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Background: Head and neck squamous cell carcinoma (HNSCC) remains a highly aggressive malignancy with poor clinical outcomes. Although poly(ADP-ribose) polymerase (PARP) inhibitors have shown promising activity in tumors with homologous recombination deficiency, their efficacy in BRCA wild-type HNSCC remains limited. Reactive oxygen species (ROS)-induced DNA damage may increase cellular dependence on DNA repair pathways and thereby enhance sensitivity to PARP inhibition. This study investigated whether ROS-mediated DNA damage could sensitize BRCA wild-type HNSCC cells to the PARP inhibitor olaparib. Methods: BRCA wild-type HSC-3 and SCC-25 HNSCC cell lines were exposed to H₂O₂ to induce oxidative stress. Intracellular ROS levels were quantified using DCFDA assays, DNA double-strand breaks were evaluated by γ-H2AX ELISA, PARP activity was assessed by ELISA, and cell viability was determined using MTT assays. Expression levels of DNA repair genes (PARP1, PARP2, BRCA1, BRCA2, RAD51, and MLH1), checkpoint kinases (ATM, ATR, and CHK1), the homologous recombination regulator FANCD2, and redox defense genes (NQO1, GPX4, and SLC7A11) were analyzed by qRT-PCR. Therapeutic selectivity was assessed using HGF-1 normal human gingival fibroblasts as a normal cell control. Apoptosis was measured through caspase-3/7 activity assays, and drug interactions were evaluated using the Chou–Talalay method. Results: H₂O₂ treatment increased intracellular ROS levels in both cell lines, accompanied by significant induction of DNA damage as demonstrated by elevated γ-H2AX levels. ROS induction markedly enhanced olaparib sensitivity, significantly reducing IC₅₀ values in both HSC-3 and SCC-25 cells. Combined H₂O₂ and olaparib treatment produced strong synergistic cytotoxicity, suppressed DNA repair, checkpoint kinase, and redox defense gene expression, and increased caspase-3/7 activity compared with control cells. Importantly, the combination demonstrated selective cytotoxicity toward cancer cells, with normal HGF-1 cells retaining significantly higher viability. Conclusions: ROS-induced DNA damage significantly enhances the anti-tumor activity of olaparib in BRCA wild-type HNSCC cells through a functional synthetic lethal-like interaction involving the simultaneous collapse of DNA repair capacity, checkpoint activation, and oxidative stress buffering, culminating in apoptosis induction. These findings support the rationale for combining ROS-generating therapies with PARP inhibitors in HNSCC treatment. Full article

Background: Chronic atrophic gastritis (CAG) is a prevalent precancerous gastric disorder characterized by persistent inflammation, glandular atrophy, and progressive mucosal damage, for which effective multi-target therapeutic strategies remain insufficient. The Lian-Huo-Hua-Zhuo formula (LHHZ), a traditional Chinese herbal prescription, has demonstrated potential anti-inflammatory and gastrointestinal protective effects in clinical practice; however, its active constituents and mechanisms of action against CAG remain undefined. This study aimed to clarify the absorbed bioactive components of LHHZ and explore its therapeutic mechanism for CAG. Methods: Ultra-high-performance liquid chromatography coupled with quadrupole Orbitrap high-resolution mass spectrometry was employed to identify the absorbed components of LHHZ in the gastric and intestinal tissues of mice. The therapeutic effects of LHHZ on CAG were assessed through histopathological staining, ultrastructural observation, and evaluation of serum and gastric functional indicators. Network pharmacology, molecular docking, and molecular dynamics simulations were integrated to predict the core targets and key signaling pathways, while the regulatory effects on the interleukin-17 (IL-17) signaling pathway were further validated by immunofluorescence staining, real-time quantitative polymerase chain reaction, and Western blotting. Additionally, 16S ribosomal RNA gene sequencing and targeted metabolomics were applied to investigate the effects of LHHZ on gut microbiota composition and short-chain fatty acid (SCFA) metabolism. Results: The results revealed that 55 and 48 absorbed components were identified in the gastric and intestinal tissues, respectively, predominantly derived from Coptis chinensis Franch. and Pogostemon cablin (Blanco) Benth. LHHZ significantly alleviated gastric mucosal lesions, reduced intestinal metaplasia, restored the ultrastructure of gastric mucosal cells, improved gastric functional indicators including pepsinogen I (PG I), pepsinogen II (PG II), and gastrin-17 (GAS-17), and decreased the levels of pro-inflammatory cytokines. Network pharmacology combined with in vitro and in vivo experiments demonstrated that the core bioactive components of LHHZ can target and regulate interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α), attenuate activation of the IL-17 signaling pathway, and suppress the secretion of downstream pro-inflammatory factors. Furthermore, LHHZ enhanced the alpha diversity of gut microbiota, reduced the Firmicutes to Bacteroidetes (F/B) ratio, restored the abundance of SCFA-producing bacteria such as Bacteroidales and Oscillospirales, and normalized the aberrant levels of eight SCFAs. Significant correlations were also observed between gut microbiota composition and SCFA metabolism. Conclusions: These findings suggest that LHHZ alleviates CAG by inhibiting inflammation via the IL-17 signaling pathway and by modulating the gut microbiota–SCFA axis, thereby providing preclinical evidence supporting its further investigation and development for multi-target therapeutic strategies against CAG. Full article

