Safe lysosomal sequestration of ferrous iron is mediated via cholesterol shielding and drives senescence and ferroptosis resistance.

Lysosomal accumulation of ferrous iron (Fe2+) in senescent cells is crucial for inducing multiple senescence-associated phenotypes, and it is “safely” handled via cholesterol shielding.

• Why it matters: Iron buildup is linked to aging, but how lysosomal Fe2+ contributes to senescence and how cells avoid ferroptosis during this process remains unclear.
• What they did: The study shows that Fe2+ accumulation triggers lysosomal alkalinization and cholesterol accumulation to reinforce lysosomal membranes, while senescent cells partition polyunsaturated fatty acids into lipid droplets.
• The result: This cholesterol-enabled safe sequestration of Fe2+ is linked to robust resistance to ferroptosis, suggesting a lysosomal iron-centered pathway that could be targeted to control senescent cell behavior.

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