Elephant seal cells export iron and form lipid droplets to evade lipid peroxidation

Elephant seals are remarkable breath-hold divers, capable of remaining submerged for up to two hours during diving bouts. These dives entail repeated, extreme hypoxia/reoxygenation events that would induce severe lipid peroxidation and tissue dysfunction in most species. Here, we show that primary vascular endothelial cells derived from elephant seals resist oxidant-induced lipid peroxidation and cell death without relying on canonical lipid hydroperoxide scavenging. Comparative transcriptomic profiling across seal, human, and sheep cells identified transcriptional signatures of lipid metabolism and iron handling as uniquely regulated in seal cells following hydroperoxide exposure. Mechanistically, seal cells exhibit high constitutive levels of acyl-CoA synthetase long-chain family member 3 (ACSL3) alongside robust, seal-specific induction of the iron exporter ferroportin-1 (FPN1). Comparative lipidomic profiling revealed that seal cells are enriched in triglycerides and monounsaturated fatty acids. ACSL3 silencing and FPN1 inhibition each partially sensitized seal cells to lipid peroxidation, identifying lipid droplet biogenesis and active iron export as complementary but non-redundant axes of protection. Together, these data reveal a protective strategy based on lipid sequestration and iron export rather than hydroperoxide reduction, with implications for ischemia-reperfusion injury in non-diving mammals.