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

Total flavonoids from Ageratum conyzoides synergize with docetaxel to induce ferroptosis in prostate cancer cells via the NRF2/SLC7A11/GPX4 signaling pathway.

Prostate cancer is one of the most common malignant tumors in men, and its treatment faces numerous challenges. This study aims to investigate whether the combined treatment of Total Flavonoids from Ageratum conyzoides (TFG) and Docetaxel (DTX) can enhance the antitumor effect of DTX on prostate cancer cells by regulating the NRF2/SLC7A11/GPX4 signaling axis and inducing mitochondria-related ferroptosis. Cell viability was detected using the CCK-8 assay. Plate colony formation, scratch, and Transwell assays were used to evaluate proliferation, migration, and invasion, respectively. Flow cytometry was employed to analyze apoptosis and cell cycle distribution. PCR-Array was used to screen differentially expressed genes. RT-PCR and Western blot were performed to measure ferroptosis-related gene and protein expression. Reactive oxygen species (ROS) levels were detected using DCFH-DA, mitochondrial membrane potential using JC-1, lipid peroxidation using BODIPY-C11, and cellular ultrastructure by transmission electron microscopy. To validate the mechanistic involvement of ferroptosis, rescue experiments were performed using Ferrostatin-1 (Fer-1, a ferroptosis inhibitor) and Z-VAD-FMK (a pan-caspase inhibitor). Pharmacological inhibitors ML385 (NRF2 inhibitor) and RSL3 (GPX4 inhibitor) were used to probe pathway causality. Key findings were further validated in LNCaP (AR-positive) prostate cancer cells. TFG and DTX dose-dependently inhibited PC3 cell viability and showed synergistic effects. The combination significantly suppressed colony formation, migration, and invasion, induced late apoptosis, and arrested the cell cycle in S phase. Mechanistically, the combination upregulated TF and HMOX1 while downregulating NRF2, SLC7A11, and GPX4 expression. Fer-1 significantly rescued combination-induced cell death (~ 70% recovery), while Z-VAD-FMK showed partial rescue (~ 30% recovery), confirming ferroptosis as the dominant mechanism with secondary apoptosis involvement. ML385 + DTX and RSL3 + DTX phenocopied the TFG + DTX effect, supporting that TFG acts upstream of NRF2 and GPX4 is a key downstream effector. BODIPY-C11 staining confirmed increased lipid peroxidation, which was blocked by Fer-1. These findings were validated in LNCaP cells, showing consistent synergistic inhibition and downregulation of GPX4 and NRF2. TFG enhances the antitumor effect of DTX in prostate cancer cells by inhibiting the NRF2/SLC7A11/GPX4 axis, inducing lipid peroxidation, and triggering mitochondria-associated ferroptosis. Pharmacological rescue and inhibitor studies confirm ferroptosis as the primary mechanism, with apoptosis playing a secondary role. These findings provide a strong mechanistic rationale for developing TFG as a natural chemosensitizer for prostate cancer therapy, particularly for overcoming DTX resistance.

Icaritin inhibits breast cancer through activating MT1X to promote ferroptosis and synergizing with NF-κB pathway suppression

Introduction Icaritin (ICT) is a natural isoprenylated flavonoid compound extracted from the traditional Chinese herbal medicine Epimedii Folium. Metallothioneins (MTs) are a group of low-molecular-weight, cysteine-rich proteins that play crucial roles in oxidative stress, metal homeostasis, and cancer drug resistance. The anticancer effect and detailed regulatory mechanism of ICT in breast cancer remain to be fully clarified. This study aims to investigate the anti-tumor activity of ICT in breast cancer and explore its underlying molecular mechanism. Methods In vitro assays were performed in breast cancer cell lines to evaluate cell viability, intracellular Fe2+ levels, reactive oxygen species (ROS) production, and protein expression of the ferroptosis-associated antioxidant molecules SLC7A11 and GPX4 following ICT treatment. A ferroptosis inhibitor was employed to confirm the causal role of ferroptosis in ICT’s efficacy. Key target genes regulated by ICT were screened via transcriptome sequencing, and functional validation was conducted through MT1X overexpression to assess its impacts on NF-κB pathway activation, cell cycle distribution, and the SLC7A11/GPX4 axis. A breast cancer xenograft mouse model was established to verify the in vivo anti-tumor effect and mechanism of ICT. Results ICT induced ferroptosis and suppressed viability in breast cancer cells, as evidenced by intracellular Fe2+ accumulation, elevated ROS levels, and downregulated SLC7A11 and GPX4. This anti-tumor effect was reversed by a ferroptosis inhibitor, confirming ferroptosis as the key mechanism of ICT. Transcriptomic analysis and functional validation showed that ICT markedly upregulated MT1X. MT1X overexpression inhibited NF-κB signaling via reducing IκBα and p65 phosphorylation, induced G1 cell cycle arrest, and suppressed the SLC7A11/GPX4 antioxidant axis, synergistically enhancing ICT’s anti-proliferative activity. In vivo, ICT-mediated MT1X upregulation promoted ferroptosis and inhibited tumor growth. Discussion This study elucidates that ICT exerts anti-breast cancer effects by activating MT1X to induce ferroptosis and cooperatively inhibit the NF-κB signaling pathway. Our findings reveal a novel molecular mechanism of ICT against breast cancer, and provide a new therapeutic target and experimental basis for breast cancer treatment.

