Can ferroptosis spread like a wave? New review explores how cell death may propagate across tissues

A new review published in EXO – Beyond the Cell (EXO) examines growing evidence that ferroptosis, an iron-dependent form of regulated cell death, may spread between cells and travel through tissues in wave-like patterns.

Ferroptosis has primarily been studied as a cell-autonomous process, in which individual cells die following the accumulation of iron-driven lipid peroxidation. However, observations from diverse experimental systems have raised a different possibility: ferroptotic death may propagate from one cell to another, leading to coordinated elimination of large cell populations.

In the review, "Ferroptosis spreading through propagative signals," researchers Saloni K. Hombalkar, Jyotirekha Das, and Michael Overholtzer synthesize recent findings from studies of kidney injury, cancer models, and developmental systems to evaluate how ferroptosis may spread through tissues.

The authors argue that propagation may help explain why ferroptosis often appears as synchronized, large-scale cell death rather than isolated death of individual cells.

The review highlights evidence that ferroptotic death can occur in the form of "death waves," where neighboring cells undergo ferroptosis sequentially through a domino-like process. Such behavior has been observed in cultured cells, kidney tubules, and, more recently, during normal muscle patterning in the developing avian limb.

The authors discuss two forms of propagation. Localized propagation occurs between directly contacting cells and depends on cell–cell adhesions. Long-range propagation, by contrast, can occur across distances exceeding 100 micrometers and does not require direct cellular contact, suggesting the existence of transferable death-inducing signals.

A central focus of the review is the identity of these signals. Current evidence points to lipid peroxides — the oxidized membrane lipids that drive ferroptotic damage — as likely candidates. Multiple studies have shown that ferroptosis propagation can be blocked by lipid radical-trapping antioxidants, even after death waves have begun.

The review also highlights iron as a potential propagative factor. Iron chelators can suppress ferroptosis spreading, while elevated iron levels have been observed at the advancing fronts of propagating death waves. Together, these observations suggest that both lipid peroxides and iron may contribute to the transmission of ferroptotic signals between cells.

Another emerging theme is the possible involvement of lysosomes and extracellular vesicles. The authors propose a working model in which damaged cells release lipid peroxide-containing membrane structures or lysosome-derived vesicles that can be taken up by neighboring cells, potentially triggering further ferroptosis. Iron-loaded ferritin transported through extracellular vesicles may also contribute to this process.

While many mechanistic questions remain unresolved, the review argues that understanding ferroptosis propagation could reshape how researchers think about tissue degeneration, developmental remodeling, and therapeutic responses in disease.

Rather than viewing ferroptosis solely as an event occurring within individual cells, the authors suggest that it may be necessary to consider ferroptosis at the level of entire cell populations and tissues.