This study investigated the effects of indirubin on autophagy and apoptosis in cervical cancer models, with a focus on elucidating the underlying molecular mechanisms. A xenograft tumor model in BALB/c-Nude mice and in vitro experiments using HeLa cell lines were employed. Indirubin treatment demonstrated a concentration-dependent inhibition of cervical cancer cell growth, accompanied by the induction of apoptosis and autophagy. Mechanistic analysis revealed that these effects were associated with the modulation of the PI3K/AKT signaling axis. This was evidenced by enhanced autophagic flux, indicated by an increased LC3-II/LC3-I ratio and decreased P62 expression, and concurrent induction of mitochondrial apoptosis, marked by upregulated pro-apoptotic Bax and downregulated anti-apoptotic Bcl-2 levels. Furthermore, indirubin treatment was linked to the inhibition of the MEKK1/SEK1/JNK/AP-1 signaling pathway, which may also contribute to its anti-tumor effects. These findings suggest that the anti-tumor activity of indirubin is associated with the regulation of the PI3K/AKT and MAPK pathways, the enhancement of autophagy, and the promotion of apoptosis, providing a theoretical basis for its therapeutic potential in cervical cancer treatment.

To explore the association between life’s essential 8 and epigenetic age based on twins population. This study included 1030 twins (515 pairs) for cross-sectional analysis and conducted cross-lagged analysis among 294 twins (147 pairs) who participated in both the baseline and follow-up surveys from the Chinese National Twin Registry. LE8 scores were obtained from measurements based on American Heart Association definitions. DNA methylation data were used to calculate epigenetic age metrics, including GrimAA, DamAA and DunedinPACE. Linear mixed-effect models were applied for cross-twin analyses and within-monozygotic-pair analyses. In the cross-sectional analysis, higher LE8 score was associated with slower epigenetic aging (DunedinPACE and DamAA) in both across-twin analyses and within-monozygotic-pair analyses. In stratified analyses, the association between LE8 score and epigenetic age appeared more significant in males and in individuals aged 50 years older. The cross-lagged analysis further revealed significant temporal associations between LE8, health factor, and DunedinPACE. Higher LE8 scores were associated with a deceleration in biological aging.

Background The discrepancies in clinicopathologic characteristics and prognosis between invasive mucinous adenocarcinoma (IMA) and nonmucinous lung adenocarcinoma with a mucin-laden feature (MNLA) remain unclear. Methods Data were collected retospectively for 978 consecutive patients with IMA/MNLA who underwent surgical resection between October 2017 and December 2019. Survival outcomes were estimated using the Kaplan-Meier method and compared using the log-rank test. The adjusted hazard ratio (aHR) with 95% confidence interval (CI) of the prognosticator was calculated using a multivariable Cox proportional hazards model. Results Pure IMA was associated with a higher prevalence of KRAS mutation (51.5%), while MNLA was associated with higher prevalences of EGFR mutation (40.4%) and EML4-ALK rearrangement (19.1%). Regarding prognosis, compared to patients with pure IMA, patients with MNLA or mixed IMA had worse disease-free survival (MNLA: aHR, 2.620, 95% CI, 1.690-4.061; mixed IMA: aHR, 3.458, 95% CI, 1.704-7.016) and overall survival (MNLA: aHR, 2.229, 95% CI, 1.185-4.193; mixed IMA: aHR, 1.723, 95% CI, 0.632-4.698). Among patients who experienced recurrence, those with pure IMA had a higher incidence of intrathoracic-only recurrence compared to those with MNLA (80.8% vs 39.6%), demonstrating that extrathoracic-only recurrence was more prevalent in MNLA (35.1% vs 7.3%). The recurrence pattern of mixed IMA was different from that of pure IMA (pure IMA vs mixed IMA: intrathoracic-only, 80.8% vs 50.0%; both intrathoracic and extrathoracic, 11.5% vs 40.0%). Conclusions Although MNLA, pure IMA, and mixed IMA have consistent mucin-laden features, they appear to exhibit differences in prognosis, clinicopathologic characteristics, and molecular profiles.