Effect of 6-gingerol on proliferation and apoptosis of ovarian cancer cells by the PI3K/AKT/mTOR pathway

Background As a major contributor to mortality among gynecological malignancies, ovarian cancer highlights an urgent need for novel therapeutic approaches. Although 6-gingerol—a primary bioactive compound found in ginger—is recognized for its anticancer properties, its precise role and underlying mechanisms in ovarian cancer remain largely unexplored. Methods SKOV3 ovarian cancer cells were treated with varying concentrations of 6-gingerol, either alone or in combination with Recilisib, an activator of the PI3K signaling pathway. Cell viability was evaluated using the MTT assay, whereas apoptosis and cell cycle distribution were assessed via flow cytometry. Western blot analysis was conducted to measure protein levels of cyclin E, cyclin B, Beclin1, Atg7, and P62. Results 6-gingerol treatment led to a concentration-dependent reduction in cell viability, induced G2-M phase arrest, and promoted apoptosis. These changes were associated with elevated expression of Beclin1 and Atg7, alongside decreased levels of cyclin E, cyclin B, and P62 (p < 0.05). Notably, co-treatment with Recilisib significantly counteracted the effects of 6-gingerol on cell viability, cell cycle regulation, apoptosis, and the expression of autophagy-related proteins (p < 0.05). Conclusion These findings indicate that 6-gingerol may exert antitumor activity in ovarian cancer cells through inhibition of the PI3K/AKT/mTOR pathway, resulting inreduced cell viability, enhanced apoptosis, and increased autophagic activity. The pivotal involvement of this signaling cascade is supported by the observation that its targeted activation effectively reverses the actions of 6-gingerol. Collectively, these results support further investigation into the biological effects of 6-gingerol in ovarian cancer models.

Puerarin Inhibits Nasopharyngeal Carcinoma Cell Growth by Inducing Ferroptosis with Involvement of the SLC7A11/GSH/GPX4 Axis

Nasopharyngeal carcinoma (NPC) is a malignant tumour with a high incidence in Southeast Asia and southern China. Currently, there is a lack of effective targeted therapy strategies for NPC in clinical practice, thus urgently necessitating the development of new treatment methods. Puerarin, the primary active isoflavonoid derived from the traditional Chinese medicine Pueraria lobata, exhibits anti-tumour efficacy in multiple cancer types. However, its function and underlying mechanism in NPC remain unclear. In this study, the human NPC cell lines C666-1 and HK-1 were treated with different concentrations of puerarin either alone or in combination with the ferroptosis inhibitor Fer-1. We employed a series of techniques to investigate the anti-tumour effects, including assessing cell viability, IC50, and apoptosis via CCK-8 and flow cytometry, measuring the levels of glutathione (GSH), malondialdehyde (MDA), and intracellular iron with biochemical detection; detecting reactive oxygen species (ROS) using immunofluorescence, and analyzing the expression of ferroptosis-related proteins GPX4 and SLC7A11 through Western blotting. The findings indicated that puerarin suppressed the viability of C666-1 and HK-1 cells in a dose-dependent manner, with IC50 values of 117.9 µM (24 h) and 85.14 µM (48 h) for C666‑1, and 89.39 µM (24 h) and 50.58 µM (48 h) for HK‑1. Puerarin induced apoptotic cell death, lowered GSH concentrations, and elevated levels of MDA, intracellular iron, and ROS. Meanwhile, puerarin reduced the protein expression of GPX4 and SLC7A11. The Fer-1 reversed all the aforementioned effects of puerarin. This in vitro study suggests that puerarin inhibits NPC cell growth by inducing ferroptosis, providing preliminary phenotypic evidence for further in vivo and mechanistic studies.

Hederacolchiside A1 targets ERO1A to suppress PI3K/AKT/mTOR signaling and induce ferroptosis in colorectal cancer.

Colorectal cancer (CRC) remains a major global health challenge due to high incidence, poor prognosis, and limited therapeutic options. Ferroptosis, an iron-dependent form of regulated cell death, has emerged as a promising anti-tumor strategy, yet pharmacological inducers remain underexplored. Hederacolchiside A1 (HeA1), a natural bioactive compound, was investigated for its potential anti-CRC effects and underlying mechanisms. In vitro, HeA1 inhibited proliferation, migration, and invasion of HT-29, SW-480, HCT-116, and MC-38 cells in a dose-dependent manner, induced apoptosis, and modulated epithelial-mesenchymal transition (EMT) markers, increasing E-cadherin and decreasing Vimentin, Slug, MMP2, and MMP9. Ferroptosis induction was evidenced by increased reactive oxygen species (ROS), lipid peroxidation, and intracellular Fe2+, along with a decrease in reduced glutathione (GSH) and a concomitant increase in oxidized glutathione (GSSG). HeA1 directly targeted endoplasmic reticulum oxidoreductase 1 alpha (ERO1A), resulting in suppression of PI3K/AKT/mTOR signaling and downregulation of ferroptosis defense proteins SLC7A11 and GPX4. In HT-29 xenograft models, HeA1 significantly reduced tumor volume and weight, decreased Ki67 and CD31 expression, increased TUNEL-positive cells, and exhibited minimal systemic toxicity. Immunofluorescence and Western blot analyses confirmed inhibition of PI3K/AKT/mTOR pathway components and ferroptosis-related proteins in vivo. Collectively, these findings demonstrate that HeA1 exerts potent anti-CRC effects by directly targeting ERO1A to induce ferroptosis through inhibition of the PI3K/AKT/mTOR-SLC7A11/GPX4 axis. This study provides a mechanistic rationale for further development of HeA1 as a potential therapeutic agent for colorectal cancer.

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