ORIGINAL RESEARCH article
Front. Oncol.
Sec. Cancer Genetics
Volume 15 - 2025 | doi: 10.3389/fonc.2025.1604377
RNLS promotes ovarian cancer growth and inhibits ferroptosis via mediating STAT3
Provisionally accepted
- Fujian Provincial Cancer Hospital, Fuzhou, China
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Introduction: Ovarian cancer (OC) is a lethal malignancy for which there are limited therapeutic options. The role of renalase (RNLS) in cancer progression and ferroptosis regulation remains unclear. This study investigates how RNLS mediates STAT3 to promote OC growth and suppress ferroptosis.Methods: RNLS expression was analyzed in OC cell lines (OVCAR3) and normal ovarian epithelial cells (IOSE80) via qPCR. Stable RNLS knockdown (sh-RNLS) and overexpression (ov-RNLS) OVCAR3 models were established via lentiviral infection. STAT3 siRNA was transfected to explore RNLS-STAT3 interactions. Functional assays (CCK8, wound healing, Transwell, flow cytometry) evaluated proliferation, migration, invasion, apoptosis, and ROS levels. Mitochondrial morphology was assessed by electron microscopy. Subcutaneous tumor models in mice validated in vivo effects. Molecular markers (STAT3, p-PI3K/PI3K, p-AKT/AKT, Ki-67, MDA, GPX4, GSH) were analyzed via Western blot, immunohistochemistry, and ELISA.Results: RNLS was significantly upregulated in OC cells, particularly OVCAR3. RNLS knockdown suppressed STAT3 expression, cell proliferation, migration, invasion, and tumor growth, while promoting apoptosis, ROS accumulation, and mitochondrial damage. Conversely, RNLS overexpression exerted opposing effects. STAT3 silencing inhibited PI3K/AKT signaling and ferroptosis resistance, which were rescued by RNLS overexpression. In vivo, sh-RNLS reduced tumor volume/weight, as well as RNLS/STAT3, Ki-67, GPX4, and GSH, while increasing MDA. ov-RNLS enhanced tumor growth and reversed these molecular changes.Conclusion: RNLS drives OC progression by activating STAT3-dependent PI3K/AKT signaling, enhancing proliferation, metastasis, and ferroptosis suppression. Targeting RNLS-STAT3 axis may offer a novel therapeutic strategy against OC.
Keywords: ovarian cancer, RNLS, stat3, PI3K/AKT, Oxidative Stress
Received: 01 Apr 2025; Accepted: 25 Jun 2025.
Copyright: © 2025 Lin, Xie, Zhong, Chen, Ma, Li, Chen and Lin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Li Chen, Fujian Provincial Cancer Hospital, Fuzhou, China
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