Testicular receptor 4 (TR4, NR2C2) is an orphan nuclear receptor involved in the regulation of metabolism, inflammation, cardiovascular disease, and cancer. Accumulating evidence indicates that TR4 exhibits functional plasticity, exerting protective or pathogenic effects depending on tissue and disease context, and sometimes displaying opposing roles within the same disease. However, the mechanisms underlying this functional duality remain poorly understood. Recent studies indicate that TR4 activity is determined not only by the receptor itself but also by dynamic coregulatory networks. Through interactions with coactivators, corepressors, epigenetic regulators, and environmental signaling pathways, TR4 integrates metabolic cues to generate context-dependent transcriptional programs. Coactivator networks centered on PGC-1α, steroid receptor coactivator (SRC) family members, and CBP/p300 support oxidative metabolism and anti-inflammatory responses, whereas RIP140-, NCoR/SMRT-, and HDAC-associated networks promote lipid accumulation, chronic inflammation, fibrosis, and tumor progression. Regulators such as JAZF1 further influence TR4 activity by reshaping coregulator recruitment and target-gene selection. In this review, we summarize the structural basis of TR4 regulation and discuss how coregulatory network remodeling governs its functions in metabolic, cardiovascular, inflammatory, and malignant diseases. We propose that TR4 functions as a context-dependent transcriptional platform whose activities are defined by its coregulatory landscape, providing a framework for precision therapies. Full article

Glioblastoma multiforme (GBM), isocitrate dehydrogenase (IDH)-wildtype, is the most aggressive primary malignant tumor of the central nervous system, characterized by poor prognosis and high recurrence rates despite standard multimodal treatment. This study investigates the molecular response of glioblastoma cells to 5-aminolevulinic acid (5-ALA)-based photodynamic therapy (PDT), focusing on gene expression changes associated with apoptosis, ferroptosis, and oxidative stress. Human glioblastoma T98G cells were treated with 5-ALA followed by light irradiation, and gene expression was analyzed using RT-qPCR. PDT induced moderate upregulation of pro-apoptotic genes (BAX, CASP3, FAS) alongside increased expression of the anti-apoptotic gene BCL2, indicating simultaneous activation of cell death and survival pathways. Ferroptosis-related genes showed mixed responses, with slight upregulation of ACSL4 and downregulation of GPX4, suggesting increased susceptibility to lipid peroxidation. The most significant change was observed in GCH1 expression, reflecting activation of oxidative stress response mechanisms. However, none of the observed changes reached statistical significance, likely due to the limited sample size. These findings demonstrate that PDT induces a complex and dual biological response in glioblastoma cells, involving both cytotoxic and adaptive mechanisms. This may limit therapeutic efficacy and contribute to treatment resistance. The results support the rationale for combining PDT with targeted molecular therapies aimed at inhibiting antioxidant defenses and anti-apoptotic pathways. Additionally, personalized therapeutic strategies based on tumor molecular profiles may enhance treatment outcomes. Further studies with larger sample sizes and functional validation are required to confirm these preliminary observations. Full article

Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related mortality worldwide and is characterized by extensive vascularization, aggressive progression, and limited therapeutic responsiveness. Angiogenesis plays a central role in HCC development by supporting tumor growth, metabolic adaptation, invasion, and metastatic dissemination. Although anti-angiogenic therapies targeting the vascular endothelial growth factor (VEGF) pathway have improved clinical management, their overall survival benefit remains modest because of compensatory signaling, adaptive resistance, and the highly complex nature of the tumor microenvironment (TME). Astrocyte elevated gene-1/metadherin (AEG-1/MTDH) has emerged as a multifunctional oncogene that functions by orchestrating interconnected angiogenic, inflammatory, metabolic, and immune-regulatory programs within the hepatic tumor microenvironment. AEG-1 regulates angiogenesis through modulation of VEGF-family signaling, NF-κB activation, hypoxia-responsive pathways, PI3K/AKT signaling, endothelial remodeling, and translational control of pro-angiogenic mediators. Emerging evidence further implicates AEG-1 in hypoxia adaptation, immune evasion, extracellular vesicle signaling, and metabolic reprogramming, supporting its role as a systems-level regulator of HCC angiogenesis. This review summarizes the current understanding of the molecular mechanisms through which AEG-1 regulates angiogenesis in HCC, discusses its interactions with the TME and anti-angiogenic resistance pathways, and highlights future translational opportunities for developing multi-targeted therapeutic strategies beyond conventional VEGF-centric approaches. Full article

Cetuximab and panitumumab are anti-EGFR monoclonal antibodies widely used for the treatment of colorectal cancers. However, due to various mechanisms of resistance to these targeted therapies, the patients’ responses vary. These resistances remain a major obstacle in treatment and overcoming them has become a key emphasis of current therapeutic strategies. Intrinsic and acquired resistance often lead to reactivation of downstream signaling pathways, mainly the RAS-RAF-MEK-ERK (MAPK pathway) and PI3K-AKT axes. Prior existing mutations in KRAS, NRAS, and BRAF result in primary resistance by constantly activating the signals, irrespective of EGFR inhibition. That said, acquired resistance manifests under therapeutic burden through the process of clonal evolution via KRAS and BRAF alterations, restoring MAPK pathway activity despite EGFR inhibition. In addition to those mutations, tumor cells exploit mechanisms independent of EGFR, such as the pathway bypass, which includes amplification of ERBB family receptors like HER2 (ERBB2) and activation of MET signaling. To overcome these resistances, novel strategies have emerged, which target multiple nodes within the oncogenic networks. Such methods include vertical pathway inhibition, multi-kinase inhibition, liquid-biopsy-guided therapy, and anti-EGFR rechallenge. Reactivation driven by secondary mutation can be prevented by targeting multiple nodes within the MAPK cascade simultaneously, which is referred to as the vertical pathway inhibition. Overall, this review underscores that overcoming therapeutic resistance requires a multidimensional approach that integrates molecular profiling, rational combination therapies, and adaptive treatment. Finally, these advances underscore the shift toward precision oncology, where therapy is tailored to tumor evolution, leading to improved response and patient outcome. Full article

Background/Objectives: Medullary thyroid carcinoma (MTC) is a rare and aggressive endocrine malignancy frequently associated with RET alterations and dysregulation of RET-associated signaling pathways. In previous studies, first-generation nitro-substituted thieno[3,2-c]quinolines 1 showed promising antiproliferative activity in TT(RET^C634R) cells, while subsequent imidazole-based optimization generated second-generation derivatives 2 with broad-spectrum antiproliferative activity in the NCI-60 human tumor cell line panel. Since thyroid cancer models are not included in the NCI-60 platform, the present study aimed to evaluate the antiproliferative potential of these optimized derivatives in clinically relevant MTC cellular models. Methods: Imidazole-functionalized thieno[3,2-c]quinoline derivatives (2a–j) were evaluated against TT(RET^C634R) and MZ-CRC-1(RET^M918T) cells. The most active compounds were further characterized through induced fit docking (IFD), MM-GBSA calculations, and molecular dynamics (MD) simulations on representative molecular targets. In silico ADME/Toxicity profiling was also performed to assess their developability. Results: Several derivatives exhibited potent activity in both MTC cell models, with multiple compounds achieving submicromolar potency. Compounds 2b and 2g emerged as the most active derivatives in TT(RET^C634R) cells, whereas compounds 2d and 2i displayed the most favorable profile in the aggressive MZ-CRC-1(RET^M918T) model, thereby extending the biological applicability of the scaffold to an additional clinically relevant RET-mutant context. Computational studies supported RET as the most plausible molecular target for all selected lead compounds, while favorable PI3Kα interaction profiles were predicted for selected derivatives, suggesting distinct target engagement profiles within the series. The most promising derivatives also exhibited an overall favorable predicted ADME/Toxicity profile. Conclusions: The present findings support the success of imidazole-based optimization of the thieno[3,2-c]quinoline scaffold and identify thieno[3,2-c]quinolines 2 as promising lead structures for the future development of novel anti-MTC agents. Further biological and mechanistic investigations will be necessary to better clarify the molecular mechanisms underlying their antiproliferative activity and to guide future lead optimization studies. Full article

