Huayu Wan induces ferroptosis and enhances anti-PD-1 efficacy in cisplatin-resistant esophageal squamous cell carcinoma
- 1Department of Thoracic Surgery, Shaoxing People’s Hospital, School of Medicine, Shaoxing University
- 2Department of Cardiac and Great Vascular Surgery, Shaoxing People’s Hospital, School of Medicine, Shaoxing University
Abstract
Cisplatin resistance remains a major therapeutic challenge in esophageal squamous cell carcinoma (ESCC). Here, we investigated the antitumor effects and underlying mechanisms of Huayu Wan (HYW) in cisplatin-resistant ESCC. HYW markedly inhibited the growth of cisplatin-resistant human KYSE150 and murine mEC25 cells and induced a ferroptotic phenotype characterized by reactive oxygen species accumulation, increased intracellular iron, glutathione depletion, lipid peroxidation, and reduced GPX4 expression. Ferrostatin-1 partially reversed HYW-induced cytotoxicity. HYW also promoted immunogenic cell death-associated changes, including extracellular ATP and HMGB1 release and cell-surface calreticulin exposure. Mechanistically, HYW increased p53 expression and impaired the SLC7A11/GCLC-dependent cystine–glutathione antioxidant system, whereas GCLC overexpression and P53 inhibition partially restored redox homeostasis and cell survival. In parallel, HYW suppressed AKT–mTOR signaling and promoted NCOA4-associated ferritinophagy, as evidenced by increased NCOA4 and LC3-II and decreased FTH expression. Pharmacological inhibition of autophagy and NCOA4 knockdown attenuated iron accumulation and HYW-induced cytotoxicity. In cisplatin-resistant syngeneic tumors, HYW suppressed tumor growth with generally acceptable systemic tolerability, enhanced ferroptosis- and immunogenic stress-associated changes, reduced PD-L1 expression, and increased CD8 ⁺ T-cell infiltration. Moreover, HYW combined with anti-PD-1 treatment produced greater antitumor effects than either monotherapy. These findings suggest that HYW promotes ferroptosis through coordinated disruption of glutathione metabolism and NCOA4-associated ferritinophagy while enhancing antitumor immune responses in cisplatin-resistant ESCC.
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BibTeX
@article{zhu2026huayu,
title = {{Huayu Wan induces ferroptosis and enhances anti-PD-1 efficacy in cisplatin-resistant esophageal squamous cell carcinoma}},
author = {Ting Zhu and Bin Wang and Haiyong Wang and Jianyi Ding and Yangjun Xu and Jianfeng Xu and Lingjun Dong and Xiang Wang and Guangmao Yu and Zhupeng Li},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1967436},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1967436/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Huayu Wan induces ferroptosis and enhances anti-PD-1 efficacy in cisplatin-resistant esophageal squamous cell carcinoma
AU - Ting Zhu
AU - Bin Wang
AU - Haiyong Wang
AU - Jianyi Ding
AU - Yangjun Xu
AU - Jianfeng Xu
AU - Lingjun Dong
AU - Xiang Wang
AU - Guangmao Yu
AU - Zhupeng Li
PY - 2026
DA - 2026/10/27
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1967436
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1967436/full
AB - Cisplatin resistance remains a major therapeutic challenge in esophageal squamous cell carcinoma (ESCC). Here, we investigated the antitumor effects and underlying mechanisms of Huayu Wan (HYW) in cisplatin-resistant ESCC. HYW markedly inhibited the growth of cisplatin-resistant human KYSE150 and murine mEC25 cells and induced a ferroptotic phenotype characterized by reactive oxygen species accumulation, increased intracellular iron, glutathione depletion, lipid peroxidation, and reduced GPX4 expression. Ferrostatin-1 partially reversed HYW-induced cytotoxicity. HYW also promoted immunogenic cell death-associated changes, including extracellular ATP and HMGB1 release and cell-surface calreticulin exposure. Mechanistically, HYW increased p53 expression and impaired the SLC7A11/GCLC-dependent cystine–glutathione antioxidant system, whereas GCLC overexpression and P53 inhibition partially restored redox homeostasis and cell survival. In parallel, HYW suppressed AKT–mTOR signaling and promoted NCOA4-associated ferritinophagy, as evidenced by increased NCOA4 and LC3-II and decreased FTH expression. Pharmacological inhibition of autophagy and NCOA4 knockdown attenuated iron accumulation and HYW-induced cytotoxicity. In cisplatin-resistant syngeneic tumors, HYW suppressed tumor growth with generally acceptable systemic tolerability, enhanced ferroptosis- and immunogenic stress-associated changes, reduced PD-L1 expression, and increased CD8 ⁺ T-cell infiltration. Moreover, HYW combined with anti-PD-1 treatment produced greater antitumor effects than either monotherapy. These findings suggest that HYW promotes ferroptosis through coordinated disruption of glutathione metabolism and NCOA4-associated ferritinophagy while enhancing antitumor immune responses in cisplatin-resistant ESCC.
SN - 1664-3224
ER -