Mitochondrial NADP(H)–dependent de novo dTMP biosynthesis counteracts the cytotoxicity of PARP inhibitors
PARP inhibitors (PARPis), known to elicit mitochondrial protection in nononcological diseases by elevating the cellular NAD + pool, exhibit potent cytotoxicity in selected human cancers. The role of mitochondrial metabolism in PARPi-mediated antitumor therapy remains unexplored. Here, we propose a causal link between mitochondrial NAD + metabolism and PARPi responsiveness. In PARPi-non-responsive tumor cells, PARP inhibition specifically expands mitochondrial NADP(H) [mito-NADP(H)] pool, thereby facilitating de novo mitochondrial dTMP (mito-dTMP) biosynthesis and maintaining mitochondrial dTTP (mito-dTTP) pool to prevent uracil misincorporation into mitochondrial DNA (mtDNA), regardless of homologous recombination (HR) status. Mechanistically, loss of PTPN1 ADPRylation by PARPi abolishes its phosphatase activity toward STAT3, yielding enhanced STAT3 phosphorylation and the subsequent transactivation of FoxO1. FoxO1 modulates transcriptomic signature governing mitochondrial NADPH fluxes to de novo mito-dTMP generation. Our results uncover a fundamental vulnerability that can be leveraged by cotargeting STAT3 and PARP to trigger mitochondrial dysfunction.
Authors
- Han Wook You (ORCID: https://orcid.org/0000-0003-1481-5465)
- Xianming Deng (ORCID: https://orcid.org/0000-0002-9354-5864)
- Xiaoniu He (ORCID: https://orcid.org/0000-0002-2238-0003)
- Fan Gao (ORCID: https://orcid.org/0000-0001-6832-3402)
- Hong Zheng (ORCID: https://orcid.org/0000-0002-8884-8211)
- Canhua Huang (ORCID: https://orcid.org/0000-0003-2247-7750)
- Wenbin Lu (ORCID: https://orcid.org/0000-0002-7320-4755)
- Wen Liu (ORCID: https://orcid.org/0000-0003-3434-4162)
- Chen Liu (ORCID: https://orcid.org/0009-0003-0430-6146)
- Chensong Zhang
- Yuanpei Li (ORCID: https://orcid.org/0000-0002-9450-1468)
- Tong Shu (ORCID: https://orcid.org/0000-0002-6923-4708)
- Pingping Liu (ORCID: https://orcid.org/0000-0003-1992-6017)
- Zhenyu Yin
- Min Zheng
- Qing Li
- Lei Zhang (ORCID: https://orcid.org/0009-0009-0855-6701)
- Huiwen Zhang (ORCID: https://orcid.org/0009-0007-6589-9917)
- Jing Ye
Institutions
- Sun Yat-sen University (CN)
- Xiamen University (CN)
- Sichuan University (CN)
- Zhongshan Hospital of Xiamen University (CN)
- Sun Yat-sen University Cancer Center (CN)
- Ministry of Education (ET)
- Xijing Hospital (CN)
- Air Force Medical University (CN)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2026-09-24
- DOI
- https://doi.org/10.1073/pnas.2607452123
- Primary Topic
- PARP inhibition in cancer therapy
- Type
- article
- Field-Weighted Citation Impact
- 0.00