE STATEMENT: This study identifies lysine acetylation as a novel post-translational modification of organic anion transporting polypeptide (OATP)1B3 and demonstrates that altered lysine acetylation following inhibition of lysine deacetylase 6 reduces OATP1B3 transport function. These findings provide a mechanistic basis for altered hepatic drug disposition and highlight a new pathway through which drug-drug interactions involving OATP1B3 may occur.

Gallium nitrate, a non-redox analog of iron (III), suppresses bacterial biofilms and virulence within the framework of bacterial regulation. This study investigates the molecular mechanisms and regulatory pathways through which gallium nitrate modulates bacterial activity and function.

Osteomyelitis is a bacterial infection of the bone that affects millions globally. Due to problems in drug delivery, bacterial resistance through biofilm formation, adverse effects of the medications in use, etc, the scientists are searching for novel antimicrobial agents. As drug repurposing is an excellent method to develop new antimicrobials, this study evaluates the antibacterial and antibiofilm effects of the antidepressant paroxetine, combined with hydroxyapatite (HA), against drug-resistant, biofilm-forming Staphylococcus aureus. The antibacterial activity of paroxetine was assessed using the agar diffusion assay, and the minimum inhibitory concentration (MIC) was determined by the microdilution method. The antibiofilm potential of paroxetine was quantified through the crystal violet assay and further examined using scanning electron microscopy and confocal laser scanning microscopy. The bacterial load on drug-loaded hydroxyapatite was determined using the viable colony count method. The expression of bacterial adhesion genes following paroxetine treatment was analyzed using real-time polymerase chain reaction. Molecular docking studies were performed to evaluate the binding affinity of paroxetine to bacterial adhesion proteins and penicillin-binding proteins. The study demonstrated promising antibacterial properties of the drug and the drug-HA combination against S aureus with a MIC of 18.75 µg/mL. Paroxetine prevented the biofilms formation by S aureus, and could eradicate mature biofilms, with 83%, 86%, and 89% efficacy after 1X MIC, and 2X treatment. The antibiofilm effect was further confirmed by in silico, in vitro methods, wherein a strong affinity was noted for biofilm adhesion protein and paroxetine. Paroxetine treatment revealed downregulation of biofilm-adhering genes, like icaA, clfA, cna, fnbpA, and fib, using RT-PCR. When combined with HA, paroxetine displayed synergistic activity, and this was visualized using confocal laser scanning microscopy, which showed 81% and 19% dead/live cells after treatment, respectively. Furthermore, the scanning electron microscopy analysis displayed the impact of the drug paroxetine on S aureus cell morphology, which showed remarkable damage to the bacterial cells. In silico docking revealed that paroxetine's mode of action was mediated through binding with proteins and penicillin-binding protein, thereby inducing cell death. These results suggest that the paroxetine-HA combination may serve as a promising adjunctive strategy for treating biofilm-associated infections caused by S aureus.

This study aimed to investigate the molecular mechanisms underlying BPA(Bisphenol A)-induced cervical cancer, to identify core targets and signaling pathways, and to provide a theoretical basis for disease prevention and therapeutic intervention. The chemical structure of BPA was obtained from PubChem(Public Chemical Database), and its toxicity profile was evaluated using ProTox-3.0. Potential BPA-associated targets were predicted using multiple databases and subsequently standardized. Differentially expressed genes (DEGs) in cervical cancer were identified from Gene Expression Omnibus datasets using the R programming language and integrated with Weighted Gene Co-expression Network Analysis (WGCNA) to determine key module genes. The cervical cancer-related target set was then established. Common targets between BPA and cervical cancer were identified using Venn diagram analysis, and a protein-protein interaction (PPI) network was constructed to screen for core targets. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to explore biological functions and pathways. Target gene expression was validated across multiple datasets, and molecular docking analysis was conducted using Cavity-Based Dock 2 (CB-Dock2). BPA exhibits endocrine toxicity and matrix metalloproteinase-mediated tissue damage, with 3 core targets identified across databases. In cervical cancer, 803 up-regulated and 1092 down-regulated DEGs were screened (|log2FC| ≥1, adjusted P <.05). WGCNA identified the turquoise module (normal group R = 0.98, P = 5 × 10-12; cancer group r = -0.98, P = 5 × 10-12), overlapping with 1110 DEGs. Nineteen common targets of BPA and cervical cancer were enriched in gene expression negative regulation and cancer pathways (hypergeometric test, false discovery rate (FDR) <0.05). PPI analysis confirmed Estrogen Receptor 1 (ESR1) and (Poly [ADP-ribose] Polymerase 1 (PARP1) as core targets: ESR1 was down-regulated (GSE122697: log2FC = -2.8, P <.0001; The Cancer Genome Atlas (TCGA): log2FC = -2.6, P <.0001), PARP1 up-regulated (GSE122697: log2FC = 3.1, P <.0001; TCGA: log2FC = 2.9, P = .0012). Both showed progressive expression changes with lesion advancement (GSE63514: ESR1 log2FC = -4.2, PARP1 log2FC = 4.5, P <.0001). Molecular docking revealed stable binding of BPA to ESR1 (-8.3 kcal/mol) and PARP1 (-8.5 kcal/mol, root-mean-square deviation [RMSD] <2.0 A). BPA may promote cervical carcinogenesis by interacting with ESR1 and PARP1 to regulate key cancer-related pathways. These targets may serve as potential biomarkers and therapeutic intervention points. Further experimental validation is required to confirm these findings.

