ArticleCell death & disease2024
Selective PI3Kδ inhibitor TYM-3-98 suppresses AKT/mTOR/SREBP1-mediated lipogenesis and promotes ferroptosis in KRAS-mutant colorectal cancer.
Article in Cell death & disease, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed.
- Targeting PI3Kδ for lymphoma and immune diseases treatment: a review.Molecular diversity · 2026Review
- Review
- Mechanisms and advances of drug resistance in colorectal cancer: A systematic overview of multi-layered regulatory networks.Translational oncology · 2026Review
- CD276 promotes lipid metabolic reprogramming and regulates ferroptosis in clear cell renal cell carcinoma by upregulating FASN expression via SREBP1.Human cell · 2026Article
- Fatty Acid Metabolism and Hypoxia in the Tumor Microenvironment: Metabolic Adaptation and Clinical Potential in Colorectal Cancer.Biomedicines · 2026Review
- Agmatine protects against MAFLD via decreasing RBM15/IGF2BP2-mediated mMolecular biology reports · 2026Article
- Genetic mutations governing ferroptosis sensitivity and resistance: a precision approach to cancer therapy.Cell death & disease · 2026Review
- Claudin18.2 positive gastric cancer: biology, tumor microenvironment, and therapeutic strategies.Journal of hematology & oncology · 2026Review
- Cooperative Roles of Class IA PI3K Isoforms in Translocation-Related Sarcoma Cell Survival and Proliferation.Cancer research communications · 2026Article
- Metabolic permissiveness: how tissue context shapes cancer.Genes & development · 2026Review
- SREBP1 knockdown triggers ferroptosis by suppressing the Nrf2-XCT/GPX4 axis in ovarian cancer.Cell death discovery · 2026Article
- FSCN1 Modulates Fatty Acid Metabolism and the Coordinated Activation of AKT/mTOR and p38 MAPK Pathways in Colorectal Cancer Cells.Oncology research · 2026Article
- The promising arsenal of ferroptosis inducers in bladder cancer.Journal of molecular medicine (Berlin, Germany) · 2025Review
- Immunoregulatory roles of post-translational modifications in colorectal cancer: mechanisms and therapeutic implications.Cellular and molecular life sciences : CMLS · 2025Review
- NRF2 as a ferroptosis gatekeeper in colorectal cancer: implications for therapy.Naunyn-Schmiedeberg's archives of pharmacology · 2025Review
- Time-restricted feeding protects against septic liver injury by reshaping gut microbiota and metabolite 3-hydroxybutyrate.Gut microbes · 2025Article
- Anti-EGFR Therapy in Metastatic Colorectal Cancer: Identifying, Tracking, and Overcoming Resistance.Cancers · 2025Review
- Unlocking the lipid code: SREBPs as key drivers in gastrointestinal tumour metabolism.Lipids in health and disease · 2025Review
- Kinsenoside Suppresses DGAT1-Mediated Lipid Droplet Formation to Trigger Ferroptosis in Triple-Negative Breast Cancer.International journal of molecular sciences · 2025Article
- Advances in Ferroptosis Research: A Comprehensive Review of Mechanism Exploration, Drug Development, and Disease Treatment.Pharmaceuticals (Basel, Switzerland) · 2025Review
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Authors and funding
8 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Colorectal cancer (CRC) is one of the most common tumors of the digestive system worldwide. KRAS mutations limit the use of anti-EGFR antibodies in combination with chemotherapy for the treatment of CRC. Therefore, novel targeted therapies are needed to overcome the KRAS-induced oncogenesis. Recent evidence suggests that inhibition of PI3K led to ferroptosis, a nonapoptotic cell death closely related to KRAS-mutant cells. Here, we showed that a selective PI3Kδ inhibitor TYM-3-98 can suppress the AKT/mTOR signaling and activate the ferroptosis pathway in KRAS-mutant CRC cells in a concentration-dependent manner. This was evidenced by the lipid peroxidation, iron accumulation, and depletion of GSH. Moreover, the overexpression of the sterol regulatory element-binding protein 1 (SREBP1), a downstream transcription factor regulating lipid metabolism, conferred CRC cells greater resistance to ferroptosis induced by TYM-3-98. In addition, the effect of TYM-3-98 was confirmed in a xenograft mouse model, which demonstrated significant tumor suppression without obvious hepatoxicity or renal toxicity. Taken together, our work demonstrated that the induction of ferroptosis contributed to the PI3Kδ inhibitor-induced cell death via the suppression of AKT/mTOR/SREBP1-mediated lipogenesis, thus displaying a promising therapeutic effect of TYM-3-98 in CRC treatment.
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