Journal article
Depletion of oxysterol-binding proteins by OSW-1 triggers RIP1/RIP3-independent necroptosis and sensitization to cancer immunotherapy
Cell death and differentiation, Vol.32(11), pp.2038-2052
11/2025
DOI: 10.1038/s41418-025-01521-8
PMCID: PMC12572256
PMID: 40329104
Abstract
Oxysterol-binding proteins (OSBPs), lipid transfer proteins functioning at intracellular membrane contact sites, are recently found to be dysregulated in cancer and promote cancer cell survival. However, their role as potential targets in cancer therapy remains largely unexplored. In this study, we found OSW-1, a natural compound and OSBP inhibitor, potently and selectively kills colon cancer cells by activating a previously unknown necroptosis pathway that is independent of receptor-interacting protein 1 (RIP1) and RIP3. OSW-1 stabilizes p53 and degrades OSBPs to promote endoplasmic reticulum (ER) stress and glycogen synthase kinase 3β (GSK3β)/Tip60-mediated p53 acetylation at Lysine 120, which selectively induces its target PUMA. PUMA-mediated mitochondrial calcium influx activates calcium/calmodulin-dependent protein kinase IIδ (CamKIIδ) to promote mixed lineage kinase domain-like (MLKL) phosphorylation and necroptotic cell death. Furthermore, OSW-1-induced necroptosis is highly immunogenic and sensitizes syngeneic colorectal tumors to anti-PD-1 immunotherapy. Together, our results identified a novel RIP1/RIP3-independent necroptosis pathway underlying the extremely potent anticancer activity of OSW-1, which can be harnessed to develop new anticancer therapies by selectively stimulating antitumor immunity.
Details
- Title: Subtitle
- Depletion of oxysterol-binding proteins by OSW-1 triggers RIP1/RIP3-independent necroptosis and sensitization to cancer immunotherapy
- Creators
- Xinyan Lu - University of Pittsburgh School of MedicineDongshi Chen - University of Pittsburgh School of MedicineMin Wang - University of Pittsburgh School of MedicineXiangping Song - University of Pittsburgh School of MedicineKaylee Ermine - University of Pittsburgh School of MedicineSuisui Hao - University of Pittsburgh School of MedicineAnupma Jha - University of Pittsburgh School of MedicineYixian Huang - University of PittsburghYing Kang - University of IowaHaibo Qiu - University of IowaHeinz-Josef Lenz - Norris Comprehensive Cancer Center, Keck School of Medicine of USC, Los Angeles, CA, USASong Li - University of PittsburghZhendong Jin - University of IowaJian Yu - University of Pittsburgh School of MedicineLin Zhang - University of Pittsburgh School of Medicine
- Resource Type
- Journal article
- Publication Details
- Cell death and differentiation, Vol.32(11), pp.2038-2052
- DOI
- 10.1038/s41418-025-01521-8
- PMID
- 40329104
- PMCID
- PMC12572256
- NLM abbreviation
- Cell Death Differ
- ISSN
- 1350-9047
- eISSN
- 1476-5403
- Publisher
- SPRINGERNATURE
- Grant note
- R01CA217141 / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) R01CA247231 / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) R01CA215481 / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) R01CA260900 / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) R01CA236271 / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) R01CA248112 / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) R01CA203028 / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) T32GM133332 / U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)
- Language
- English
- Electronic publication date
- 05/06/2025
- Date published
- 11/2025
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984820562202771
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