Securinine, a novel alkaloid, regulates cell cycle and EMT in gastric cancer by inducing iron-dependent cell death

Weiwei Yuan^1*Hao Song²Yin Shi³Jianye Han²Shaohe Jiao²Song Liang⁴Yuanmin Xu⁵Zhangming Chen²Limin Liu¹Aman Xu²Zhou Xu¹

• ¹Shanghai Baoshan Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, China
• ²First Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China
• ³Yiwu Maternity and Children Health Care Hospital, Jinhua, Zhejiang Province, China
• ⁴Lu'an People's Hospital, Lu'an, Anhui Province, China
• ⁵Department of Anesthesiology, The First Affiliated Hospital of University of Science and Technology of China Anhui Provincial Hospital, Hefei, Anhui Province, China

Background Gastric cancer remains one of the most prevalent and lethal cancers worldwide, with its insidious onset hindering early diagnosis and effective treatment. Despite advances, the overall survival rate for gastric cancer remains low, primarily due to late diagnosis, tumor 2 heterogeneity, and resistance to current therapies. This highlights the urgent need for novel therapeutic strategies.Methods Gastric cancer cell lines were treated with securinine, followed by analysis of cell proliferation, cycle, and EMT using Western blot and immunofluorescence techniques.Transcriptomic analysis was performed to identify changes in ferroptosis-related iron metabolism pathways. In vivo studies were conducted using xenograft mouse models to assess tumor growth.Results Securinine significantly inhibited proliferation and modulated the cell cycle, arresting cells at the G2/M transition, while also enhancing EMT, which altered cell migration and invasiveness. Transcriptomic analysis revealed that securinine activated ferroptosisrelated iron metabolic pathways, upregulating key genes such as HMOX1, FTH1, and FTR.Inhibition of these genes reversed the effects on cell proliferation and EMT, highlighting the role of ferroptosis in the anticancer effects of securinine. In vivo studies demonstrated a significant reduction in tumor growth in xenograft models.Conclusions Securinine shows potential as a novel therapeutic agent for gastric cancer by inducing ferroptosis and modulating key cell death and survival pathways. Its ability to regulate iron metabolism and EMT suggests that it could be a promising candidate for developing new therapeutic strategies against gastric cancer, especially for drug-resistant cases.