ArticleCell death discovery2025
SPHK1 enhances olaparib resistance in ovarian cancer through the NFκB/NRF2/ferroptosis pathway.
Article in Cell death discovery, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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The trial behind it
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Who cites it
16 citing papers in PubMed.
- Research progress of ferroptosis in gynecological diseases.Annals of medicine · 2026Review
- Subtype-specific mechanisms of lipid metabolism in gynecological malignancies and novel targeted intervention strategies (Review).Oncology letters · 2026Review
- Review
- Chemotherapy Enrichment of ID Family Expression Is Associated with IL-6 Signaling in Ovarian Cancer.Cancers · 2026Article
- A phase I dose-escalation study of Lobaplatin combined with paclitaxel in platinum-sensitive recurrent ovarian epithelial carcinoma: preliminary safety and tolerability supporting clinical trial dosing.Gynecologic oncology reports · 2026Article
- A comprehensive review of the emerging role of NRF3 in ovarian cancer tumorigenesis and progression.Journal of ovarian research · 2026Review
- Advances in ferroptosis research in ovarian cancer: molecular mechanisms and therapeutic perspectives.American journal of cancer research · 2026Review
- Sphingolipid-Neuroinflammation Axis in Parkinson's Disease: Focus on S1P/SPHK1-NF‑κB Signaling.Journal of inflammation research · 2026Review
- The SP1-SuperEnhancer-SPHK1 Axis Mediates Niraparib Resistance in TNBC.Pharmaceuticals (Basel, Switzerland) · 2025Article
- From mechanism to application: programmed cell death pathways in nanomedicine-driven cancer therapies.Bioactive materials · 2025Review
- The Combination of PF-543 and TRAIL Effectively Induces Apoptotic Cell Death and Inhibits Stem Cell-Like Properties Through the SPHK1/S1PR1/STAT3 Pathway in TRAIL-Resistant Colorectal Cancer Cells.Digestive diseases and sciences · 2025Article
- TTK activates ATR through RPA2 phosphorylation to promote olaparib resistance in ovarian cancer.Communications biology · 2025Article
- Crosstalk between ferroptosis and endoplasmic reticulum stress: A potential target for ovarian cancer therapy (Review).International journal of molecular medicine · 2025Review
- Identification of Sphingosine Kinase 1 as a Novel Protein Regulated by High Molecular Weight Hyaluronan in Ovarian Cancer.Journal of cellular and molecular medicine · 2025Article
- FAM46C Expression Sensitizes Multiple Myeloma Cells to PF-543-Induced Cytotoxicity.Biomolecules · 2025Article
- Research progress on ferroptosis and PARP inhibitors in ovarian cancer: action mechanisms and resistance mechanisms.Frontiers in pharmacology · 2025Review
Corrections and comments
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Authors and funding
5 authors.
Funding
Abstract
PARPis resistance is a challenge in the treatment of ovarian cancer. To investigate the potential mechanism involved in olaparib resistance of ovarian cancer, high-throughput sequencing was performed on olaparib-resistant SKOV3 cell line named SK/Ola. SPHK1 was upregulated in SK/Ola cells and was related to the PFS and OS in ovarian cancer patients. However, the effect and mechanism of SPHK1 on olaparib sensitivity in ovarian cancer were obscure. In this study, we found that SPHK1 promoted olaparib resistance. While, SPHK1 knockdown and SPHK1 inhibitor (PF-543 hydrochloride, named PF-543 in this article) enhanced the effect of olaparib on ovarian cancer cells. In mechanism, SPHK1 activated the NF-κB pathway through promoting p-IκBα degradation. Moreover, SPHK1 inhibited, but PF-543 activated ferroptosis in OC cells. Further investigation revealed that SPHK1 activated NF-κB p65, which in turn transcriptionally regulated NRF2 to inhibit ferroptosis in OC cells. Functionally, NF-κB p65 attenuated the PF-543-induced ferroptosis, and this effect was rescued by ferroptosis inducer erastin and RSL3. We conclude that SPHK1 inhibition triggers ferroptosis by restricting NF-κB-activated NRF2 transcription, thereby enhancing olaparib sensitivity in ovarian cancer. In vivo experiments also confirmed that the SPHK1 inhibitor increased olaparib sensitivity. A combination of SPHK1 inhibitors and olaparib may provide a therapeutic strategy for ovarian cancer.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.