Glycyrrhetinic Acid and Autocrine Motility Factor Converge on G6PD Suppression, Oxidative Stress, and Drug Retention to Impair Pancreatic Ductal Adenocarcinoma Cell Growth

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.

Se-methylselenocysteine induces NRF2-ATF4 stress signaling and ferroptosis-associated remodeling in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by profound resistance to therapy, driven in part by its capacity to adapt to oxidative, metabolic, and proteotoxic stress. In this study, we investigated how the redox-active selenium compound Se-methylselenocysteine (MSC), following metabolic activation by kynurenine aminotransferase 1 (KYAT1), reprograms stress-response pathways in PDAC cells. RNA sequencing across three PDAC cell lines revealed pronounced, phenotype-dependent transcriptional adaptations upon MSC exposure. CAPAN-2 cells predominantly activated an NRF2-centered antioxidant response accompanied by ferroptosis-associated gene signatures, whereas PANC-1 cells exhibited robust co-activation of NRF2 and ATF4, along with induction of unfolded protein response signaling and extensive redox and metabolic remodeling. MSC treatment suppressed TXNIP, a negative regulator of the thioredoxin system, while inducing canonical NRF2 target genes including TXNRD1, NQO1, G6PD, SLC7A11, and GLRX. In MSC-responsive models, pathways linked to iron metabolism and ferroptosis-associated processes were significantly altered, accompanied by changes in iron-handling proteins and lipid peroxidation defenses. Functional assays further demonstrated increased lipid peroxidation and partial rescue of cytotoxicity by ferrostatin-1 and the iron chelator deferoxamine, supporting the involvement of iron-dependent oxidative stress mechanisms. In contrast, HPAF-II cells, characterized by low KYAT1 expression, showed minimal transcriptional engagement and intrinsic resistance to MSC. Collectively, these findings identify KYAT1-dependent metabolic activation and convergence of NRF2-ATF4 stress pathways as key determinants of MSC responsiveness, revealing phenotype-dependent remodeling of redox and ferroptosis-associated networks in PDAC. This work provides a mechanistic framework for exploiting redox vulnerabilities and supports the continued development of selenium-based therapeutic strategies in pancreatic cancer.

Salvianolic acid B suppresses non-small cell lung cancer growth by promoting Nrf2 proteasomal degradation and triggering autophagy-dependent ferroptosis.

A Bioactivated Lepidium latifolium Formulation Disrupts Mitochondrial Bioenergetics and Metabolic Adaptation in KRAS-Mutant Cancer Cells

Pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) are aggressive malignancies frequently driven by oncogenic Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations associated with metabolic reprogramming and resistance to apoptosis. In this study, we evaluated the antitumor and anti-inflammatory activity of a Lepidium latifolium L.-derived formulation (CTP) enriched in glucosinolate hydrolysis products in KRAS-mutant colorectal and pancreatic cancer models. The formulation was designed to promote the generation of the epithionitrile 1-cyano-2,3-epithiopropane (CETP) through iron-dependent myrosinase-mediated sinigrin hydrolysis. CTP induced dose-dependent cytotoxicity and morphological alterations consistent with apoptosis in KRAS-mutant cancer cell lines. Treatment significantly reduced mitochondrial membrane potential, ATP production, oxygen consumption rate (OCR), and extracellular acidification rate (ECAR), indicating severe bioenergetic impairment. In parallel, CTP downregulated the metabolic and proliferative regulators C-myc, PKM2, GLUT1, and Cyclin E1. RNA-seq analysis revealed extensive transcriptional reprogramming associated with oxidative stress, metabolic adaptation, and cell-cycle regulation. In addition, CTP significantly suppressed nitric oxide, IL-6, and IL-8 production in LPS-stimulated RAW 264.7 macrophages. These findings demonstrate that glucosinolate-derived metabolites from L. latifolium interfere with metabolic and inflammatory pathways critical for KRAS-driven tumor survival and support the therapeutic potential of Brassicaceae-derived epithionitriles as multitarget anticancer agents.

