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Peer-reviewedCC BYCell death & disease

Targeting SLC1A5-mediated glutamine metabolism overcomes PARP inhibitor resistance in ovarian cancer.

  • Fang Han1,2,3
  • Hongjie Du1,2,4
  • Kunlin Tian1,2
  • Gonghua Qi1,2
  • Beihua Kong1,2
  • Xia Luo5,6
  • Hanlin Ma7,8
8 affiliations
  1. 1Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China.
  2. 2Shandong Key Laboratory of Reproductive Health and Birth Defects Prevention and Control, Qilu Hospital of Shandong University, Jinan, China.
  3. 3Department of Ophthalmology, Qilu Hospital of Shandong University, Jinan, China.
  4. 4Department of Otorhinolaryngology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
  5. 5Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China. [email protected].
  6. 6Shandong Key Laboratory of Reproductive Health and Birth Defects Prevention and Control, Qilu Hospital of Shandong University, Jinan, China. [email protected].
  7. 7Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, China. [email protected].
  8. 8Shandong Key Laboratory of Reproductive Health and Birth Defects Prevention and Control, Qilu Hospital of Shandong University, Jinan, China. [email protected].
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Abstract

Poly(ADP-ribose) polymerase inhibitors (PARPi), such as olaparib, have significantly improved outcomes in ovarian cancer (OC); however, therapy resistance remains a major clinical challenge. Here, we showed that glutamine metabolism was upregulated in PARPi-resistant OC cells and identified the glutamine transporter SLC1A5 as a key mediator of this metabolic adaptation. Inhibition of SLC1A5 increased the sensitivity of OC cells to olaparib both in vitro and in vivo. Mechanistically, we demonstrated that the deubiquitinating enzyme USP14 directly interacted with and stabilized SLC1A5 by removing K48-linked polyubiquitin chains, thereby enhancing glutamine uptake, promoting glutathione synthesis, alleviating oxidative stress, and activating the mTORC1 pathway. This metabolic rewiring improved DNA damage repair capacity and ultimately contributed to PARPi resistance. Notably, combined treatment with the SLC1A5 inhibitor V-9302 and olaparib synergistically suppressed tumor growth in a patient-derived xenograft (PDX) model. Collectively, our findings identify the USP14-SLC1A5 axis as a novel regulator of PARPi resistance and suggest that targeting glutamine metabolism represents a promising therapeutic strategy to overcome PARPi resistance in ovarian cancer.

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Cite

BibTeXRIS
BibTeX
@article{han2026targeting,
  title = {{Targeting SLC1A5-mediated glutamine metabolism overcomes PARP inhibitor resistance in ovarian cancer.}},
  author = {Fang Han and Hongjie Du and Kunlin Tian and Gonghua Qi and Beihua Kong and Xia Luo and Hanlin Ma},
  journal = {Cell death \& disease},
  year = {2026},
  month = jul,
  doi = {10.1038/s41419-026-09123-z},
  url = {https://europepmc.org/article/MED/42893982},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Targeting SLC1A5-mediated glutamine metabolism overcomes PARP inhibitor resistance in ovarian cancer.
AU  - Fang Han
AU  - Hongjie Du
AU  - Kunlin Tian
AU  - Gonghua Qi
AU  - Beihua Kong
AU  - Xia Luo
AU  - Hanlin Ma
PY  - 2026
DA  - 2026/07/01
JO  - Cell death & disease
DO  - 10.1038/s41419-026-09123-z
UR  - https://europepmc.org/article/MED/42893982
AB  - Poly(ADP-ribose) polymerase inhibitors (PARPi), such as olaparib, have significantly improved outcomes in ovarian cancer (OC); however, therapy resistance remains a major clinical challenge. Here, we showed that glutamine metabolism was upregulated in PARPi-resistant OC cells and identified the glutamine transporter SLC1A5 as a key mediator of this metabolic adaptation. Inhibition of SLC1A5 increased the sensitivity of OC cells to olaparib both in vitro and in vivo. Mechanistically, we demonstrated that the deubiquitinating enzyme USP14 directly interacted with and stabilized SLC1A5 by removing K48-linked polyubiquitin chains, thereby enhancing glutamine uptake, promoting glutathione synthesis, alleviating oxidative stress, and activating the mTORC1 pathway. This metabolic rewiring improved DNA damage repair capacity and ultimately contributed to PARPi resistance. Notably, combined treatment with the SLC1A5 inhibitor V-9302 and olaparib synergistically suppressed tumor growth in a patient-derived xenograft (PDX) model. Collectively, our findings identify the USP14-SLC1A5 axis as a novel regulator of PARPi resistance and suggest that targeting glutamine metabolism represents a promising therapeutic strategy to overcome PARPi resistance in ovarian cancer.
SN  - 2041-4889
ER  -