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Using Hepa1-6 and Huh7 models, the work assesses wound healing and migration, apoptosis via flow cytometry and TUNEL, and ferroptosis/apoptosis proteins by RNA-seq, immunoblotting, and immunohistochemistry. Results indicate dose-dependent suppression of proliferation and invasion, with elevated ROS, apoptosis, and reduced tumor 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[https://doi.org/10.1007/s10238-024-01550-6](https://doi.org/10.1007/s10238-024-01550-6)  \nDonafenib activates the p53 signaling pathway in hepatocellular carcinoma, induces ferroptosis, and enhances cell apoptosis  \nJiaming Liang1 · Meifeng Chen1 · Guohong Yan1 · Pham Thi Thai Hoa2 · Shuxin Wei3 · Hailian Huang3 · Qichong Xie3 · Xiaoling Luo3 · Shutian Mo1 · Chuangye Han1  \nReceived: 25 October 2024 / Accepted: 23 December 2024 / Published online: 3 January 2025 © The Author(s) 2025  \nAbstract  \nDonafenib is an improved version of sorafenib in which deuterium is substituted into the drug’s chemical structure, enhancing its stability and antitumor activity. Donafenib exhibits enhanced antitumor activity and better tolerance than sorafenib in preclinical and clinical studies. However, the specific mechanism of its effect on hepatocellular carcinoma has not been reported. Iron deposition is a cell death pattern caused by disturbances in iron metabolism. Apoptosis is a form of programmed cell death. They may interact with each other during cell death. This study mainly explores the potential mechanism of donafenib activating the p53 signaling pathway, inducing iron deposition, and enhancing cell apoptosis in hepatocellular carcinoma. Hepa1-6 and Huh7 cells were treated with various concentrations of donafenib. Scratch healing and pore migration tests were conducted. Analyze apoptosis through flow cytometry and TUNEL fluorescence labeling. RNA sequencing was conducted on both untreated and donafenib-treated Huh7 cells. The key proteins involved in ferroptosis (SLC7A11, GPX4) and apoptosis (caspase3, caspase8, Bax, Bcl-2, p53) were then evaluated using immunoblotting and immunohistochemical staining. Reactive oxygen species (ROS) levels in the cancer cells were measured. Donafenib treatment resulted in a dose-dependent decrease in the proliferation, migration, and invasion capabilities of cancer cells. There was an increase in apoptosis rates and ROS accumulation, and a reduction in tumor volume. The key proteins involved in ferroptosisand apoptosis underwent significant changes. Donafenib activates the p53 signaling pathway, induce ferroptosis, and enhance apoptosis, suggesting its potential as an effective therapeutic agent for HCC.  \nKeywords Hepatocellular carcinoma · Donafenib · p53 · Ferroptosis · Cell apoptosis  \nJiaming Liang and Meifeng Chen have contributed equally to this work.  \n* Shutian Mo[moshutian95@163.com](moshutian95@163.com)  \n* Chuangye Han [hanchuangye@hotmail.com](hanchuangye@hotmail.com)  \n1 Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China  \n2 Research and Development Centre of Zhuang and Yao Medicines, Guangxi International Zhuang Medical Hospital, Nanning, China  \n3 School of Basic Medical Sciences, Guangxi Medical University, Nanning, China  \nIntroduction  \nHepatocellular carcinoma (HCC), the predominant malignancy of the liver, ranks among the most common types of cancer worldwide, currently occupying the second spot in China in terms of mortality rates linked to primary liver cancer [1, 2] . Due to the insidious nature of HCC, as well as its high rates of late-stage metastasis and recurrence, diagnosis and treatment are challenging. At present, surgery is still the main treatment for liver cancer [3] . However, many patients diagnosed with liver cancer are already in the middle or late-stages and have thus exceeded the window for surgical intervention [4] . Liver cancer has a high recurrence rate and distant metastasis, while radiotherapy, chemotherapy, targeted therapy, and immunotherapy all have limited effects on this condition, resulting in a poor prognosis [5–7] .  \nDonafenib, a deuterated derivative of sorafenib, isan oral multi-receptor kinase small molecule inhibitor.  \nDeuterium is a stable isotope with a larger mass than hydrogen, therefore it has higher metabolic stability. Introduc","cbCaiqaOh383USfd","https://ap.wps.com/l/cbCaiqaOh383USfd","pdf",33539315,"English","# Abstract\n# Introduction\n## Background on hepatocellular carcinoma\n## Sorafenib deuterated derivative: donafenib\n## Cell death, apoptosis, and ferroptosis\n## Role of p53 in tumor suppression","[{\"question\":\"How does the study propose donafenib affects hepatocellular carcinoma cells?\",\"answer\":\"It proposes that donafenib activates the p53 signaling pathway, induces ferroptosis through iron deposition, and enhances apoptosis in hepatocellular carcinoma cells.\"},{\"question\":\"What cell-based experiments were used to evaluate the effects of donafenib?\",\"answer\":\"Hepa1-6 and Huh7 cells were treated with different donafenib concentrations, followed by scratch healing and pore migration tests to evaluate migration and invasion changes.\"},{\"question\":\"Which molecular markers were examined to assess ferroptosis and apoptosis?\",\"answer\":\"Key ferroptosis and apoptosis proteins were evaluated, including SLC7A11 and GPX4 for ferroptosis, and caspase3, caspase8, Bax, Bcl-2, and p53 for apoptosis, using immunoblotting and immunohistochemical staining.\"}]","Donafenib activates the p53 signaling pathway in hepatocellular carcinoma, induces ferroptosis, and enhances cell apoptosis | PDF",1790216096]