2. Academic Validation
  3. Vorapaxar enhanced mitochondria-associated ferroptosis primes cancer immunotherapy via targeting FOXO1/HMOX1 axis

Vorapaxar enhanced mitochondria-associated ferroptosis primes cancer immunotherapy via targeting FOXO1/HMOX1 axis

  • Cell Rep Med. 2025 Sep 25:102371. doi: 10.1016/j.xcrm.2025.102371.
Qian Zhou 1,  Yuming Sun 2,  Songtao Du 3,  Yating Dian 1,  Lei Yao 4,  Hui Su 1,  Ziyu Guo 1,  Yu Meng 1,  Yixiao Xiong 5,  Zhili Deng 6,  Xinwei Kuang 1,  Xiaowei Liang 1,  Hong Liu 1,  Guangtong Deng 7,  Xiang Chen 8,  Furong Zeng 9
Affiliations

Affiliations

  • 1 Department of Dermatology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, Hunan Province, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, 87 Xiangya Road, Changsha 410008, Hunan Province, China; Furong Laboratory, 87 Xiangya Road, Changsha 410008, Hunan Province, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, Hunan Province, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, 87 Xiangya Road, Changsha 410008, Hunan Province, China.
  • 2 Department of Plastic and Cosmetic Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, Hunan Province, China.
  • 3 Department of Colorectal Surgical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province 150000, China.
  • 4 Department of General Surgery, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, Hunan Province, China.
  • 5 Department of Dermatology, Tongji Hospital, Huazhong University of Science and Technology, 1095 Jiefang Road, Wuhan 430030, Hubei, China.
  • 6 Department of Dermatology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, Hunan Province, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, 87 Xiangya Road, Changsha 410008, Hunan Province, China; Furong Laboratory, 87 Xiangya Road, Changsha 410008, Hunan Province, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, 87 Xiangya Road, Changsha 410008, Hunan Province, China; Hunan Key Laboratary of Aging Biology, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China.
  • 7 Department of Dermatology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, Hunan Province, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, 87 Xiangya Road, Changsha 410008, Hunan Province, China; Furong Laboratory, 87 Xiangya Road, Changsha 410008, Hunan Province, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, Hunan Province, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, 87 Xiangya Road, Changsha 410008, Hunan Province, China. Electronic address: dengguangtong@outlook.com.
  • 8 Department of Dermatology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, Hunan Province, China; National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, 87 Xiangya Road, Changsha 410008, Hunan Province, China; Furong Laboratory, 87 Xiangya Road, Changsha 410008, Hunan Province, China; Hunan Key Laboratory of Skin Cancer and Psoriasis, Hunan Engineering Research Center of Skin Health and Disease, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, Hunan Province, China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, 87 Xiangya Road, Changsha 410008, Hunan Province, China. Electronic address: chenxiangck@126.com.
  • 9 Department of Oncology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, Hunan Province, China. Electronic address: zengflorachn@hotmail.com.
PMID: 41005298 DOI: 10.1016/j.xcrm.2025.102371
Abstract

Immunotherapy has revolutionized Cancer treatment, yet challenges persist, such as resistance and lethal thromboembolism, necessitating dual-purpose strategies. Targeting Ferroptosis emerges as a promising strategy to enhance immunotherapy efficacy, prompting our investigation of antiplatelet agents that simultaneously promote Ferroptosis and mitigate thromboembolic risks. Through systematic screening of 20 Food and Drug Administration (FDA)-approved antiplatelet agents, we identify vorapaxar as a potent pro-ferroptotic drug. Mechanistically, vorapaxar binds forkhead box O1 (FOXO1), inhibits its phosphorylation at Ser256, and facilitates nuclear translocation to upregulate heme oxygenase 1 (HMOX1), promoting mitochondrial iron overload and mitochondria-associated Ferroptosis. Vorapaxar enhances immunotherapy-induced tumor Ferroptosis and antitumor immunity across diverse melanoma models, including B16F10 tumor-bearing mice, Braf/Pten-driven spontaneous melanoma mice, and peripheral blood mononuclear cell (PBMC)-humanized mice. Clinically, high FOXO1/HMOX1 co-expression correlates with improved immunotherapy response and progression-free survival. These findings position vorapaxar as a promising adjunct to immunotherapy, offering a dual benefit for Cancer patients requiring both antithrombotic therapy and immunotherapy.

Keywords

FOXO1; HMOX1; ferroptosis; immunotherapy; vorapaxar.

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