Aims: Brown adipose tissue (BAT) relies heavily on mitochondrial activity and reactive oxygen species homeostasis to regulate thermogenesis and metabolic balance. However, the specific role of glutathione peroxidase 4 (GPX4), a critical antioxidant enzyme and central regulator of ferroptosis, in BAT remains unclear. This study aims to investigate the necessity of GPX4 for the functional integrity and thermogenic capacity of BAT. Methods: Initially, we employed pharmacological inhibition of GPX4 in vitro using differentiated brown adipocytes. To investigate its role in vivo, we generated a BAT-specific Gpx4 knockout mouse model. The physiological and metabolic impacts of GPX4 deficiency were evaluated across three different conditions: cold exposure, high-fat diet, and vitamin E-deficient diet. Comprehensive evaluations were conducted using metabolic, histological, ultrastructural, and transcriptomic (RNA-seq) analyses. Results: In vitro, pharmacological inhibition of GPX4 induced ferroptosis in differentiated brown adipocytes, suggesting its potential regulatory role. Strikingly, in vivo histological, ultrastructural, and metabolic analyses indicated that the genetic deletion of GPX4 does not impair BAT morphology or thermogenic function under any of the tested conditions. Consistent with these physiological findings, RNA-seq revealed that GPX4 deficiency did not significantly alter the expression of genes associated with ferroptosis or thermogenic pathways. Conclusion: Although pharmacological inhibition of GPX4 triggers ferroptosis in brown adipocytes in vitro, GPX4 is not essential for maintaining the morphological integrity and thermogenic capacity of BAT in vivo under the specific experimental conditions tested.

The development of novel low-toxicity, high-efficacy therapeutics for colorectal cancer is urgently needed, given its global burden of approximately two million new cases and one million deaths annually. In the present study, we demonstrated for the first time that Ginsenoside Rg5 (Rg5), a small-molecule compound isolated from red ginseng, significantly inhibited tumor growth of colorectal cancer in mouse models. In addition, the levels of autophagy-related proteins, including LC3-II and p62, were significantly increased in tumors from Rg5-treated mice. Further mechanistic investigations revealed that Rg5 suppresses lysosomal degradation in colorectal cancer cells through inhibition of ATP6V1A (a key subunit of V-ATPase), consequently blocking autophagic flux. This impairment of autophagy ultimately induces apoptosis in colorectal cancer cells and inhibits tumor progression. This study provides evidence that Rg5 functions as an autophagy inhibitor, laying the foundation for its application in colorectal cancer adjuvant therapy.

The molecular heterogeneity of brain metastases hampers therapeutic development for cures. To address this unmet and urgent need, we construct a comprehensive multi-omic, single cell, and spatially resolved atlas of 1,032 pan-cancer brain metastases, identifying four robust molecular subtypes with distinct biological programs and clinical associations. These brain metastases subtypes (BrMS) are defined by unique biological states: neural-like (BrMS1), metabolic (BrMS3), highly proliferative/immune-excluded (BrMS4), and an immune-infiltrated (BrMS2) state featuring a coordinated epithelial-mesenchymal transition program. Patient-derived organoids coupled with targeted drug screening indicate subtype-specific molecular dependencies and putative targets, notably mTOR signaling activation in BrMS3 and CDK4/6 axis activation in BrMS4, while BrMS1 and BrMS2 display distinct radiobiologic and immunologic signatures. This atlas provides a rigorous classification framework of BrMs and offers insights into subtype-specific molecular vulnerabilities. The molecular heterogeneity of brain metastases (BrMs) poses challenges for their treatment. Here, the authors generate a multi-omic, single cell, and spatially resolved atlas of 1,032 pan-cancer BrMs and identify four molecular subtypes with distinct biological and clinical features.

