Rabitha R, Shivani S, Showket Y, Sudhandiran G. Ferroptosis regulates key signaling pathways in gastrointestinal tumors: Underlying mechanisms and therapeutic strategies. World J Gastroenterol 2023; 29(16): 2433-2451 [PMID: 37179581 DOI: 10.3748/wjg.v29.i16.2433]
Corresponding Author of This Article
Ganapasam Sudhandiran, MPhil, PhD, Full Professor, Department of Biochemistry, University of Madras, Cell Biology Research Laboratory, Gandhi Mandapam Road, Chennai 600 025, Tamil Nadu, India. sudhandiran@unom.ac.in
Research Domain of This Article
Biochemistry & Molecular Biology
Article-Type of This Article
Review
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This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Ravichandiran Rabitha, Sethuraman Shivani, Yahya Showket, Ganapasam Sudhandiran, Department of Biochemistry, University of Madras, Cell Biology Research Laboratory, Chennai 600 025, Tamil Nadu, India
Author contributions: Rabitha R and Shivani S collected the data and equally wrote the paper; Showket Y and Sudhandiran G in part wrote and revised the manuscript and analyzed the data; Shivani S, Showket Y, and Sudhandiran G created the figures.
Conflict-of-interest statement: All authors report having no relevant conflicts of interest for this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Ganapasam Sudhandiran, MPhil, PhD, Full Professor, Department of Biochemistry, University of Madras, Cell Biology Research Laboratory, Gandhi Mandapam Road, Chennai 600 025, Tamil Nadu, India. sudhandiran@unom.ac.in
Received: December 11, 2022 Peer-review started: December 11, 2022 First decision: January 11, 2023 Revised: January 26, 2023 Accepted: April 7, 2023 Article in press: April 7, 2023 Published online: April 28, 2023 Processing time: 134 Days and 1.9 Hours
Abstract
Ferroptosis is an emerging novel form of non-apoptotic, regulated cell death that is heavily dependent on iron and characterized by rupture in plasma membrane. Ferroptosis is distinct from other regulated cell death modalities at the biochemical, morphological, and molecular levels. The ferroptotic signature includes high membrane density, cytoplasmic swelling, condensed mitochondrial membrane, and outer mitochondrial rupture with associated features of accumulation of reactive oxygen species and lipid peroxidation. The selenoenzyme glutathione peroxidase 4, a key regulator of ferroptosis, greatly reduces the lipid overload and protects the cell membrane against oxidative damage. Ferroptosis exerts a momentous role in regulating cancer signaling pathways and serves as a therapeutic target in cancers. Dysregulated ferroptosis orchestrates gastrointestinal (GI) cancer signaling pathways leading to GI tumors such as colonic cancer, pancreatic cancer, and hepatocellular carcinoma. Crosstalk exists between ferroptosis and other cell death modalities. While apoptosis and autophagy play a detrimental role in tumor progression, depending upon the factors associated with tumor microenvironment, ferroptosis plays a decisive role in either promoting tumor growth or suppressing it. Several transcription factors, such as TP53, activating transcription factors 3 and 4, are involved in influencing ferroptosis. Importantly, several molecular mediators of ferroptosis, such as p53, nuclear factor erythroid 2–related factor 2/heme oxygenase-1, hypoxia inducible factor 1, and sirtuins, coordinate with ferroptosis in GI cancers. In this review, we elaborated on key molecular mechanisms of ferroptosis and the signaling pathways that connect ferroptosis to GI tumors.
Core Tip: Gastrointestinal tumors contribute to the majority of cancer-related deaths. Ferroptosis is a novel form of non-apoptotic cell death that plays a vital role in reducing the invasiveness and metastasis of gastrointestinal tumors. Herein, we discussed the regulatory mechanisms involved in ferroptosis through the hallmark pathways of glutathione peroxidase 4, iron metabolism, lipid peroxidation, and redox signaling that provide a novel therapeutic approach for gastrointestinal cancers.
