Targeting Hsp70 triggers ferroptosis: a novel anti-cancer mechanism of a marine natural product in prostate cancer

doi:10.1007/s13659-025-00586-9

Natural Products and Bioprospecting ›› 2026, Vol. 16 ›› Issue (3): 34-34.DOI: 10.1007/s13659-025-00586-9

• ORIGINAL ARTICLE • Previous Articles

Targeting Hsp70 triggers ferroptosis: a novel anti-cancer mechanism of a marine natural product in prostate cancer

Qiuyu Liu^1,3, Mengjing Cong², Chenghai Gao³, Yonghong Liu^2,3, Junfeng Wang², Xueni Wang^1,3,4

1. Guangxi Engineering Research Center for High-Value Utilization of Guangxi-Produced Authentic Medicinal Herbs, Institute of Traditional Chinese and Zhuang-Yao Ethnic Medicine, Guangxi University of Chinese Medicine, Nanning 530200, China;
2. State Key Laboratory of Tropical Oceanography/Guangdong Key Laboratory of Marine Materia Medica, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510301, China;
3. Guangxi Key Laboratory of Marine Drugs, Institute of Marine Drugs, Guangxi University of Chinese Medicine, Nanning 530200, China;
4. Guangxi Innovation Center of Zhuang Yao Medicine, Institute of Traditional Chinese and Zhuang-Yao Ethnic Medicine, Guangxi University of Chinese Medicine, Nanning 530200, China

Received:2025-11-10 Online:2026-06-24
Contact: Yonghong Liu,E-mail:yonghongliu@scsio.ac.cn;Junfeng Wang,E-mail:wangjunfeng@scsio.ac.cn;Xueni Wang,E-mail:wangxueni@gxtcmu.edu.cn
Supported by:
This research was supported by the National Key R& D Program of China (2024YFC2815900), the Natural Science Foundation of Guangxi (2025GXNSFAA069334), the visiting Scholar Program of Bagui (Xueni Wang), the Foundation of Guangxi Key Laboratory of Marine Drugs (LMD2M023-4), the Hainan Provincial Joint Project of Sanya Yazhou Bay Science and Technology City (2021JJLH0097), the Hainan Provincial Natural Science Foundation of China (823CXTD393), the National Natural Science Foundation of China (U23A20528, 42376124).

Targeting Hsp70 triggers ferroptosis: a novel anti-cancer mechanism of a marine natural product in prostate cancer

Qiuyu Liu^1,3, Mengjing Cong², Chenghai Gao³, Yonghong Liu^2,3, Junfeng Wang², Xueni Wang^1,3,4

1. Guangxi Engineering Research Center for High-Value Utilization of Guangxi-Produced Authentic Medicinal Herbs, Institute of Traditional Chinese and Zhuang-Yao Ethnic Medicine, Guangxi University of Chinese Medicine, Nanning 530200, China;
2. State Key Laboratory of Tropical Oceanography/Guangdong Key Laboratory of Marine Materia Medica, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510301, China;
3. Guangxi Key Laboratory of Marine Drugs, Institute of Marine Drugs, Guangxi University of Chinese Medicine, Nanning 530200, China;
4. Guangxi Innovation Center of Zhuang Yao Medicine, Institute of Traditional Chinese and Zhuang-Yao Ethnic Medicine, Guangxi University of Chinese Medicine, Nanning 530200, China

通讯作者: Yonghong Liu,E-mail:yonghongliu@scsio.ac.cn;Junfeng Wang,E-mail:wangjunfeng@scsio.ac.cn;Xueni Wang,E-mail:wangxueni@gxtcmu.edu.cn
基金资助:
This research was supported by the National Key R& D Program of China (2024YFC2815900), the Natural Science Foundation of Guangxi (2025GXNSFAA069334), the visiting Scholar Program of Bagui (Xueni Wang), the Foundation of Guangxi Key Laboratory of Marine Drugs (LMD2M023-4), the Hainan Provincial Joint Project of Sanya Yazhou Bay Science and Technology City (2021JJLH0097), the Hainan Provincial Natural Science Foundation of China (823CXTD393), the National Natural Science Foundation of China (U23A20528, 42376124).