BACKGROUND:Colitis-associated colorectal cancer (CAC) is driven by chronic inflammation and immune dysregulation. However, how macrophage state heterogeneity is organized across different stages of CAC progression remains unclear. METHODS:Here, using genetic depletion, single-cell transcriptomics, and pharmacological intervention, and analysis of human colitis-associated colorectal cancer specimens, we identify stage-associated remodeling of CD169-associated macrophage states during CAC progression. RESULTS:We demonstrate that CD169 marks functionally distinct macrophage states with opposing roles: CD169-low macrophages predominate during colitis and exhibit pro-inflammatory features, whereas CD169-mid/high macrophages emerge at tumor stages, localize preferentially to para-tumor regions, and display immunosuppressive and immune-inert interaction profiles. These observations support stage-associated remodeling of CD169-associated macrophage states during CAC progression. Importantly, CD169 depletion restrains tumor growth and enhances intratumoral T cell infiltration, highlighting CD169-associated macrophages as potential therapeutic targets in inflammation-driven colorectal tumorigenesis. CONCLUSIONS:Together, our findings reveal stage-associated remodeling of CD169-associated macrophage states during CAC progression, with distinct CD169 states exhibiting divergent immune regulatory features at different disease stages. These findings highlight the importance of considering macrophage state heterogeneity when targeting CD169-associated pathways and support further investigation of state-informed therapeutic strategies in inflammation-driven colorectal tumorigenesis.

Cancer remains a major therapeutic challenge due to drug resistance and metastasis, processes driven by oxidative stress and redox imbalance. Targeting this vulnerability through ferroptosis (iron-dependent lipid peroxidation) and cuproptosis (copper-driven mitochondrial dysfunction), two ROS-mediated cell death pathways, offers a promising therapeutic strategy. However, clinical translation is hindered by incomplete understanding of their redox regulation and limited immunogenicity. A genome-wide CRISPR knockout screen was performed to identify key regulators of ferroptosis. Genetic depletion or pharmacological inhibition of candidate genes was evaluated across multiple cancer cell lines for sensitivity to ferroptosis inducer RSL3 and the cuproptosis inducer elesclomol (Es). Antitumor efficacy was assessed in xenograft, orthotopic, metastatic, and syngeneic mouse models, alone or combined with immune checkpoint inhibitors. Mechanistic studies also examined ROS production, mitochondrial stress, mitochondrial DNA release, cGAS-STING activation, and immune responses within the tumor microenvironment. Glutathione reductase (GSR), a central enzyme maintaining reduced glutathione (GSH) homeostasis, was identified as the top suppressor of ferroptosis. GSR knockout or pharmacological inhibition markedly sensitized diverse cancer cell lines to RSL3-induced ferroptosis, while GSR overexpression conferred resistance. Strikingly, GSR depletion also enhanced sensitivity to cuproptosis triggered by the copper ionophore Es. In multiple in vivo tumor models, GSR inhibition synergizes with RSL3 or Es to suppress tumor growth, inhibit lung metastasis, and prolong survival. Mechanistically, GSR deficiency amplified ROS production, induced mitochondrial stress, and triggered the cytosolic mitochondrial DNA release under ferroptotic or cuproptotic stress, activating the cGAS-STING pathway in vitro and in vivo. This increased inflammatory cytokine production, promoted immunogenic cell death, and enhanced the release of damage-associated molecular patterns (DAMPs), including HMGB1. Together, GSR inhibition combined with a ferroptosis or cuproptosis inducer transformed the tumor microenvironment into a highly immune stimulatory state, thereby enhancing the efficacy of immune checkpoint blockade through increased dendritic cell activation and T-cell infiltration and activation. GSR represents a key molecular node connecting and modulating ferroptosis and cuproptosis through redox regulation. Targeting GSR amplifies ROS-mediated immunogenic cell death, triggers cGAS-STING activation in cancer cells, and enhances the efficacy of cancer immunotherapy, providing a promising redox-based therapeutic strategy.

