Ferroptosis serves as a physiological, cell-intrinsic mechanism that selectively governs lymphatic but not blood endothelial cell survival during development and injury-induced remodeling, driven by lymphatic-specific vulnerabilities including reduced cystine import and glutathione availability, SH3RF3-mediated GPX4 degradation, and enrichment of polyunsaturated fatty acid-containing membrane phospholipids, which can be therapeutically exploited to prevent pathological lymphangiogenesis while modulating immune responses.

Whether, when, and how lymphatic vessels undergo cell death remains poorly understood. Here we identify ferroptosis as a physiological, cell-intrinsic regulator of the lymphatic endothelial cell survival during development and following injury, in stark contrast to the resilient organotypic blood endothelial cells. The lymphatic susceptibility to ferroptosis stems from tampered cystine/ hydropersulfide metabolism, alongside reduced glutathione availability triggered by an SH3RF3 E3 ligase mediated GPX4 degradation, and enhanced integration of polyunsaturated fatty acid enriched membrane phospholipids. Inducing ferroptosis genetically or pharmacologically elevated lymphatic lipid peroxidation, halted embryonic lymphangiogenesis and prevented post-injury lymphatic overgrowth while simultaneously shaped immune responses. Conversely, ferroptosis inhibition through saturated fatty acid supplementation led to pathological lymphatic hyperplasia. Targeting lymphatic ferroptotic mechanisms holds promise against pathological lymphatic growth in response to injury.