Ferroptosis-Based Nanotherapy for Pancreatic Ductal Adenocarcinoma Through Glutathione Depletion and Iron Accumulation

Abstract Pancreatic ductal adenocarcinoma (PDAC) has a very poor prognosis and remains highly refractory to standard chemotherapy owing to its unique tumor microenvironment (TME) and metabolic reprogramming. A defining feature of PDAC is that the near-ubiquitous presence of oncogenic KRAS mutations, together with NRF2 activation, generates abnormally high levels of reactive oxygen species (ROS) and renders the cells strongly dependent on an amplified glutathione (GSH)-based antioxidant program (the SLC7A11–GSH–GPx4 axis) for survival. This single metabolic axis simultaneously neutralizes drug-induced ROS to sustain chemoresistance and, through GPx4-mediated detoxification of lipid peroxides, suppresses ferroptosis—an iron-dependent, apoptosis-independent form of cell death. Because ferroptosis does not rely on the apoptotic or immune machinery that PDAC readily evades, its induction directly exploits this redox-metabolic vulnerability, distinguishing the GSH–GPx4 and iron-metabolism axes from conventional immune- or DNA-damage-based targets. This review analyzes the regulatory mechanisms of GSH homeostasis linked to treatment resistance in PDAC and discusses nanoparticle therapeutics rationally designed around the two central ferroptosis pathways: the GSH–GPx4 axis and the iron-metabolism axis.

Gaudichaudione H induces GSDME-mediated pyroptosis and apoptosis in esophageal squamous cell carcinoma via ROS-dependent YAP degradation.

BACKGROUND Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy with limited therapeutic options. Therefore, novel treatment strategies are urgently needed. PURPOSE This study aimed to evaluate the antitumor effects of Gaudichaudione H (GH), a natural caged xanthone isolated from Garcinia oligantha Merr., and to elucidate its underlying mechanisms with a focus on cell death regulation in ESCC. METHODS The antitumor activity of GH was evaluated in ESCC cell lines (KYSE150, KYSE450, Eca-109) and a xenograft mouse model. Cell viability, LDH release, morphological changes, and protein expression were assessed. RNA sequencing, pharmacological inhibitors, and genetic manipulation of YAP (knockdown and overexpression) were used to investigate the underlying mechanism. RESULTS GH exhibited dose-dependent cytotoxicity against ESCC cell lines, with IC₅₀ values ranging from 5.7 to 7.9 μM in KYSE150, KYSE450, and Eca-109 cells. GH induced apoptotic and pyroptotic morphological features accompanied by increased LDH release in a caspase-3-dependent manner. Transcriptomic analysis revealed enrichment of the MAPK/JNK signaling pathway. Mechanistically, GH elevated intracellular ROS levels, leading to ubiquitin-proteasome-dependent degradation of YAP. Loss of YAP activated JNK signaling, resulting in caspase-3 activation and GSDME cleavage. ROS scavenging or JNK inhibition significantly attenuated GH-induced cell death. In vivo, GH inhibited tumor growth by approximately 75% compared with the vehicle-treated group in a xenograft model without observable systemic toxicity. CONCLUSION GH induces ESCC cell death through a ROS-dependent YAP ubiquitination axis involving JNK signaling activation, which regulates the crosstalk between apoptosis and pyroptosis in ESCC. These findings highlight GH as a promising natural lead compound for ESCC therapy. ABBREVIATIONS CHX, Cycloheximide; DMSO, Dimethyl sulfoxide; ECL, Enhanced chemiluminescence; ESCC, Esophageal squamous cell carcinoma; GSDME, Gasdermin E; GH, Gaudichaudione H; JNK, c-Jun N-terminal kinase; KEGG, Kyoto Encyclopedia of Genes and Genomes; LDH, Lactate dehydrogenase; MAPK, Mitogen-activated protein kinase; NAC, N-acetylcysteine; PARP, Poly(ADP-ribose) polymerase; PBS, Phosphate-buffered saline; PCD, Programmed cell death; PPI, Protein-protein interaction; RNA-seq, RNA sequencing; ROS, Reactive oxygen species; siRNA, Small interfering RNA; YAP, Yes-associated protein.