Harnessing ferroptosis for precision oncology: challenges and prospects

Abstract

The discovery of diverse molecular mechanisms of regulated cell death has opened new avenues for cancer therapy. Ferroptosis, a unique form of cell death driven by iron-catalyzed peroxidation of membrane phospholipids, holds particular promise for targeting resistant cancer types. This review critically examines current literature on ferroptosis, focusing on its defining features and therapeutic potential. We discuss how molecular profiling of tumors and liquid biopsies can generate extensive multi-omics datasets, which can be leveraged through machine learning-based analytical approaches for patient stratification. Addressing these challenges is essential for advancing the clinical integration of ferroptosis-driven treatments in cancer care.

Keywords: Cancer; Cell-free DNA; DNA methylation; Ferroptosis; Liquid biopsy; Machine learning; Nanopore sequencing; Precision oncology.

Fig. 1

Overview of publication trends from 2012 to 2022 related to specific established cell death mechanisms. a Total number of publications. b Publications focused exclusively on cancer research. In both cases, the data on ferroptosis were fitted to an exponential growth curve (curve in red: y = y₀e^kt, where t is the time, y is the number of publication at time t, y₀ is the initial quantity in the first year considered, e is the base of the natural logarithm, and k is the growth rate constant). R² is the coefficient of determination and T_d, or doubling time, is a metric that quantifies the time (expressed here in years) it takes for the number of published articles on ferroptosis to double. A search for publications on these cell death subroutines was conducted in October 2024 using the Science Citation Index Expanded (SCI-EXPANDED) database of the Web of Science Core Collection (WoSCC). The retrieval formulas, adapted and expanded from Wu et al. (2023) [37], are provided in SI part 1—Advanced search formulas

Fig. 2

A ferroptosis-based VOSviewer-generated map. Visualization is based on bibliographic data from all publications related to ferroptosis, retrieved from the Web of Science using the Science Citation Index Expanded (SCI-EXPANDED) database [38]. The map presents a co-occurrence analysis using fractional counting as the counting method, based on author keywords. To improve the visibility of co-occurrence patterns, some obvious ferroptosis-related keywords like “ferroptosis,” “lipid peroxidation,” “cell death,” and “GPX4” were excluded from the map. A complete table containing all keywords is available in SI part 2—Table S3

Fig. 3

Snapshot of ferroptosis execution and its major defense mechanisms. Ferroptosis is executed by excessive peroxidation of PUFA-containing PLs within cellular membranes. This free radical chain reaction is catalyzed by O₂ and Fe²⁺. Two major defense mechanisms suppress the process of PL peroxidation: (1) direct conversion of reactive PL-OOH to unreactive PL-OH by GPX4, and (2) dampening by an arsenal of lipophilic radical traps, such as vitamin E, A or KH₂, BH4, 7-DHC, and CoQ10H₂. BH4, tetrahydrobiopterin; CoQ10H₂, reduced form of coenzyme Q10; DHODH, dihydroorotate dehydrogenase; FSP1, ferroptosis suppressor protein 1; GCH1, GTP cyclohydrolase 1; GPX4, glutathione peroxidase 4; GSH, glutathione (reduced form); GSSG, glutathione disulfide (oxidized form)

Fig. 4

A precision oncology scenario outline. A prospective workflow for ferroptosis-based cancer therapy, emphasizing the integration of liquid biopsy technology, real-time nanopore sequencing for epigenetic profiling, and machine learning (ML)-driven patient and treatment stratification based on ferroptosis responsiveness. Created with BioRender

Fig. 5

Evolution of research in the field of ferroptosis. Early studies focused on elucidating the pathways that regulate ferroptosis, conceptualizing it as a distinct cell death mechanism. This foundational work continued to deepen the understanding of these pathways, consistently depicting ferroptosis as governed by well-defined molecular circuits. In parallel, machine learning-assisted investigations emerged, prioritizing the development of prognostic models for specific cancer types. Looking ahead, ferroptosis is envisioned as a key component in precision oncology, where its modulation will be leveraged for cancer therapies. Created with BioRender