Melanoma remains highly lethal with frequent resistance to current therapies. Here we identify a marine-derived cyclopentapeptide, turnagainolide B, as a potent anti-melanoma agent that selectively kills B16-F10 melanoma cells (IC₅₀ = 50 μM) with low toxicity to normal skin cells. Using bioassay-guided isolation, we also obtained a new analogue, turnagainolide H, and elucidated their structures and biosynthetic pathways. Mechanistically, turnagainolide B induces a previously undescribed “dual-hit” autophagic signature: it simultaneously promotes autophagy initiation (via PI3K/mTOR suppression, evidenced by ATG5 and LC3B-II upregulation) and blocks autophagic degradation (evidenced by p62 accumulation). Co-treatment with chloroquine partially rescued cell viability and decreased LC3B levels, confirming that cell death depends on active autophagic flux disruption. Transcriptomic analysis, together with AI target prediction and docking, identified PI3K as a potential direct target, with downregulation of PI3K, mTOR, and BNIP3 supporting an imbalanced autophagic state. In a syngeneic mouse melanoma model, turnagainolide B significantly suppressed tumor growth, reduced melanin content and Ki67 expression, and enhanced CD8⁺ T cell infiltration. Collectively, this work expands the chemical diversity of the turnagainolide family, uncovers a unique “dual-hit” autophagic mechanism, and establishes turnagainolide B as a promising lead for melanoma therapy. Full article

Ganoderma leucocontextum, a fungus discovered by our group, is highly valued for its immune modulation and anti-tumor polysaccharides significantly. Thus, this research aims to select a substrate formulation to enhance its polysaccharides and reveal the underlying mechanism. Seven distinct substrate formulations, incorporating combinations of fruit-tree wood, bagasse, oak wood, and cottonseed hulls, were explored. Interesting, the fruiting bodies grown on GMTZ fruit-tree wood–bagasse formulation showed the highest polysaccharide content at 3.19 ± 0.56% (p < 0.01 or 0.05). Moreover, GMTZ efficiently channeled resources toward diterpenoids synthesis at the expense of flavonoid and most triterpenoid production. It also dramatically enhanced androgen synthesis, while showing no corresponding accumulation of storage lipids or certain hormone signals, reinforcing a specific metabolic commitment. Furthermore, PCA analysis of the metabolomics confirmed the profound impact of substrate formulations. Correlation analysis revealed that GMTZ promoted a growth-and-synthesis metabolic phenotype, which was characterized by metabolic signatures of supporting anabolism and cellular homeostasis. In contrast, formulations that induced the defense-and-stress phenotype were often rich in lignin, which diverted resources toward detoxification and stress responses and suppressed growth-oriented metabolite synthesis. Moreover, prostaglandin A1, deoxycholic acid, cucurbitacin E, and 1-hydroxy-2-naphthoic acid were found to be positively correlated with polysaccharide synthesis. In addition, networks for polysaccharide biosynthesis were mapped and it was proposed, accordingly, that prostaglandin A1-phosphoglucomutase may be a mechanism by which GMTZ enhances polysaccharides. This research provided a substrate formulation for elevating polysaccharides in G. leucocontextum. Full article

