Quercetin induces molecular hallmarks of immunogenic cell death and cGAS-STING pathway activation via mitochondrial DNA release in hepatocellular carcinoma cells.

Carvacrol induces apoptosis, modulates oxidative stress, and promotes G0/G1 cell cycle arrest in colorectal cancer cells.

Medicarpin triggers Fas cell surface death receptor-mediated apoptosis by inhibiting epidermal growth factor receptor/signal transducer and activator of transcription 3 pathway and protective autophagy in liver cancer.

BACKGROUND Liver cancer remains the leading cause of cancer-related mortality worldwide, highlighting the need for novel therapeutics. Medicarpin is a pterocarpan, an isoflavonoid derivative, isolated from Spatholobus suberectus Dunn, exhibiting diverse bioactivities, yet its anticancer potential in liver cancer and underlying mechanisms are not well characterized. PURPOSE This study aims to investigate the therapeutic efficacy of medicarpin against liver cancer and to elucidate its molecular mechanisms, focusing on its interplay with the epidermal growth factor receptor (EGFR)/signal transducer and activator of transcription 3 (STAT3) signaling and autophagy regulation. METHODS A series of in vitro and in vivo assays were conducted to assess medicarpin's effects on apoptosis, EGFR stability, STAT3 signaling and autophagy in liver cancer cells. Molecular docking, cellular thermal shift assay, and drug affinity responsive target stability were employed to confirm target engagement. In vivo efficacy was evaluated using HepG2 xenograft models. RESULTS Medicarpin selectively induced apoptosis in liver cancer cells while sparing normal hepatocytes. This effect was independent of p53 status and was mediated through upregulation and membrane accumulation of Fas (Fas cell surface death receptor). Mechanistically, medicarpin directly bound to EGFR, promoted its ubiquitin-mediated degradation, and consequently suppressed the EGFR-STAT3 signaling pathway. Furthermore, medicarpin concurrently triggered protective autophagy, and its inhibition synergistically enhanced its cytotoxicity. In xenograft models, medicarpin significantly suppressed tumor growth. CONCLUSION Our findings identify medicarpin as a novel EGFR‑modulating natural compound that induces Fas-mediated apoptosis in liver cancer, independent of p53 status. The concomitant induction of protective autophagy presents a rational combinatory strategy to enhance its therapeutic efficacy. This study underscores the translational potential of medicarpin as a promising candidate for phytotherapy-based liver cancer treatment.

Oncolytic virus OHSV2 induces pyroptosis in bladder cancer cells via the TLR4/NLRP3/Caspase-1/GSDMD pathway

Bladder cancer remains a significant clinical challenge due to high recurrence and progression rates, necessitating novel therapeutic strategies. Oncolytic viruses, such as the herpes simplex virus type 2-based OHSV2, have demonstrated promising antitumor effects through direct oncolysis and immune activation. This study investigated the efficacy, safety, and molecular mechanisms of OHSV2 in the treatment of bladder cancer. In vitro and in vivo experiments demonstrated that OHSV2 potently inhibited bladder cancer cell proliferation, migration, and clonogenicity in a dose-dependent manner, while exhibiting a favorable safety profile. Critically, OHSV2 treatment triggered a pro-inflammatory tumor immune microenvironment, characterized by increased infiltration and activation of CD8+ T cells. Mechanistically, OHSV2 induced pyroptosis in bladder cancer cells via the canonical Caspase-1/Gasdermin D (GSDMD) pathway, accompanied by increased interleukin-18 (IL-18), interleukin-1β (IL-1β), and lactate dehydrogenase (LDH) release. Further analysis identified NOD-like receptor family pyrin domain containing 3 (NLRP3) as the key upstream pattern recognition receptor for Caspase-1/GSDMD activation, and Toll-like receptor 4 (TLR4) as a critical mediator of NLRP3-dependent pyroptosis. Inhibition of TLR4 or NLRP3 partially reversed OHSV2-induced cytotoxicity, confirming their functional roles. Additionally, combining OHSV2 with the TLR4 agonist enhanced pyroptosis in a subcutaneous xenograft model, amplified antitumor immunity, and improved tumor control in vivo, suggesting potential synergism for clinical translation. These findings elucidate a novel TLR4/NLRP3/Caspase-1/GSDMD axis as the core mechanism behind the antitumor effect of OHSV2 and propose a rationale for its combination with immunomodulators to improve outcomes in bladder cancer.