Breast cancer survivorship requires attention to treatment related changes in body composition, nutrition, and quality of life. Phase angle from bioelectrical impedance analysis reflects cellular health and may identify early nutritional or functional decline. This study examined perioperative body composition and phase angle trajectories in women receiving neoadjuvant chemotherapy versus surgery first treatment and evaluated pilot feasibility. BC-NUTRITION was a prospective two cohort observational pilot study. Women aged 18 to 80 years with primary invasive breast cancer followed either neoadjuvant chemotherapy then surgery or surgery first treatment. Assessments were planned at five points from admission to six months after discharge. Measures included segmental bioelectrical impedance, anthropometry, nutrition screening, patient reported outcomes, biochemistry, surgical variables, and treatment toxicity. The pilot dataset included 95 women, 30 in neoadjuvant chemotherapy and 65 in surgery first treatment. Retention to postoperative day 7 was 100 percent, 95 of 95, and all evaluable feasibility metrics met prespecified thresholds. At admission, whole body composition was largely comparable. The neoadjuvant chemotherapy cohort had lower albumin, 40.52 versus 42.58 g per L, p = 0.020, lower lymphocyte count, 1.17 versus 1.79 ×10⁹ per L, p < 0.001, lower Prognostic Nutritional Index, 46.36 versus 51.55, p < 0.001, higher extracellular to total body water ratio, 0.39 versus 0.38, p < 0.001, and lower whole body 50 kHz phase angle, 4.64 degrees versus 5.23 degrees, p < 0.001. During the surgical week, operated side 50 kHz phase angle decreased in both cohorts. The mean decrease was 0.50 degrees after neoadjuvant chemotherapy, 95 percent CI 0.34 to 0.66, p < 0.001, and 0.51 degrees after surgery first treatment, 95 percent CI 0.42 to 0.60, p < 0.001. Whole body phase angle decreased in the surgery first cohort, mean decrease 0.25 degrees, 95 percent CI 0.16 to 0.33, p < 0.001. In the neoadjuvant chemotherapy cohort, the mean change was smaller and not significant, with a 0.11 degree decrease and a 95 percent CI ranging from a 0.25 degree decrease to a 0.03 degree increase, p = 0.112. The BC NUTRITION pilot showed strong feasibility and identified phase angle as a promising tissue level signal of perioperative cellular health in breast cancer. These results support the definitive 214 participant study and future phase angle guided nutrition and prehabilitation interventions. MR-44-24-028962

Background: Polycystic ovary syndrome (PCOS) is a frequently encountered endocrine disturbance with a still poorly defined etiology that arises in women during their reproductive years. Increased apoptosis of granulosa cells has been identified as one of the key factors contributing to abnormal follicular development. This study aimed to elucidate the role of six-transmembrane epithelial antigen of prostate 4 (STEAP4) in granulosa cell function using in vitro and in vivo models relevant to PCOS. Methods: We treated KGN cells (a human granulosa-like cell line) and C57BL/6 mice with dehydroepiandrosterone (DHEA) to establish experimental models mimicking PCOS features. STEAP4 expression was assessed by qRT-PCR, Western blot, and immunohistochemistry. Proliferative capacity and apoptotic rates were gauged with CCK-8 assays, EdU labeling, and flow cytometry. The regulatory mechanisms were investigated through immunofluorescence staining for nuclear factor erythroid-2-related factor 2 (Nrf2) nuclear translocation and immunoprecipitation assays for HIF-1α ubiquitination. Results: Exposure to androgen markedly raised both STEAP4 transcript and protein abundance in KGN cells as well as in PCOS model mice. STEAP4 knockdown resulted in increased proliferation and reduced apoptosis in DHEA-treated KGN cells. Mechanistically, STEAP4 enhanced reactive oxygen species levels, promoted Nrf2 nuclear translocation, and stabilized HIF-1α protein by reducing its ubiquitination, leading to increased TERT expression and subsequent TP53 pathway activation. In vivo, STEAP4 silencing significantly alleviated hormonal imbalances, estrous cycle disorders, and reduced oxidative stress levels in ovarian tissue of DHEA-induced PCOS-like mice. Conclusions: Taken together, evidence from these experimental models indicates that STEAP4 shapes oxidative stress and granulosa cell apoptosis by operating through the ROS-TERT-TP53 axis. The data point to a possible contribution of STEAP4 to PCOS pathogenesis and mark it as a candidate therapeutic target that merits additional clinical study.

