Introduction: Ulcerative Colitis (UC) is driven by disrupted epithelial barrier function and chronic inflammation, yet the interaction between oxidative stress and inflammasome signaling remains unclear. This study investigated whether Nrf2 expression correlates with NLRP3 inflammasome activity in intestinal epithelial cells under inflammatory conditions and whether the natural Nrf2 activator, Sulforaphane (SFN), modulates this axis. Methods: A UC-like inflammatory state was established in Caco-2 cells using a cytokine cocktail (TNF-α, LPS, IFN-γ, IL-1β). Nrf2 was silenced using siRNA, and SFN was administered for activate Nrf2. Gene and protein expression were assessed by qPCR, ELISA, and Western blot. Public bulk and single-cell RNA-seq datasets from UC patients were analyzed to validate clinical relevance. Results: Cytokine stimulation significantly reduced Nrf2 expression while upregulating NLRP3, IL-1β, and IL-18 (p < 0.001). Nrf2 knockdown was associated with enhanced inflammasome activation, as evidenced by increased levels of NLRP3, caspase-1, and pro-inflammatory cytokines. Conversely, SFN pretreatment restored Nrf2 expression and markedly suppressed NLRP3 and IL-18 expression (p < 0.01 to p < 0.001). Multiomic analyses of UC patient samples confirmed an inverse expression pattern between Nrf2 and NLRP3 signaling pathways. Discussion: These findings indicate that reduced Nrf2 expression is strongly associated with enhanced NLRP3 inflammasome activation in inflamed intestinal epithelial cells. Pharmacologic activation of Nrf2 by SFN correlates with restored redox balance and attenuated inflammation, supporting the Nrf2-NLRP3 axis as a potential therapeutic target warranting further investigation. Limitations include use of a single cell line and lack of in vivo validation. Conclusion: This study provides correlative evidence for a redox-inflammasome axis in UC pathogenesis and suggests that further investigation of SFN as a candidate therapeutic approach is warranted.
Introduction/Objective: Bromodomain-containing protein 9 (BRD9) is a newly identified oncogenic regulatory factor in multiple human malignancies, yet its precise roles in hepatocellular carcinoma (HCC) remain largely unknown. This study aimed to investigate the function and mechanism of BRD9 in HCC, particularly its involvement in molecular targeted drug resistance. Methods: BRD9 expression was either overexpressed or knocked down in HCC cells. PXR transcription factor activity was assessed using luciferase reporter assays, quantitative polymerase chain reaction (qPCR), and chromatin immunoprecipitation (ChIP). HCC cells were treated with serial concentrations of molecularly targeted drugs. Antitumor activity was evaluated by MTT assays, colony formation assays, flow cytometry for apoptosis analysis, and subcutaneous tumor models. Drug metabolic rates were quantified using high-performance liquid chromatography (HPLC). Results: Overexpression of BRD9 significantly enhanced the transcriptional activity of PXR and promoted the expression of PXR-dependent multidrug resistance-related genes, including CYP3A4 and ABCB1. Mechanistically, BRD9 overexpression facilitated the recruitment of PXR to the promoter and enhancer regions of CYP3A4, thereby accelerating the metabolic clearance of sorafenib in HCC cells. Functionally, enforced expression of BRD9 rendered HCC cells more resistant to molecularly targeted agents, whereas knockdown of BRD9 sensitized them to these drugs. Furthermore, combination therapy experiments demonstrated that the BRD9 smallmolecule inhibitor I-BRD9 exerted synergistic antitumor activity with sorafenib against HCC cells. Discussion: These findings reveal that BRD9 mediates molecular targeted drug resistance in HCC through enhancing the transcription factor activation of PXR. This mechanism provides a potential therapeutic target for overcoming drug resistance in HCC, and the synergistic effect of IBRD9 with sorafenib suggests a promising combination strategy. Conclusion: BRD9 promotes resistance to molecular targeted drugs in HCC via PXR-dependent transcriptional activation. Targeting BRD9 may represent a novel approach to sensitize HCC cells to existing therapies.
Abstract: General anesthetics are indispensable for surgical procedures, procedural sedation, and intensive care, but their mechanisms of action in the human brain are not fully understood. Classical biochemical approaches have delineated key targets of general anesthetics, such as GABAA and NMDA receptors, ion channels, mitochondria, neurotransmission, and inflammatory pathways. However, animal models and two-dimensional cultures do not represent human-specific neurodevelopment, regional cellular diversity, or three-dimensional brain architecture. Human brain organoids offer a complementary system to investigate anesthetic effects during human development. Recent reports on cerebral, forebrain, and midbrain organoids indicate that propofol and sevoflurane may affect neural progenitor cell proliferation, neuronal differentiation, apoptosis, autophagy, mitochondrial metabolism, long non-coding RNA networks, synaptic gene programs, and regionspecific maturation. These results do not preclude clinically required anesthesia, particularly as large-scale human studies have failed to demonstrate deficits in general intelligence following single short-term exposures. Rather, organoid models help establish which types of neural cells, developmental stages, and molecular mechanisms might be vulnerable to anesthesia. This review highlights recent advances in organoid-based research on the mechanisms of general anesthesia, particularly for propofol and volatile anesthetics. It also explores how region-specific organoids, assembloids, vascularized systems, microglia-enriched models, and multi-omics techniques may help resolve developmental vulnerability and aid more targeted translational studies of anesthesia.
