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Ferroptosis: a novel pharmacological mechanism against multiple myeloma
Jingbo Shi1, Yitong Lu1, Wenjian Wei1
1Department of First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China.
Background:
Multiple myeloma (MM) is a malignant disease characterized by the clonal proliferation of plasma cells in the bone marrow. Currently incurable, relapse and drug resistance remain significant challenges, necessitating the exploration of novel anti-MM agents. Ferroptosis, a form of cell death driven by iron-dependent lipid peroxidation, has emerged as a critical player in MM pathology and treatment. With advancing research, emerging evidence links ferroptosis to MM pathogenesis and therapeutic strategies. Natural products (NPs) and certain antitumor agents, owing to their broad bioactivities, demonstrate unique pharmacological advantages in MM therapy by targeting ferroptosis-related pathways.
Purpose:
This review systematically examines ferroptosis-related pathways in MM pathogenesis, focusing on pharmacological and toxicological mechanisms of natural products (NPs) and antitumor compounds in modulating ferroptosis-related pathways. It aims to provide novel insights and strategies for MM research and clinical therapy.
Methods:
We systematically retrieved data from PubMed, Web of Science, ScienceDirect, SciFinder, Scopus, and the China National Knowledge Infrastructure (CNKI) spanning database inception to March 2025, followed by taxonomic integrative analysis of NPs' and antitumor compounds' echanistic classifications.
Results:
NPs and antitumor compounds exert anti-MM effects via ferroptosis modulation, mechanistically mediated through: 1) lipid metabolism reprogramming; 2) ferritinophagy-driven iron homeostasis regulation; 3) Reactive oxygen species (ROS)-mediated oxidative stress potentiation; 4) autophagic activation; 5) Genes and proteins regulation.
Conclusion:
NPs and antitumor compounds demonstrate therapeutic potential against MM through multi-dimensional ferroptosis modulation, yet clinical translation faces two critical hurdles: 1) predominant focus on single-target mechanisms lacking systems pharmacology-level network analysis; 2) overreliance on in vitro models with insufficient clinical validation. Prioritize developing biomarkers and ferroptosis inducers to advance novel ferroptosis-targeting anticancer compounds.
Insights
Natural products and antitumor agents show promise in treating multiple myeloma (MM) by targeting ferroptosis, a cell death pathway. Further research is needed to overcome clinical translation challenges for these ferroptosis-targeting therapies.
Area of Science:
- Oncology
- Cell Death Mechanisms
- Pharmacology
Background:
- Multiple myeloma (MM) is a fatal plasma cell malignancy with challenges in relapse and drug resistance.
- Ferroptosis, an iron-dependent cell death, is increasingly recognized in MM pathogenesis and treatment.
- Natural products (NPs) and antitumor agents offer potential therapeutic advantages by targeting ferroptosis pathways in MM.
Purpose of the Study:
- To systematically review ferroptosis-related pathways in MM.
- To analyze the pharmacological and toxicological mechanisms of NPs and antitumor compounds in modulating ferroptosis.
- To provide insights for novel MM research and clinical strategies targeting ferroptosis.
Main Methods:
- Comprehensive literature search across major scientific databases (PubMed, Web of Science, etc.) up to March 2025.
- Systematic retrieval and analysis of data on ferroptosis pathways in MM.
- Taxonomic and mechanistic classification of NPs and antitumor compounds targeting ferroptosis.
Main Results:
- NPs and antitumor compounds combat MM by modulating ferroptosis through various mechanisms.
- Key mechanisms include reprogramming lipid metabolism, regulating iron homeostasis via ferritinophagy, potentiating oxidative stress via ROS, activating autophagy, and regulating gene/protein expression.
- These agents demonstrate multi-dimensional ferroptosis modulation against MM.
Conclusions:
- NPs and antitumor compounds hold therapeutic potential for MM via ferroptosis modulation.
- Clinical translation is hindered by a lack of systems pharmacology analysis and overreliance on in vitro models.
- Future directions include developing biomarkers and ferroptosis inducers for novel anticancer therapies.
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