Iron-dependent phospholipid peroxidation by free radical species contributes to membrane damage, which can induce a non-apoptotic cell death pathway known as ferroptosis. Deregulation of this pathway has been implicated in multiple diseases, including cancer, driving interest in elucidating the underlying molecular mechanism for therapeutic exploitation.

In the first study, Li et al. performed a whole-genome genetic screen in the presence of a ferroptosis-inducing drug to identify regulators of ferroptosis. Multiple enzymes involved in distal cholesterol biosynthesis were identified that can either suppress or promote ferroptosis. Given this dual role in regulating this cell death pathway, the authors speculated that the metabolite 7-DHC might be involved; 7-DHC is synthesized by sterol C5-desaturase (SC5D), a suppressor of ferroptosis, and serves as a substrate for the pro-ferroptotic enzyme 7-DHC reductase (DHCR7). Indeed, 7-DHC levels positively correlated with resistance to ferroptosis, and pharmacological inhibition of DHCR7 or direct supplementation with 7-DHC protected cells from ferroptosis.