Acid ceramidase modulates the lipid profile and exacerbates sensitivity to ferroptosis in WI-38 replicative senescent cells

Cellular senescence, a complex biological process characterized by irreversible cell cycle arrest and the senescence-associated secretory phenotype, has emerged as a critical target for therapeutic development for age-related diseases. Ferroptosis, an iron-dependent regulated cell death pathway driven by the accumulation of lipid peroxidation in cell membranes, has been implicated in age-related disorders. This study investigated the relationship between cellular senescence and ferroptosis. Using human fetal lung WI-38 fibroblasts induced to senesce via replicative exhaustion, we report a novel role for acid ceramidase (ACase), which breaks down ceramides into sphingosine and free fatty acids, in regulating the sensitivity of senescent cells to RSL3-induced lipid peroxidation and ferroptosis through the modulation of polyunsaturated fatty acid composition of membrane phospholipids. Furthermore, we demonstrate a cell non-autonomous paracrine sensitization of non-senescent cells to ferroptosis by senescent cells. Together, these findings unveil ACase as a novel regulator of the ferroptosis pathway and open promising therapeutic avenues for targeting senescence-linked disorders and advancing healthy aging strategies.