Sodium butyrate induces mitochondrial pathway apoptosis in liver cancer via ATF4/SLC7A11-mediated ferroptosis.

Authors

Xiaolan Meng, Yubin Li, Miao He, Chen Wang, Haoran Shengsong, Jiacheng Guo, Jiayu Zhang, Shuang Zhao, Yulei Zhu, Bowen Li, Yuqiang Li, Hongzhi Sun

Published in

PloS one. Volume 21. Issue 7. Pages e0353653. Epub Jul 15, 2026.

Abstract

Liver cancer, a prevalent and aggressive malignancy globally, is associated with high morbidity and mortality rates. Butyrate, a metabolite produced by intestinal microbiota, is capable of restricting cancer initiation and progression. However, the precise mechanisms underlying its effects on liver cancer remain poorly understood. This study utilized a CCK-8 cytotoxicity assay to demonstrate that sodium butyrate (NaB) suppresses liver cancer cell proliferation through ferroptosis and apoptosis. The involvement of ATF4/SLC7A11 signaling and mitochondrial dysfunction in NaB-induced ferroptosis and apoptosis was further investigated. Results revealed a decrease in ATF4 and SLC7A11 expression, an elevation in the levels of malondialdehyde (MDA) and reactive oxygen species (ROS), and a reduction in glutathione (GSH) in NaB-treated liver cancer cells. These ferroptosis-related alterations could be reversed by an ATF4 activator. Additionally, NaB-treated liver cancer cells presented a decrease in mitochondrial membrane potential (MMP), accumulation of mitochondrial ROS, and mitochondrial damage. These cellular changes disrupted the BAX/BCL-2 balance, leading to cytochrome C release, which subsequently activated caspase9 and caspase3, initiating mitochondrial pathway apoptosis. In vivo, NaB treatment resulted in increased iron content in liver cancer tissues, along with upregulated cytochrome C, activated caspase9, and caspase3 expression; these effects were counteracted by ferrostatin-1 (Fer-1). Collectively, this study elucidates that NaB induces mitochondrial damage via ferroptosis mediated by ATF4/SLC7A11, ultimately triggering mitochondrial pathway apoptosis in hepatoma cells. These findings may offer novel insights into therapeutic strategies for hepatoma.

PMID:
42455831
Bibliographic data and abstract were imported from PubMed on 16 Jul 2026.

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