Cooperative inhibition of mTORC1 disrupts iron–redox homeostasis and triggers ferritinophagy-dependent ferroptosis in hepatocellular carcinoma
9 affiliations
- 1Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, China; Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
- 2Chongqing Key Laboratory of Sichuan-Chongqing Co-construction for Diagnosis and Treatment of Infectious Diseases Integrated Traditional Chinese and Western Medicine, Department of Laboratory Medicine, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, 400021, China
- 3Department of General Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
- 4Department of Pathology, College of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400016, China; Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, China; Molecular Medicine Diagnostic and Testing Center, Chongqing Medical University, Chongqing, 400016, China
- 5Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, China
- 6Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, China; Department of General Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
- 7State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, 999078, Macao Special Administrative Region of China
- 8Sichuan Key Medical Laboratory of New Drug Discovery and Drug Ability Evaluation, Key Laboratory of Medical Electrophysiology of Ministry of Education, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China; Corresponding author.
- 9Chongqing Key Laboratory of Sichuan-Chongqing Co-construction for Diagnosis and Treatment of Infectious Diseases Integrated Traditional Chinese and Western Medicine, Department of Laboratory Medicine, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, 400021, China; Corresponding author.
Abstract
Hepatocellular carcinoma (HCC) remains a leading cause of cancer mortality, and the clinical utility of β-lapachone (β-Lap) is limited by dose-dependent toxicity. Here, we identify cryptotanshinone (CPT), a bioactive compound derived from Salvia miltiorrhiza , as a synergistic partner that enables dose reduction while enhancing antitumor efficacy. Integrated transcriptomic profiling, biochemical analyses, target engagement assays, and in vivo validation support that β-Lap and CPT cooperatively induce ferroptosis through disruption of iron–redox homeostasis. Mechanistically, β-Lap and CPT engage Raptor and mTOR, respectively, in vitro, supporting a model wherein their cooperative action leads to dual suppression of mTORC1 signaling. mTORC1 inhibition activates NCOA4-mediated ferritinophagy, promoting ferritin degradation and expansion of the labile Fe 2+ pool. The consequent iron-dependent Fenton reaction drives excessive reactive oxygen species (ROS) accumulation and lipid peroxidation, culminating in ferroptotic cell death. Notably, this process occurs without downregulation of the canonical GPX4-SLC7A11 axis, defining a non-canonical, iron-amplified ferroptosis pathway. In xenograft models, the combination therapy significantly suppressed tumor growth without detectable systemic toxicity and recapitulated the molecular hallmarks observed in vitro, including mTORC1 inhibition, enhanced ferritinophagy, iron overload, and lipid peroxidation. Collectively, our findings support cooperative mTORC1 inhibition as a strategy to trigger ferritinophagy-dependent iron–redox collapse and non-canonical ferroptosis, providing a mechanistically informed and low-toxicity therapeutic approach for HCC.
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BibTeX
@article{chen2026cooperative,
title = {{Cooperative inhibition of mTORC1 disrupts iron–redox homeostasis and triggers ferritinophagy-dependent ferroptosis in hepatocellular carcinoma}},
author = {Xinyu Chen and Zhen Tan and Shiqiao Zhao and Fan Li and Yilin Liu and Cong Ren and Jiaying Li and Hanghong Lo and Yue Cui and Aie Zhou and Chuanlin Zhu and Anguo Wu and Ning Jiang and Fang Ren},
journal = {Redox Biology},
year = {2026},
month = oct,
doi = {10.1016/j.redox.2026.104369},
url = {https://doi.org/10.1016/j.redox.2026.104369},
note = {CC BY},
}
RIS
TY - JOUR
TI - Cooperative inhibition of mTORC1 disrupts iron–redox homeostasis and triggers ferritinophagy-dependent ferroptosis in hepatocellular carcinoma
AU - Xinyu Chen
AU - Zhen Tan
AU - Shiqiao Zhao
AU - Fan Li
AU - Yilin Liu
AU - Cong Ren
AU - Jiaying Li
AU - Hanghong Lo
AU - Yue Cui
AU - Aie Zhou
AU - Chuanlin Zhu
AU - Anguo Wu
AU - Ning Jiang
AU - Fang Ren
PY - 2026
DA - 2026/10/30
JO - Redox Biology
DO - 10.1016/j.redox.2026.104369
UR - https://doi.org/10.1016/j.redox.2026.104369
AB - Hepatocellular carcinoma (HCC) remains a leading cause of cancer mortality, and the clinical utility of β-lapachone (β-Lap) is limited by dose-dependent toxicity. Here, we identify cryptotanshinone (CPT), a bioactive compound derived from Salvia miltiorrhiza , as a synergistic partner that enables dose reduction while enhancing antitumor efficacy. Integrated transcriptomic profiling, biochemical analyses, target engagement assays, and in vivo validation support that β-Lap and CPT cooperatively induce ferroptosis through disruption of iron–redox homeostasis. Mechanistically, β-Lap and CPT engage Raptor and mTOR, respectively, in vitro, supporting a model wherein their cooperative action leads to dual suppression of mTORC1 signaling. mTORC1 inhibition activates NCOA4-mediated ferritinophagy, promoting ferritin degradation and expansion of the labile Fe 2+ pool. The consequent iron-dependent Fenton reaction drives excessive reactive oxygen species (ROS) accumulation and lipid peroxidation, culminating in ferroptotic cell death. Notably, this process occurs without downregulation of the canonical GPX4-SLC7A11 axis, defining a non-canonical, iron-amplified ferroptosis pathway. In xenograft models, the combination therapy significantly suppressed tumor growth without detectable systemic toxicity and recapitulated the molecular hallmarks observed in vitro, including mTORC1 inhibition, enhanced ferritinophagy, iron overload, and lipid peroxidation. Collectively, our findings support cooperative mTORC1 inhibition as a strategy to trigger ferritinophagy-dependent iron–redox collapse and non-canonical ferroptosis, providing a mechanistically informed and low-toxicity therapeutic approach for HCC.
SN - 2213-2317
ER -