Abstract

Abstract: Prostate cancer (PCa) remains one of the most common malignant tumors among men worldwide, typically relying on the androgen receptor (AR) signaling pathway. Inducing ferroptosis, a novel form of iron-dependent cell death, represents a promising strategy; however, its regulation by AR signaling is complex. The molecular chaperone heat shock protein 70 (HSP70) is critical for AR stability and function, yet its role as a therapeutic target in this context is underexplored. The anti-proliferative effect of the compound nidurufin (Nid) was assessed across PCa cell lines using MTT, clonogenic, and 3D spheroid assays. Ferroptosis was evaluated by transmission electron microscopy, reactive oxygen species (ROS) detection, and lipid peroxidation analysis. Mechanistic insights were gained through Western blot, qPCR, immunofluorescence, ChIP-qPCR, molecular docking, and cellular thermal shift assay (CETSA). In vivo efficacy was validated in a zebrafish xenograft model. Nid exhibited potent, selective anti-proliferative activity against AR-positive PCa cells, particularly 22Rv1 (IC₅₀= 10.30 μM), and induced ferroptosis characterized by mitochondrial shrinkage and ROS accumulation. Mechanistically, Nid did not bind to AR, but it directly bound to HSP70, disrupting its chaperone function and leading to AR protein destabilization and transcriptional downregulation. This consequently suppressed the expression of the AR-target gene membrane-associated O-acyltransferase domain protein 2 (MBOAT2), a key ferroptosis suppressor enzyme. ChIP-qPCR confirmed AR directly binds the MBOAT2 promoter, and Nid treatment reduced this enrichment. In vivo, Nid significantly inhibited tumor growth and metastasis in a zebrafish xenograft model. Our study identifies Nid as a novel HSP70-targeted compound that triggers ferroptosis by disrupting the HSP70-AR-MBOAT2 axis. This work not only reveals a previously unrecognized connection between protein chaperone function and ferroptotic susceptibility but also positions HSP70 as a compelling therapeutic target for overcoming AR-pathway dependency in PCa.

Key words: Prostate cancer, Heat shock protein 70, Androgen receptor, Membrane-associated O-acyltransferase domain protein 2, Ferroptosis, Marine natural product

摘要： Prostate cancer (PCa) remains one of the most common malignant tumors among men worldwide, typically relying on the androgen receptor (AR) signaling pathway. Inducing ferroptosis, a novel form of iron-dependent cell death, represents a promising strategy; however, its regulation by AR signaling is complex. The molecular chaperone heat shock protein 70 (HSP70) is critical for AR stability and function, yet its role as a therapeutic target in this context is underexplored. The anti-proliferative effect of the compound nidurufin (Nid) was assessed across PCa cell lines using MTT, clonogenic, and 3D spheroid assays. Ferroptosis was evaluated by transmission electron microscopy, reactive oxygen species (ROS) detection, and lipid peroxidation analysis. Mechanistic insights were gained through Western blot, qPCR, immunofluorescence, ChIP-qPCR, molecular docking, and cellular thermal shift assay (CETSA). In vivo efficacy was validated in a zebrafish xenograft model. Nid exhibited potent, selective anti-proliferative activity against AR-positive PCa cells, particularly 22Rv1 (IC₅₀= 10.30 μM), and induced ferroptosis characterized by mitochondrial shrinkage and ROS accumulation. Mechanistically, Nid did not bind to AR, but it directly bound to HSP70, disrupting its chaperone function and leading to AR protein destabilization and transcriptional downregulation. This consequently suppressed the expression of the AR-target gene membrane-associated O-acyltransferase domain protein 2 (MBOAT2), a key ferroptosis suppressor enzyme. ChIP-qPCR confirmed AR directly binds the MBOAT2 promoter, and Nid treatment reduced this enrichment. In vivo, Nid significantly inhibited tumor growth and metastasis in a zebrafish xenograft model. Our study identifies Nid as a novel HSP70-targeted compound that triggers ferroptosis by disrupting the HSP70-AR-MBOAT2 axis. This work not only reveals a previously unrecognized connection between protein chaperone function and ferroptotic susceptibility but also positions HSP70 as a compelling therapeutic target for overcoming AR-pathway dependency in PCa.

关键词: Prostate cancer, Heat shock protein 70, Androgen receptor, Membrane-associated O-acyltransferase domain protein 2, Ferroptosis, Marine natural product

Qiuyu Liu, Mengjing Cong, Chenghai Gao, Yonghong Liu, Junfeng Wang, Xueni Wang. Targeting Hsp70 triggers ferroptosis: a novel anti-cancer mechanism of a marine natural product in prostate cancer[J]. Natural Products and Bioprospecting, 2026, 16(3): 34-34.

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Targeting Hsp70 triggers ferroptosis: a novel anti-cancer mechanism of a marine natural product in prostate cancer

Targeting Hsp70 triggers ferroptosis: a novel anti-cancer mechanism of a marine natural product in prostate cancer

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