Breast cancer presents a formidable global health challenge, with traditional monotherapies frequently hampered by limited specificity and off-target toxicity. Herein, we developed a highly integrated, biomimetic, and pH-responsive zeolitic imidazolate framework-8 (ZIF-8) nanoplatform, RBCm-coated nanoparticles (R-A/G@Z), tailored for cascaded starvation and potentiated ferroptosis therapy. Through a one-pot biomineralization approach, the hydrophobic ferroptosis inducer artesunate (ART) and the hydrophilic metabolic enzyme glucose oxidase (GOx) were co-encapsulated within a ZIF-8 framework, followed by red blood cell membrane (RBCm) surface cloaking. The R-A/G@Z platform demonstrates enhanced tumor accumulation and undergoes acid-triggered disassembly within the tumor microenvironment (TME). Upon internalization, GOx-mediated glucose oxidation serves to starve the tumor of its primary energy source while continuously generating hydrogen peroxide (H2O2) and protons. This localized acidification accelerates structural degradation, supplying ample H2O2 to fuel an ART-triggered Fenton-like reaction. Crucially, the concurrent liberation of Zn2+ from the ZIF-8 lattice orchestrates a dual-regulatory axis: it downregulates ferroportin 1 (FPN1) to retain reactive iron intracellularly, and upregulates tumor protein p53 (p53) to suppress the solute carrier family 7 member 11-glutathione-glutathione peroxidase 4 (SLC7A11-GSH-GPX4) antioxidant shield. This integrated strategy overcomes the tumor's redox defenses, leading to ferroptotic cell death. In vitro and in vivo evaluations confirm that R-A/G@Z effectively suppresses aggressive breast tumors while maintaining a good safety profile, offering a promising strategy for intelligent metabolic-chemodynamic cancer nanomedicine.

While classical tumor suppressors in colorectal cancer (CRC) are predominantly recognized for restraining cell-autonomous proliferation, their extrinsic mandate in orchestrating the tumor immunometabolic niche remains poorly defined. Clinically, we document that APC membrane recruitment protein 1 (AMER1) downregulation correlates with advanced progression and cytotoxic CD8+ T cell spatial exclusion in CRC patients. Using parallel homograft models in diverse host immune backgrounds, we show that tumoral AMER1 confers robust in vivo tumor-suppressive effects that are dependent on a fully functional immune system. Single-cell RNA sequencing reveals that tumoral AMER1 enrichment actively preserves CD8+ T cell effector stemness by expanding the CXCR5+ precursor exhausted subset (Tpex) across regional lymph nodes and primary tumor microenvironments. Integrated multi-omics and biochemical tracking identify dopamine (DA) as the conserved neurometabolic effector driving this niche remodeling. Mechanistically, AMER1 physically binds and rescues dopa decarboxylase (DDC) from post-translational degradation to sustain tumoral DA secretion; conversely, AMER1 loss creates a localized DA void. Cell-autonomously, tumoral DA accumulation triggers Gasdermin D (GSDMD)-dependent tumor pyroptosis. Therapeutically, local DA administration halts multi-lineage carcinoma progression by reversing CD8+ T cell terminal exhaustion and reinforcing central memory differentiation. Collectively, our findings redefine AMER1 as a critical immunometabolic gatekeeper and establish neurotransmitter metabolic bypassing as a promising therapeutic strategy for CRC.

Glioma, the most aggressive primary brain tumor, progresses in close association with an immunosuppressive microenvironment. By integrating the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) databases, we identified six immune chemokine-related prognostic genes, with particular focus on mitochondrial E3 ubiquitin protein ligase 1 (MUL1). MUL1 was significantly upregulated in glioma, and its elevated expression correlated with malignant features including isocitrate dehydrogenase (IDH) wild-type status, the aggressive molecular subtypes (including Mesenchymal and Classical), high World Health Organization (WHO) grades, and poor prognosis. This upregulation was also associated with increased immune checkpoint expression and enhanced M2 macrophage infiltration. A nomogram constructed based on MUL1 expression demonstrated relatively reliable prognostic performance. In vitro experiments showed that silencing MUL1 significantly inhibited glioma cell proliferation, migration, and invasion. These findings help clarify the potential role of MUL1 in regulating the immune microenvironment of glioma and provide new evidence supporting its utility as a prognostic biomarker and therapeutic target.

