7-Dehydrocholesterol is an endogenous suppressor of ferroptosis

Abstract

Ferroptosis is a form of cell death that has received considerable attention not only as a means to eradicate defined tumour entities but also because it provides unforeseen insights into the metabolic adaptation exploited by tumours to counteract phospholipid oxidation. Here, we identify a pro-ferroptotic activity of 7-dehydrocholesterol reductase (DHCR7) and an unexpected pro-survival function of its substrate, 7-dehydrocholesterol (7-DHC). Although previous studies suggested that high levels of 7-DHC are cytotoxic to developing neurons and favour lipid peroxidation, we now demonstrate that 7-DHC accumulation confers a robust pro-survival function in cancer cells. 7-DHC, due to its far superior reactivity towards peroxyl radicals, is shown here to effectively shield (phospho)lipids from autoxidation and subsequent fragmentation. We further demonstrate in a subset of ferroptosis-sensitive Burkitt lymphomas - where DHCR7 mutations have been reported - that the accumulation of 7-DHC is sufficient to suppress the basal sensitivity of cells toward ferroptosis, thereby translating into an unexpected growth advantage. Conclusively, our findings provide compelling evidence of a yet-unrecognised anti-ferroptotic activity of 7-DHC as a cell-intrinsic mechanism that could be exploited by cancer cells to escape ferroptosis.

Live-cell imaging reveals impaired detoxification of lipid-derived electrophiles is a hallmark of ferroptosis

“…At the time of submission of this work we became aware of a recent study by Friedmann Angeli et al showing that the specic formation of short chain truncated PLs is responsible for membrane permeabilization in ferroptosis. 22 LDE detoxication failure and the ensuing alkylation of critical ferroptosis regulatory proteins together with membrane permeabilization by truncated PLs provides a putative molecular cell death mechanism of ferroptosis (Scheme 1). Whether specic LDEs are responsible for either MRP inhibition or the alkylation of critical ferroptosis regulatory proteins remains to be discovered.…”

“…17,18 The breakdown of LOOHs to diffusible lipid-derived electrophiles (LDEs) and truncated phospholipids (PLs) represents a promising link between LOOH accumulation, membrane permeabilization and cell death in ferroptosis. [13][14][15][16][20][21][22] LDE increase following LOOH accumulation has been characterized during ferroptosis [23][24][25][26] while the upregulation of specic aldoketoreductases, the class of enzymes responsible for reduction of LDEs to their less reactive alcohols, has been observed and is associated with partial ferroptosis resistance. 27,28 LDEs are highly reactive species capable of protein and DNA alkylation as well as cellular signalling pathway activation, while truncated PLs are known to impair lipid membrane integrity and are probable candidates to mediate membrane permeabilization in ferroptosis.…”

Dose–Response Effects of 7-Dehydrocholesterol Reductase Inhibitors on Sterol Profiles and Vesicular Stomatitis Virus Replication

“…Recent important studies have suggested that the exceptional reactivity of 7-DHC plays a role in mediating ferroptosis, a form of programmed cell death. − 7-DHC and 7-DHD, being orders of magnitude more vulnerable to free radical oxidation than polyunsaturated fatty (PUFA) ester phospholipids, apparently serve sacrificial roles by diverting membrane oxidative chains from PUFAs to sterols. The cellular protective response to a ferroptotic oxidative stress is upregulation of genes coding enzymes before 7-DHC and 7-DHD on the biosynthesis pathway and downregulation of DHCR 7 . The result of such a response is a change in the cellular sterol profile, with a presumed decrease in sterols biosynthesized after DHCR7 in the pathway (desmosterol and cholesterol) and an increase in levels of sterols before DHCR7 (7-DHC and 7-DHD).…”

“…The cellular protective response to a ferroptotic oxidative stress is upregulation of genes coding enzymes before 7-DHC and 7-DHD on the biosynthesis pathway and downregulation of DHCR7. 16 The result of such a response is a change in the cellular sterol profile, with a presumed decrease in sterols biosynthesized after DHCR7 in the pathway (desmosterol and cholesterol) and an increase in levels of sterols before DHCR7 (7-DHC and 7-DHD).…”

Ferroptosis: A Promising Therapeutic Target for Neonatal Hypoxic-Ischemic Brain Injury

“…Within the last decade, the association between lipid peroxidation and cell death has become more relevant, with the description of a regulated necrotic cell death modality characterized by increased phospholipid peroxidation [4,[25][26][27]. The use of different small molecules and genetic animal models then led to the understanding that this method of cell death was iron-dependent [28], leading to its name: ferroptosis.…”