Thymoquinone Potentiates Docetaxel-Induced Antitumor Activity with the Involvement of ROS and PI3K/AKT Pathway Modulation in Triple-Negative Breast Cancer Cells

Background: Drug resistance and treatment-associated toxicity remain major limitations of conventional chemotherapy for triple-negative breast cancer (TNBC). Thymoquinone (TQ), a bioactive phytochemical derived from Nigella sativa, has demonstrated anticancer properties and may enhance the therapeutic efficacy of docetaxel (DTX) through complementary molecular mechanisms. Objective: To investigate whether TQ potentiates the antitumor activity of DTX in MDA-MB-231 TNBC cells by affecting apoptosis, oxidative stress, wound closure, and PI3K/AKT pathway-related gene expression. Methods: MDA-MB-231 TNBC cells and HaCaT keratinocytes were treated with TQ, DTX, or their combination. Cell viability was determined using the MTT assay, and drug interactions were evaluated by the Chou–Talalay combination index (CI) method. Apoptosis, intracellular reactive oxygen species (ROS) production, ROS rescue experiments using N-acetyl-L-cysteine (NAC), caspase-9 expression, wound closure, and gene-expression changes were assessed using Annexin V/PI flow cytometry, DCFH-DA-based flow cytometric and fluorescence analyses, immunocytochemistry, wound-healing assay, and quantitative real-time PCR (qRT-PCR), respectively. Bioinformatic analyses were performed to identify signaling pathways associated with the observed molecular alterations. Results: The TQ + DTX combination demonstrated synergistic cytotoxicity and significantly increased apoptotic cell death compared with either monotherapy. Combination treatment markedly enhanced intracellular ROS accumulation, whereas NAC pretreatment significantly attenuated ROS generation and partially reversed the cytotoxic and pro-apoptotic effects, suggesting the involvement of ROS in the observed antitumor effects. Caspase-9 immunoreactivity was markedly increased following combination treatment, suggesting the involvement of the intrinsic apoptotic pathway. Furthermore, the combination significantly suppressed wound closure and downregulated BCL2, PIK3CA, and AKT1 while upregulating BAX, CASP9, and PTEN. Bioinformatic analyses identified apoptosis, p53, PI3K/AKT, mTOR, and MAPK signaling as the principal pathways potentially associated with the observed gene expression changes. Conclusions: TQ potentiates the antitumor activity of DTX, with the involvement of oxidative stress, apoptotic signaling, suppression of wound closure, and regulation of PI3K/AKT pathway-related gene expression in TNBC cells. These findings provide evidence supporting further preclinical investigation of the TQ + DTX combination as a promising therapeutic strategy for triple-negative breast cancer.

8-gingerol from Zingiber officinale induces ER stress-mediated ferroptosis and apoptosis in ovarian cancer involving TRPV1 activation.

It is demonstrated that 8-gingerol induces coordinated apoptotic and ferroptotic cell death through a Ca2+-dependent ER stress mechanism, highlighting its potential as a novel therapeutic strategy for the treatment of ovarian cancer.

Marbofloxacin Suppresses Breast Cancer Growth Through Oxidative Stress and Metabolic Reprogramming with Predicted HSP90AA1–EGFR Network Modulation

Background: Drug repurposing represents an accelerated and cost-effective approach to discovering novel oncologic therapeutics. Here, we investigated the anticancer potential and underlying mechanisms of marbofloxacin (MBF), a veterinary fluoroquinolone (FQ), against breast cancer (BC) cells. Methods: The cellular impacts of MBF on cell viability, anchorage-dependent growth, tumorigenicity, migration, apoptosis, proliferation, senescence, and mitochondrial function were thoroughly characterized. To further elucidate its mechanistic activity, real-time qRT-PCR, untargeted LC-MS/MS-based metabolomics, network pharmacology, and molecular docking analysis were integrated. Results: MBF suppressed BC cell growth by inhibiting cellular proliferation and migration, disrupting mitochondrial membrane potential, and inducing ROS-mediated apoptosis and irreversible cellular senescence. These phenotypic impacts were accompanied by upregulation of tumor suppressors such as CDKN1A and PUMA and downregulation of oncogenes including MKI67, BIRC5, and BCL-2. Metabolomic analysis revealed broad suppression of biosynthesis-related metabolic pathways, characterized by the depletion of critical polyamines and nucleotide pathways. Network pharmacology and molecular docking analyses identified EGFR and HSP90AA1 as putative hub proteins potentially associated with the observed anticancer phenotype. Conclusions: These results provide initial evidence that MBF induces metabolic and molecular rewiring in BC, highlighting its promise as a repositionable therapeutic candidate.