Ferroptosis of hematopoietic stem cells in the pathogenesis of age-associated solid tumors

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Abstract

Ferroptosis (FP), an iron-dependent form of regulated cell death driven by the accumulation of lipid peroxides and the impairment of antioxidant defenses, has recently emerged as a key pathophysiological mechanism in oncogenesis and aging. Concurrently, growing evidence indicates that age-associated alterations in hematopoietic stem cells, including the development of clonal hematopoiesis of indeterminate potential (CHIP), exert systemic effects on the formation of a pro-oncogenic microenvironment outside the bone marrow. This review evaluates the hypothesis that FP acts as a key selective mechanism (in aging hematopoiesis, driving the depletion of the normal hematopoietic stem cells pool while promoting the corresponding expansion of mutant clones with relative resistance to oxidative and iron-dependent stress.

We examine in detail the molecular mechanisms of FP (the SLC7A11–GSH–GPX4 axis, iron metabolism, lipid peroxidation, and the role of mitochondria), involutive shifts in the metabolic and redox status of hematopoietic stem cells, and their links to myeloid-biased differentiation and the inflammatory phenotype of CHIP clones. Special attention is dedicated to how macrophages and monocytes derived from FP-resistant clones sustain chronic, low-grade inflammation (inflammaging), impair antitumor immune surveillance, and shape a tissue stroma conducive to the initiation and progression of age-associated solid tumors. Based on clinical and experimental data, we discuss the pathogenetic link between CHIP and an elevated risk of lung, liver, pancreatic, and colorectal cancers. Furthermore, the role of disrupted iron homeostasis and lipid metabolism directly within the tumor microenvironment is analyzed. We propose the concept of FP as a “selection filter” in aging hematopoiesis that dictates the clonal selection of cells with pro-oncogenic properties. In conclusion, we evaluate the prospects of targeted modulation of FP and pro-inflammatory signaling pathways in distinct cell types as a novel strategy for the prevention and treatment of age-associated solid tumors.

 

About the authors

Valery E. Shevchenko

N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia

Author for correspondence.
Email: vshev2015@yandex.ru
ORCID iD: 0000-0002-0401-9900
Russian Federation, 24 Kashirskoe Shosse, Moscow 11552

T. I. Kushnir

N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia

Email: vshev2015@yandex.ru
ORCID iD: 0000-0001-9626-6847
Russian Federation, 24 Kashirskoe Shosse, Moscow 115522

M. V. Gudkova

N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia

Email: vshev2015@yandex.ru
ORCID iD: 0000-0003-2694-5232
Russian Federation, 24 Kashirskoe Shosse, Moscow 115522

N. E. Arnotskaya

N. N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia

Email: vshev2015@yandex.ru
ORCID iD: 0000-0002-0154-8604
Russian Federation, 24 Kashirskoe Shosse, Moscow 115522

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