Serum apolipoprotein H determines ferroptosis resistance by modulating cellular lipid composition.

Ferroptosis is a regulated cell death process dependent on iron, triggered by the accumulation of lipid peroxidation. The environmental context significantly impacts cellular sensitivities to ferroptosis. Serum, constituting the extracellular fluid composition in vivo, provides crucial environmental biomolecules. In this study, we investigated the influence of sera on ferroptosis induction, pinpointing the serum protein apolipoprotein H (APOH) as a pivotal inhibitor of ferroptosis. Moreover, we elucidated that APOH suppresses ferroptosis by activating the phosphoinositide 3-kinase (PI3K)-AKT-sterol regulatory element-binding proteins (SREBPs) pathway, thereby elevating stearoyl-CoA desaturase (SCD) levels and augmenting cellular monounsaturated fatty acid-containing phospholipids (MUFA-PLs). Furthermore, ApoHinfer, the peptide derivative of the active region of APOH, mimics its ferroptosis inhibitory activity. Our findings underscore the critical role of serum protein APOH in the inhibition of ferroptosis and indicates potential therapeutic applications in treating cancer and diseases associated with ferroptosis.