Plastic stabilizers (PSs) are chemical additives that are widely used to inhibit the degradation of plastics. However, their safety concerns and potential carcinogenic risks remain unclear. This study employed network toxicology strategies to elucidate the potential toxic effects and underlying molecular mechanisms of representative PSs, including 2,6-di-tert-butylphenol (2,6-DTB), tert-butylhydroquinone (TBHQ), and 2-(2H-benzotriazol-2-yl)-4,6-di-tert-pentylphenol (UV-328) in breast cancer (BC). Herein, we identified 69 potential genes related to PSs exposure and BC, and optimized five core targets: GSK3B, MAPK14, PARP1, PIM1, and TRDMT1, through subsequent LASSO and SVM algorithms. Based on these core genes, we constructed risk score and nomogram models, both of which revealed that high expression of these five core genes predicts poor prognosis in BC patients. Additionally, molecular docking and dynamic simulations indicated high-affinity interactions between PSs and these core targets (binding energies < -5 kcal/mol). Further correlation analysis with prediction analysis of microarray 50 (PAM50) revealed increased expression of all core genes in the basal-like subtype, especially PIM1 and TRDMT1, which also exhibited the highest risk scores. In vitro, PSs transcriptionally upregulated MAPK14, PIM1, and TRDMT1, with STAT3 mediating their transcription. Importantly, cell counting kit-8 and wound healing assays demonstrated that PSs promote BC cell proliferation and migration. Our research re-evaluates the carcinogenic risks of plastic stabilizers and suggests that PSs may enhance breast cancer progression via targets such as MAPK14, PIM1, and TRDMT1. This study introduces a new approach for evaluating the safety of plastic additives and offers novel insights into the toxicological effects of PSs.

Hyperuricemic nephropathy (HN) is a progressive kidney disease resulting from impaired urate metabolism, with limited effective therapies using natural sources. Sea cucumber peptides (SCPs) have shown metabolic regulatory potential in chronic diseases, but their efficacy in HN and underlying mechanisms remain unclear. This study investigated SCPs' effects using hyperuricemic mouse models and HK-2 cells. Interestingly, SCPs did not inhibit xanthine oxidase activity, yet significantly reduced serum uric acid (UA) levels, improved renal function, and attenuated pathological damage in mice. Mechanistically, SCPs reversed HN-induced metabolic reprogramming by downregulating key glycolytic enzymes (HK2, PFKFB3, and LDHA), reducing lactate accumulation, and enhancing ATP production. Multi-omics analyses revealed that SCPs optimized glycolysis-TCA cycle flux. Crucially, SCPs restored lactylation homeostasis via the SIRT1/p300 axis, suppressing global protein and histone lactylation. Concurrently, SCPs inhibited the HIF-1α/NF-κB/STAT3 pathway, decoupling metabolic-inflammatory signaling. These findings demonstrate that SCPs alleviate HN through multi-targeted regulation of urate metabolism, metabolic reprogramming, and lactylation, offering a novel strategy for functional food development.

Abnormal activation and pyroptosis of microglia caused by cerebral ischemia‑reperfusion injury (CIRI) are key mechanisms underlying neuronal damage. The NF‑κB/NLRP3 pathway is a core mediator of microglial pyroptosis and neuroinflammatory cascades in CIRI. Milk fat globule‑EGF factor 8 (MFG‑E8) is a critical anti‑inflammatory and neuroprotective factor. Propofol (PPF) exhibits antioxidant activity and ameliorates neuronal injury, but its effects on CIRI and underlying mechanisms remain unclear. The present study aimed to investigate whether PPF alleviates neuronal injury by modulating NF‑κB/NLRP3 pathway via regulating MFG‑E8 expression. An oxygen‑glucose deprivation/reoxygenation (OGD/R) model was established using mouse microglial BV‑2 and hippocampal neuronal HT22 cells and cell survival was assessed via Cell Counting Kit‑8 assay. Polarity in BV‑2 cells was evaluated using flow cytometry, while cell death was assessed by Calcein AM/PI and TUNEL staining. A transient middle cerebral artery occlusion (tMCAO) mouse model was established and neurological deficit scores were assessed. The impacts of PPF on cortical damage, neuroinflammation, apoptosis and pyroptosis in tMCAO mice were observed by histopathological staining. Inflammatory factor levels were assessed using ELISA kits. Western blotting was performed to assess MFG‑E8, pyroptosis and NF‑κB/NLRP3 pathway‑related proteins. OGD/R decreased viability, increased apoptosis and pyroptosis rates in BV‑2 and HT22 cells and promoted M1 polarization in BV‑2 cells; PPF treatment reversed these effects. MFG‑E8 was downregulated in OGD/R‑treated BV2 cells, while PPF upregulated MFG‑E8 expression. Additionally, PPF decreased cerebral infarction volume in tMCAO mice, improved neurological deficit score, mitigated pathological brain tissue damage and decreased the number of degenerating neurons. PPF also inhibited pro‑inflammatory microglia activation and decreased pro‑inflammatory factor levels. Mechanistically, PPF suppressed NF‑κB pathway activation and downregulated NLRP3 by upregulating MFG‑E8; silencing MFG‑E8 reduced the protective effects of PPF in tMCAO mice and OGD/R cell models. PPF improved neuronal injury in CIRI by upregulating MFG‑E8 to inhibit pyroptosis induced by the NF‑κB/NLRP3 pathway.