Cellular preconditioning and mesenchymal stem cell ferroptosis

In this editorial, we comment on the article published in the recent issue of the World Journal of Stem Cells. They focus on stem cell preconditioning to prevent ferroptosis by modulating the cystathionine γ-lyase/hydrogen sulfide (H₂S) pathway as a novel approach to treat vascular disorders, particularly pulmonary hypertension. Preconditioned stem cells are gaining popularity in regenerative medicine due to their unique ability to survive by resisting the harsh, unfavorable microenvironment of the injured tissue. They also secrete various paracrine factors against apoptosis, necrosis, and ferroptosis to enhance cell survival. Ferroptosis, a regulated form of cell death characterized by iron accumulation and oxidative stress, has been implicated in various pathologies encompassing degenerative disorders to cancer. The lipid peroxidation cascade initiates and sustains ferroptosis, generating many reactive oxygen species that attack and damage multiple cellular structures. Understanding these intertwined mechanisms provides significant insights into developing therapeutic modalities for ferroptosis-related diseases. This editorial primarily discusses stem cell preconditioning in modulating ferroptosis, focusing on the cystathionase gamma/H₂S ferroptosis pathway. Ferroptosis presents a significant challenge in mesenchymal stem cell (MSC)-based therapies; hence, the emerging role of H₂S/cystathionase gamma/H₂S signaling in abrogating ferroptosis provides a novel option for therapeutic intervention. Further research into understanding the precise mechanisms of H₂S-mediated cytoprotection against ferroptosis is warranted to enhance the therapeutic potential of MSCs in clinical settings, particularly vascular disorders.