Histone deacetylases (HDACs) are important epigenetic regulatory enzymes contributing to cancer proliferation, which could be critical targets in cancer therapy. The structural similarities of the existing HDAC inhibitors have resulted in an increase in the drug resistance. In this study, coumarin was employed as the core scaffold for structural derivatisation to develop a novel class of HDAC inhibitors based on computer-aided design (CADD). Their anti-tumor activity was evaluated against esophageal squamous cell lines. The results showed that most compounds exhibited potent anti-proliferative activity against KYSE70 and KYSE150. Among them, compound 4s and 4p exhibited the most potent activity with IC₅₀ values of 3.44 μM and 3.39 μM against KYSE70. To validate the target of the synthesized compounds, transcriptome sequencing was performed and the results revealed that a total of 487 genes were differentially expressed, including 190 up-regulated and 297 down-regulated genes. Among these, 79 genes were associated with the HDAC regulatory network, accounting for 16.2% of the differentially expressed genes. Molecular docking demonstrated that compound 4s could effectively enter the active site of HDAC, engaging with the cap group, zinc-binding group, and linker region. This multiple interaction network provides a structural basis for the potent inhibitory activity of compound 4s. In conclusion, a series of novel HDAC inhibitors with a coumarin scaffold were discovered, and their mode of action was revealed. This provides a valuable guide for the development of novel HDAC-targeting therapeutics. Full article

Hepatocellular carcinoma is one of the most aggressive malignancies worldwide, with limited therapeutic options. Boswellia serrata Roxb., an Indian medicinal tree, produces a resin rich in essential oil and boswellic acids, particularly acetyl-11-keto-β-boswellic acid (AKBA), with demonstrated antiproliferative and pro-apoptotic activities. This study investigated the cytotoxic effects of B. serrata essential oil and AKBA on hepatocarcinoma Huh-7 cells in both monolayer and three-dimensional spheroid cultures and characterized the underlying molecular targets. Essential oil was extracted and analyzed by gas chromatography-mass spectrometry (GC-MS). Cytotoxicity was assessed using the cell counting kit-8 (CCK-8). Three-dimensional spheroid cultures were also established to evaluate anti-tumoral potential. Expression of cyclin D1, cyclin-dependent of kinase 4 (CDK4) (cyclin-dependent kinase inhibitor 1A (p21), E-cadherin, (alpha fetoprotein) AFP, epithelial cell adhesion molecule (EpCAM), Myeloid cell leukemia-1 (Mcl-1), and caspase-3 was analyzed by western blot. In addition, an in silico analysis was performed on the main constituents of B. serrata essential oil targeting 5-lipoxygenase (5LO). The results showed cytotoxic effects, with AKBA exhibiting greater potency than the essential oil. Cytotoxicity was associated with caspase-3-mediated apoptosis, with minimal effects on cell cycle and epithelial–mesenchymal transition markers. The in silico analysis predicted that some compounds may act as competitive inhibitors of the 5LO at the catalytic site and partially activate pro-apoptotic pathways. These data support the potential of B. serrata-derived compounds as novel anti-hepatocarcinoma agents, with AKBA and longifolene as leads for further preclinical and clinical research. Full article

Glioblastoma (GBM) remains a lethal brain tumor with poor prognosis and limited therapeutic efficacy from temozolomide (TMZ) treatment. Prodigiosin (PG), a bioactive secondary metabolite, has demonstrated anti-tumor activity across a broad spectrum of tumors. This study aims to investigate the therapeutic potential and mechanism of PG combined with TMZ in treating GBM. The results demonstrated that the combination of PG and TMZ synergistically inhibited GBM cell proliferation, triggered apoptosis, and suppressed migration and invasion. Transcriptomic analysis revealed downregulation of focal adhesion and related signaling pathways. Functionally, the combination therapy reduced focal adhesion numbers and AKT phosphorylation. Co-treatment with PG and TMZ impaired autophagic flux, evidenced by LC3-II and p62 accumulation. Furthermore, the anti-proliferative effect and the accumulation of LC3-II and P62 by the combination therapy were enhanced by the autophagy inhibitor chloroquine (CQ) but not reversed by the autophagy activator rapamycin (Rapa), confirming autophagy inhibition as a key mechanism. In conclusion, PG sensitized GBM cells to TMZ by impairing autophagy and focal adhesion signaling, providing a preclinical rationale for the combinatorial strategy. Full article

