Citation: Jia-Yin Su, Shiyao Song, Zi-Min Song, Xi Sun, Niangji Tsomo, Ying-Li Liu, Jingxuan Ma, Jie-Si Luo, Li-Na Wang, Suoyu Xiang, Cong Liang, Xue-Qun Luo, Jun Wu, Li-Bin Huang, Yan-Lai Tang. Arsenic trioxide-induced pyroptosis promotes the release of HMGB1 to activate natural killer cells related immunogenic cell death in leukemia[J]. Chinese Chemical Letters, ;2026, 37(7): 111585. doi: 10.1016/j.cclet.2025.111585 shu

Arsenic trioxide-induced pyroptosis promotes the release of HMGB1 to activate natural killer cells related immunogenic cell death in leukemia

Jia-Yin Su ^{a, d, 1} ,
Shiyao Song ^{a, 1} ,
Zi-Min Song ^b ,
Xi Sun ^c ,
Niangji Tsomo ^e ,
Ying-Li Liu ^f ,
Jingxuan Ma ^g ,
Jie-Si Luo ^a ,
Li-Na Wang ^a ,
Suoyu Xiang ^c ,
Cong Liang ^a ,
Xue-Qun Luo ^a ,
Jun Wu ^{h, i, *,} ,
Li-Bin Huang ^{a, *,} ,
Yan-Lai Tang ^{a, *,}

a.
Department of Paediatrics, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
b.
Center of Hepato-Pancreato-Biliary Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
c.
Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
d.
School of Life Science, The Chinese University of Hong Kong, Hong Kong SAR 999077, China
e.
Research Center for High Altitude Medicine, School of Medicine, Qinghai University, Xining 810000, China
f.
Shenzhen Longgang Otorhinolaryngology Hospital, Shenzhen 518100, China
g.
West China School of Medicine, Sichuan University, Chengdu 610044, China
h.
Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong SAR 999077, China
i.
Bioscience and Biomedical Engineering Thrust, The Hong Kong University of Science and Technology (Guangzhou), Guangzhou 511400, China

junwuhkust@ust.hk

huanglb3@mail.sysu.edu.cn

tangylai@mail.sysu.edu.cn

Received Date: 16 April 2025
Revised Date: 11 July 2025
Accepted Date: 13 July 2025
Available Online: 14 July 2025

Figures(4)

The application of Arsenic trioxide (ATO) has greatly improved the cure rates in patients with acute promyelocytic leukemia (APL) and has shown therapeutic effects in other leukemia types, as evidenced by an increasing number of preclinical trials. However, its clinical application is still limited due to a lack of understanding of the underlying mechanisms. In this report, we have demonstrated that ATO can induce pyroptosis and release damage-associated molecular patterns (DAMPs), such as high mobility group box 1 (HMGB1) and interleukin-1β (IL-1β). DAMPs can activate the immunogenic cell death (ICD) mechanism. Our study elucidated the pivotal role of pyroptosis and demonstrated the activation of the caspase-3/gasdermin E (GSDME) pathway both in vivo and in vitro upon ATO intervention. Proteomic analysis of cell supernatants revealed the release of the ICD-associated molecule HMGB1. Results from both in vitro and in vivo experiments collectively demonstrated that the release of HMGB1 is contingent upon GSDME-mediated pyroptosis. Furthermore, label-free quantitative proteomics in vivo indicated that ATO-induced pyroptosis activates natural killer cells (NKs) and promotes the release of granzyme B (GZMB). Our study is the first to demonstrate the synergistic interplay between pyroptosis and ICD mechanisms during ATO treatment, providing novel insights into the potential of ATO for immunotherapy and synergistic treatment approaches.
- Arsenic trioxide,
- Pyroptosis,
- Natural killer cells,
- Acute myeloid leukemia,
- Immunogenic cell death
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