Introduction: Endometrial Cancer (EC) is the most prevalent gynecologic malignancy, and its incidence continues to rise globally. PTEN mutations occur frequently in EC and lead to aberrant activation of the PI3K/AKT pathway, driving uncontrolled cellular proliferation and survival. In murine models, uterine-specific deletion of Pten results in rapid EC development. Emerging evidence implicates Histone Deacetylases (HDACs) as key epigenetic regulators of tumor progression, yet the specific role of HDAC3 in EC remains poorly defined. Methods: We generated uterine-specific Pten and Hdac3 double-knockout mice (Pgrcre/+Hdac3f/fPtenf/f; Hdac3d/dPtend/d) to investigate the functional and therapeutic relevance of HDAC3. Histopathologic analysis was performed to examine the effect of Hdac3 ablation on EC with Pten deficiency compared with Pten single-knockout mice (Pgrcre/+Ptenf/f; Ptend/d) at 1 and 2 months of age. To evaluate the effect of the HDAC3 inhibitor (RGFP966), 6-week-old Ptend/d (Stage Ⅰ EC) mice were treated with vehicle or RGFP966 (10 mg/kg) twice per week for 5 weeks via intraperitoneal injection. Results: Histopathological analysis revealed marked regression of EC in Hdac3d/dPtend/d mice compared to Ptend/d controls to investigate the functional and therapeutic relevance of HDAC3. Pharmacologic inhibition of HDAC3 using the selective inhibitor RGFP966 in Ptend/d mice significantly reduced tumor burden and metastatic dissemination compared to vehicle treatment. Mechanistically, HDAC3 inhibition suppressed tumor cell proliferation and enhanced apoptosis, concomitant with reduced phosphorylation of ERK1/2 and AKT levels. Discussion: While our findings demonstrate significant antitumor effects of HDAC3 inhibition in PTEN-deficient endometrial cancer, further studies are needed to define the downstream molecular pathways responsible for these effects. Conclusion: Collectively, these findings establish HDAC3 as a critical epigenetic driver of endometrial tumorigenesis and support selective HDAC3 inhibition as a promising therapeutic strategy for PTEN-deficient EC.
Abstract: Metabolically Dysfunctional-Associated Steatohepatitis (MASH), affecting approximately 5.27% of the global population, represents a critical unmet medical need with limited therapeutic options. The complex pathophysiology involving multiple interconnected pathways necessitates innovative therapeutic approaches beyond traditional targets. This review comprehensively examines emerging pharmacological targets for MASH treatment, focusing on novel mechanisms that address key pathogenic processes, including lipogenesis, inflammation, endoplasmic reticulum stress, and immune cell recruitment. We conducted a systematic analysis of preclinical and clinical evidence for six promising therapeutic targets: cyclophilins, ATP citrate lyase (ACLY), NLRP3 inflammasome, X-box binding protein 1 (XBP1), farnesoid X receptor (FXR), and chemokine receptors (CCR). Cyclophilin inhibitors (CRV431, NV556) demonstrate anti-fibrotic efficacy in Phase 2A trials by targeting mitochondrial dysfunction and collagen synthesis. ACLY inhibition offers advantages over acetyl-CoA carboxylase targeting by upstream modulation of de novo lipogenesis, with bempedoic acid showing clinical promise. NLRP3 inflammasome inhibitors (MCC950, JT001, GDC-2394) effectively reduce hepatic inflammation through caspase-1/IL-1β pathway modulation. XBP1 targeting addresses ER stress-mediated lipogenesis and inflammation crosstalk. FXR agonists (obeticholic acid, cilofexor, tropifexor) demonstrate robust clinical efficacy in improving steatosis, inflammation, and fibrosis. Chemokine receptor antagonists (cenicriviroc, AZD5069) show potential in reducing inflammatory cell recruitment, though mixed clinical results highlight the complexity of immune modulation. These novel targets represent a paradigm shift in MASH therapeutics, offering mechanistically distinct approaches that could enable personalized treatment strategies. The advanced clinical development of several candidates, particularly FXR agonists and cyclophilin inhibitors, suggests near-term therapeutic breakthroughs. Future combination therapies targeting multiple pathways simultaneously may optimize treatment efficacy for this multifaceted disease.