Background/Objectives: Aerobic glycolysis is a standard mechanism that cancer cells use to support their anabolic processes. Lactate and proton production, byproducts of this LDHA-catalyzed transformation of pyruvate, may contribute to acidifying the tumor microenvironment and to repressing the cytotoxic activity of anti-tumor immune cells. Prostate cancer radiotherapy outcome could be diminished by cancer cell metabolism and immunosuppression. Methods: The tumor infiltrating lymphocyte (TIL) density was assessed in 110 prostate adenocarcinoma biopsies from patients treated with radical radiotherapy. Immunohistochemistry was performed to evaluate LDH5 expression by cancer cells (encoded by the LDHA gene). Results: Higher tumor stages (T3 and T4) were associated with lower TIL density (p = 0.02). Approximately half of the patients (51%) displayed strong LDH5 cancer cell expression, which was linked with advanced T-stage and higher Gleason scores (p = 0.05 and p = 0.01, respectively). High LDH5 expression was significantly correlated with low TIL density (p ≤ 0.0004). In univariate analysis, high LDH5 and low TIL density were associated with poor biochemical relapse-free survival (BRFS) (p ≤ 0.006). In multivariate analysis, TIL density, but not LDH5, was an independent predictor of BRFS (p = 0.03). Conclusions: LDH5 overexpression is associated with low tumor lymphocytic infiltration. Stratifying prostate carcinomas according to LDH5/TIL density identifies a group of patients with low TIL density and high LDH5 expression, who have a higher risk of tumor relapse. Targeting glycolysis to disrupt cancer cell metabolism offers an interesting research area for prostate cancer therapy. Full article

Alzheimer’s Disease (AD) is now understood as a biologically diverse condition, with amyloid and tau pathology evolving within dynamic neuroimmune networks. This challenges the traditional view that AD-related inflammation can be broadly suppressed therapeutically. We review evidence showing that neuroinflammation in AD is stage-dependent, cell-state-specific, spatially organized, and functionally complex. Microglia and astrocytes can aid in plaque containment, debris clearance, synaptic balance, metabolic adaptation, and tissue repair, but may also exacerbate injury through type-I interferon, inflammasome, complement, tumor necrosis factor, and lipid pathways. Many failed anti-inflammatory trials likely stem from mismatches in targets, timing, spatial considerations, pathway redundancy, and biomarker selection, rather than invalidating neuroinflammation as a therapeutic target. Recent single-cell and spatial transcriptomic, proteomic, metabolomic, and network-medicine studies offer a framework for precision intervention by identifying inflammatory endotypes, anatomical niches, and pathway modules. We propose the Stage–State–Space Neuroimmune Reprogramming Model (S3-NRM), aligning AD immunotherapy with disease stage, glial/endotype state, and spatial inflammatory niche, guided by fluid, imaging, and omics biomarkers. Future therapies should selectively suppress harmful immune responses while preserving beneficial glial functions. Full article

Colorectal Cancer (CRC) is a prevalent global malignant tumor, and conventional therapies and drugs for CRC are limited by poor targeting and severe toxic side effects. Existing reviews on hydrogel-based CRC treatments mainly focus on synthetic materials or single-responsive systems concerning drug loading and local delivery. Natural polysaccharides possess inherent anti-inflammatory, antioxidant and antitumor activities, and polysaccharide hydrogels (PSHs) prepared from them exhibit favorable biocompatibility, tunable structures and potential targeting capability, which can synergistically enhance the efficacy of loaded drugs and thus become a research hotspot. This article summarizes the pathogenesis and conventional treatments of CRC, introduces monocomponent and composite PSHs as well as physical and chemical crosslinking methods, and emphasizes their tumor microenvironment (TME)-responsive mechanisms, combined drug effects and clinical applications. It also analyzes the challenges in safety evaluation and practical application, and summarizes recent advances in the use of artificial intelligence (AI) for PSHs design, regulation, performance prediction and implementation. This paper serves as a reference for follow-up research and clinical translation of hydrogels prepared from natural polysaccharides for the treatment of CRC. Full article