Redox Report

Ferroptosis: from mechanisms to drug discovery

Ferroptosis is a regulated cell death pathway driven by excessive lipid peroxidation and subsequent loss of membrane integrity and cellular function. Since its initial description, ferroptosis has emerged as central mechanism linking redox imbalance and iron homeostasis to diverse pathological processes. Mechanistically, ferroptosis arises when antioxidant defense systems fail to control lipid peroxidation due to impaired redox regeneration, dysregulated iron metabolism, and phospholipid alterations that increase susceptibility to oxidative membrane damage. The resulting accumulation of toxic lipid peroxides ultimately causes irreversible membrane damage and cell death.

Our understanding of the ferroptotic machinery is rapidly expanding, revealing complex and context-dependent interconnections with cellular metabolism and signaling pathways. Growing evidence implicates ferroptosis in neurodegeneration, ischemia-reperfusion injury, inflammatory disorders, and metabolic diseases, while ferroptosis-inducing strategies are actively being explored for the treatment of hyperproliferative diseases, particularly aggressive and therapy-resistant cancers. At the same time, pro-tumorigenic functions of ferroptosis have also been reported, highlighting the need for further mechanistic and translational investigation.

Pharmacological modulation of ferroptosis is increasingly recognized as a promising strategy for the treatment of diseases associated with oxidative stress and aberrant cell survival or cell loss. Despite substantial progress, important questions remain unresolved. The physiological and pathophysiological functions of ferroptosis, including its anti-cancer defense, as well as the extent to which ferroptosis contributes to disease initiation and progression, are still incompletely understood. Moreover, although ferroptosis is generally considered an immunogenic form of necrotic cell death, notable exceptions and significant mechanistic gaps remain. Translational progress is further limited by challenges in the specific detection of ferroptosis in vivo, the lack of robust biomarkers, and the emerging complexity of crosstalk with other cell death programs. Meanwhile, the number of ferroptosis-modulating compounds is rapidly increasing, including both natural products and rationally designed drug candidates with favorable drug-like and preclinical properties. However, translation into clinical trials remains limited, underscoring the need for interdisciplinary efforts bridging mechanistic research, analytical innovation, and drug discovery.

This article collection welcomes both original research and review articles addressing emerging directions in ferroptosis research, ranging from fundamental insights into molecular mechanisms to clinical translation. The collection aims to cover frontier research in biochemistry, cell biology, molecular biology, (patho)physiology, analytics, target identification, drug discovery, and drug development, with a particular focus on the role of ferroptosis in degenerative diseases, metabolic diseases, and cancer. Overall, this collection aims to provide an interdisciplinary platform and resource for researchers seeking to overcome current challenges in translating ferroptosis-modulating strategies from bench to bedside.

Subtopics of special interest

• Mechanistic investigation of ferroptosis and its interconnections with cellular metabolism and signaling
• Crosstalk between ferroptosis and other cell death programs or cellular processes, including immunoregulation and inflammation
• Novel concepts for ferroptosis induction as an anti-cancer strategy
• Advances in ferroptosis inhibition for the treatment of degenerative and metabolic diseases
• Roles of ferroptosis in physiology and pathophysiology, with a particular focus on degenerative diseases, metabolic diseases, and cancer
• Identification and validation of molecular targets within the ferroptosis machinery
• Methodological advances in the specific detection of ferroptosis, including biomarker research and emerging analytical technologies
• Discovery of ferroptosis-modulating entities with novel core structures, mechanisms of action, or substantially improved pharmacological and safety profiles
• In-depth pharmacological characterization of ferroptosis-modulating entities, including their optimization toward drug-like candidates and clinical translation

Keywords:

• Ferroptosis
• Lipid peroxidation
• Cell metabolism
• Redox signaling
• Drug action

Guest Advisors:

Andreas Koeberle is Full Professor of Pharmacognosy at the University of Graz and a member of the Field of Excellence BioHealth. Trained as a biochemist and pharmacist, his research focuses on the interplay between lipid diversity, inflammation, cancer, and redox metabolism. His group employs mass spectrometry-based functional lipidomics for target identification and the discovery of bioinspired anti-inflammatory and anticancer drug candidates. A major focus of his current work is the development of innovative therapeutic strategies targeting lipid signaling and redox metabolism in ferroptosis and therapy-resistant cancer. His research has been recognized by multiple national and international awards. For further details about Prof. Koeberle's professional profile, kindly refer to these links: https://pharmazie.uni-graz.at/en/research/pharmacognosy/univ.-prof.-dr.-rer.-nat.-habil.-andreas-koeberle/, https://orcid.org/0000-0001-6269-5088.

Priv.-Doz. Dr. Solveigh Koeberle is a molecular pharmacologist at the University of Graz. She studied pharmacy and obtained her PhD in medicinal chemistry at the University of Tübingen. Following postdoctoral research at Tokyo Medical University and the Leibniz Institute on Aging (FLI Jena), she held academic positions in Germany and Austria and served as interim Professor of Medicinal Chemistry at the University of Regensburg from 2022 to 2024. Supported by the prestigious Elise Richter Program of the Austrian Science Fund (FWF), her research focuses on redox signaling, target identification, and the development of bioinspired chemical probes and drug candidates. Her work aims to elucidate redox-dependent disease mechanisms and to identify novel therapeutic strategies targeting ferroptosis in metabolic and neurodegenerative disorders, including metabolic-associated fatty liver disease (MAFLD), Alzheimer's disease, and Parkinson's disease. For further details about Dr. Koeberle's professional profile, kindly refer to these links: https://pharmazie.uni-graz.at/en/research/pharmacognosy/dr.-rer.-nat.-dipl.-pharm.-solveigh-koeberle/, https://orcid.org/0000-0002-8008-494X.

Disclosure Statement: Guest Advisors have no conflicts of interest to disclose.

Please review the journal scope and author submission instructions prior to submitting a manuscript.

To submit your papers to this Article Collection, please:

1. Check "yes" for the question, "Are you submitting your paper for a specific special issue or article collection?"
2. Select the Article Collection "Ferroptosis: from mechanisms to drug discovery" from the drop-down menu under the question, "Special Issue or Article Collection Name."

Please contact Changluan Zhou at [email protected] with any queries and discount codes regarding this Article Collection.