Peripheral arterial disease (PAD) is characterized by impaired angiogenesis, yet the molecular mechanisms linking metabolic dysregulation to epigenetic reprogramming in endothelial cells (ECs) remain poorly understood. Here, we identify hexokinase 2 (HK2) as a critical regulator of angiogenesis through histone lactylation in PAD. In clinical specimens and murine hindlimb ischemia (HLI) models, HK2 expression was significantly downregulated. Functional assays in hypoxia-serum starved (HSS) human umbilical vein ECs (HUVECs) demonstrated that HK2 overexpression rescued angiogenesis by enhancing proliferation, migration, tube formation, and pro-angiogenic protein expression (VEGFA), while HK2 knockdown suppressed these phenotypes. Mechanistically, HK2 deficiency selectively reduced histone H3 lysine 18 lactylation (H3K18la) among eight tested histone lactylation sites, and HK2 restoration under HSS restored H3K18la level. Exogenous lactate reversed angiogenic defects in HK2-knockdown HUVECs by elevating H3K18la, which directly activated VEGFA transcription, as shown by Chromatin Immunoprecipitation coupled with quantitative Polymerase Chain Reaction (ChIP-qPCR). Furthermore, Sirtuin 2 (SIRT2), as a de-lactylase, inhibition in HK2-knockdown HUVECs restored H3K18la, angiogenesis, and pro-angiogenic protein expression. In HLI mice, SIRT2 inhibitor treatment improved blood flow recovery, increased EC density, and upregulated H3K18la. Our findings establish HK2 as a metabolic-epigenetic nexus driving angiogenesis via lactate-dependent H3K18la modification and propose SIRT2 inhibition as a novel therapeutic strategy to bypass HK2 deficiency in PAD.

Hepatocellular carcinoma presents with three distinct immune phenotypes, including immune-desert, immune-excluded, and immune-inflamed, indicating various treatment responses and prognostic outcomes. The clinical application of multi-omics parameters is still restricted by the expensive and less accessible assays, although they accurately reflect immune status. A comprehensive evaluation framework based on "easy-to-obtain" multi-model clinical parameters is urgently required, incorporating clinical features to establish baseline patient profiles and disease staging; routine blood tests assessing systemic metabolic and functional status; immune cell subsets quantifying subcluster dynamics; imaging features delineating tumor morphology, spatial configuration, and perilesional anatomical relationships; immunohistochemical markers positioning qualitative and quantitative detection of tumor antigens from the cellular and molecular level. This integrated phenomic approach aims to improve prognostic stratification and clinical decision-making in hepatocellular carcinoma management conveniently and practically.

Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation driven by intestinal barrier disruption, immune dysregulation, and microbiota imbalance. Barrier dysfunction not only aggravates intestinal inflammation but also promotes metabolic liver diseases, such as non-alcoholic steatohepatitis (NASH), through the gut-liver axis. However, current IBD therapies mainly target intestinal oxidative stress and inflammation, with limited efficacy, while NASH treatments focus on the liver, and interventions targeting the gut-liver axis remain limited. Here, we developed a synergistic quadruple intestinal barrier repair system, termed PGaA Gel, based on an inulin hydrogel loaded with gallium-based mesoporous polydopamine nanoparticles (MPDA-Ga) and L-alanyl-L-glutamine (ALG). PGaA Gel was designed to simultaneously restore the physical, chemical, immune, and microbial barriers of the intestine. MPDA-Ga effectively scavenged reactive oxygen species and inhibited pathogenic bacteria, while ALG promoted epithelial regeneration and mucin production. In addition, inulin enhanced intestinal retention and acted as a prebiotic to produce short-chain fatty acids, thereby reinforcing immune tolerance. In mouse models, PGaA Gel exhibited superior efficacy in restoring multidimensional intestinal barrier integrity and significantly alleviated IBD symptoms compared with single-component treatments. Importantly, PGaA Gel also repaired intestinal barrier dysfunction associated with NASH, reduced lipopolysaccharide translocation via the gut-liver axis, and mitigated hepatic inflammation and lipid accumulation. These findings highlight comprehensive intestinal barrier repair as an effective therapeutic strategy for IBD and gut-liver axis-related liver diseases.

Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP), a common organophosphate flame retardant, is extensively used in various consumer products and has emerged as an environmental pollutant. Recent studies have documented the neurotoxic effects of TDCIPP, highlighting its ability to promote neuronal apoptosis and induce autophagy. Nonetheless, the underlying regulatory mechanisms remain poorly understood. The present study observed an upregulation of Brain and Muscle ARNT-Like 1 (BMAL1) in TDCIPP-treated mouse HT22 cells, indicating that BMAL1 may play a critical role in TDCIPP-induced neuronal autophagy and apoptosis. Furthermore, the impact of BMAL1 knockdown on TDCIPP-induced autophagy and apoptosis in HT22 cells was explored using Western blot (WB) and flow cytometry (FACS) analysis. The results demonstrated that TDCIPP exposure modulated the expression levels of BMAL1 and autophagy-related proteins and increased the phosphorylation of mTOR. The suppression of BMAL1 expression resulted in decreased AMPK expression, thereby blocking cell autophagy. Collectively, the results highlight the role of BMAL1 in the cell death mechanism induced by TDCIPP through the AMPK signaling pathway in HT22 cells. Therefore, the present study provides a new perspective and evidence on the mechanism of TDCIPP-induced neurotoxicity in HT22 cells.

BACKGROUND:Recurrence and metastasis significantly impact the prognosis of lung adenocarcinoma (LUAD), yet effective therapies targeting these processes remain limited, especially in advanced stages. This study investigates the role of S100A10 as an oncogenic driver in LUAD progression via epithelial-mesenchymal transition (EMT). METHODS:S100A10 expression was analyzed in public datasets and correlated with patient survival. Functional studies involved S100A10 knockdown or overexpression in LUAD cell lines, assessing viability (CCK-8), migration, invasion (Transwell, wound healing), mRNA (qPCR), and protein (Western blot). Tumorigenicity was evaluated using in vivo models. A small-molecule inhibitor, [D-Leu-4]-OB3, was identified through virtual screening and tested for its effect on S100A10 and LUAD. RESULTS:High S100A10 expression correlated with poor outcomes in LUAD. Knockdown of S100A10 suppressed cell viability, migration, invasion, and EMT both in vitro and in vivo, while overexpression enhanced these malignant traits. Mechanistically, S100A10 activated JUND and Tenascin-C (TNC), promoting EMT. Re-expression of TNC rescued the anti-metastatic effects of S100A10 inhibition. [D-Leu-4]-OB3 specifically targeted S100A10, inhibiting LUAD growth and metastasis. CONCLUSION:S100A10 promotes LUAD progression and metastasis through JUND/TNC-mediated EMT. [D-Leu-4]-OB3 represents a promising targeted therapy for LUAD by inhibiting S100A10.

As a key experimental method to study the pathogenesis of brain tumors, the establishment of standardized operation process for intracranial orthotopic tumor modeling is of great significance. At present, although this technology has become the main method for brain tumor research, it has been reported in the literature that there is significant heterogeneity in the injection sites, and there is a lack of systematic verification, which leads to the repeatability of the experiment being questioned. In view of this technical bottleneck, this study used female C57BL mice as a model to establish a standardized intracranial tumor formation operation system. By systematically analyzing the two anatomical markers of bregma and lambda in mice, we not only clarified the quantitative relationship between body weight and bregma-lambda distance in C57BL mice, but also defined the normal range of bregma-lambda distance. More importantly, we found and verified a new standardized injection site. Based on this finding, this study finally constructed a complete set of intracranial tumor formation technology scheme including positioning method, operation specification and quality control.