2. Academic Validation
  3. Mitochondrial fatty acid oxidation as the target for blocking therapy-resistance and inhibiting tumor recurrence: The proof-of-principle model demonstrated for ovarian cancer cells

Mitochondrial fatty acid oxidation as the target for blocking therapy-resistance and inhibiting tumor recurrence: The proof-of-principle model demonstrated for ovarian cancer cells

  • J Adv Res. 2025 Mar 17:S2090-1232(25)00186-9. doi: 10.1016/j.jare.2025.03.026.
Hui Lin 1,  Lingfang Wang 2,  Hanwen Chen 3,  Yuqing Shen 4,  Conghui Wang 5,  Yite Xue 6,  Zhi Zheng 7,  Yanan Zhang 8,  Dajing Xia 9,  Yihua Wu 9,  Fenfen Wang 5,  Xiao Li 5,  Xiaodong Cheng 5,  Hui Wang 10,  Junfen Xu 11,  Weiguo Lu 12
Affiliations

Affiliations

  • 1 Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006 Zhejiang, China; Zhejiang Key Laboratory of Maternal and Infant Health, Hangzhou 310006 Zhejiang, China.
  • 2 Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006 Zhejiang, China.
  • 3 Department of Gastroenterology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009 Zhejiang, China.
  • 4 Department of Endocrinology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003 Zhejiang, China.
  • 5 Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006 Zhejiang, China; Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology, Hangzhou 310006 Zhejiang, China.
  • 6 Department of Gynecological Oncology, Zhejiang Cancer Hospital, Institute of Basic Medicine and Cancer, Chinese Academy of Sciences, Hangzhou 310022 Zhejiang, China.
  • 7 Department of Obstetrics and Gynecology, Wenzhou People's Hospital, Wenzhou 325000 Zhejiang, China.
  • 8 Department of Obstetrics and Gynecology, Peking University People's Hospital, Beijing 100044, China.
  • 9 Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006 Zhejiang, China; Department of Toxicology, Zhejiang University School of Public Health, Hangzhou 310058 Zhejiang, China.
  • 10 Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006 Zhejiang, China; Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology, Hangzhou 310006 Zhejiang, China; Zhejiang Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Hangzhou 310006 Zhejiang, China.
  • 11 Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006 Zhejiang, China; Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology, Hangzhou 310006 Zhejiang, China. Electronic address: xjfzu@zju.edu.cn.
  • 12 Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006 Zhejiang, China; Zhejiang Key Laboratory of Maternal and Infant Health, Hangzhou 310006 Zhejiang, China; Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology, Hangzhou 310006 Zhejiang, China. Electronic address: lbwg@zju.edu.cn.
PMID: 40107354 DOI: 10.1016/j.jare.2025.03.026
Abstract

Introduction: Cancer patients treated with current chemotherapeutic and targeted therapies frequently achieve partial remission, which ultimately relapse with more aggressive, drug-resistant tumor phenotypes. To a certain extent, drug-tolerant persister (DTP) cells are responsible for residual tumors after systemic Anticancer therapy and the onset of acquired drug resistance. Therefore, novel therapies targeting DTP cells to prevent drug resistance and tumor recurrence are urgently needed.

Objectives: We aimed to investigate the traits and key vulnerabilities of drug-tolerant ovarian Cancer persister cells and to seek out potential therapeutic strategies.

Methods: We constructed paclitaxel-tolerant ovarian Cancer persister cells by exposing ovarian Cancer parental cells to a lethal dose of paclitaxel. Proteomics analysis, in vitro and in vivo assays were performed to identify biological processes that could serve as potential vulnerabilities in persister cells.

Results: Paclitaxel-tolerant ovarian Cancer persister cells were found to undergo a metabolic reprogramming through the upregulation of fatty acid oxidation (FAO). Treatment with the FAO inhibitor ST1326 suppressed FAO and increased sensitivity to paclitaxel in persister cells. Moreover, combination therapy with paclitaxel and ST1326 prevented ovarian tumor recurrence with satisfactory biosafety in a mouse model of ovarian Cancer relapse, indicating that FAO disruption can improve the efficacy of paclitaxel-based therapy in ovarian Cancer. Mechanistically, we found that paclitaxel treatment upregulated CEBPB, a transcription factor that induced the expression of the FAO-related Enzyme HADHA and contributed to FAO elevation in persister cells.

Conclusions: This study revealed an upregulation of FAO in paclitaxel-tolerant ovarian Cancer persister cells and provided a prospective paclitaxel-ST1326 combination therapy targeting persister cells that may prevent the development of acquired drug resistance and achieve superior long-term ovarian Cancer control in the future. Our research established a conceptual framework for advancing personalized treatment approaches and enhancing patient outcomes in ovarian Cancer therapy.

Keywords

Drug-tolerant persister; Fatty acid oxidation; Improved individual outcomes; Mitochondrial metabolism; Ovarian cancer; Paclitaxel.

Figures
Products