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Riboflavin metabolism shapes FSP1-driven ferroptosis resistance

ABSTRACT: Membrane protection against oxidative damage is tightly buffered by glutathione peroxidase 4 (GPX4), and endogenous radical-trapping antioxidants such as ubiquinone, vitamin E and K. Deficiencies in these protective systems have been linked to the accumulation of phospholipid peroxidation and ferroptosis induction. Recently, ferroptosis suppressor protein 1 (FSP1) was identified as a key player in this process, preventing phospholipid peroxidation and ferroptosis by regenerating radical-trapping antioxidants. Yet, regulators of FSP1 have remained largely unknown, and their identification is critical for understanding the mechanism regulating phospholipid peroxidation and ferroptosis. In this study, we conducted a CRISPR-Cas9 screen to uncover factors influencing FSP1 function, identifying vitamin B2 (riboflavin) as a yet-unaccounted modulator of ferroptosis sensitivity. We demonstrate that vitamin B2, unlike other vitamins that directly act as radical-trapping antioxidants, facilitates the recycling of lipid-soluble antioxidants by directly supporting FSP1 stability and activity, thereby mitigating phospholipid peroxidation. Thus, we uncovered a direct role of vitamin B2 in maintaining membrane integrity and supporting membrane tolerance to lipid peroxidation and ferroptosis resistance. Our findings provide a rational strategy to modulate the FSP1-antioxidant recycling pathway, with potential implications for treating cancer and other diseases where ferroptosis plays a pivotal role.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Melanocyte, Skin

DISEASE(S): Melanoma

SUBMITTER: Dominic Helm

LAB HEAD: José Pedro Friedmann Angeli

PROVIDER: PXD061038 | Pride | 2025-10-31

REPOSITORIES: pride

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			Action	DRS
	2024-02-09_UP000005640_9606_one_prot_seq_per_gene.fasta	Fasta
	contaminants.fasta	Fasta
	oecf3-HA0926-01.raw	Raw
	oecf3-HA0926-02.raw	Raw
	oecf3-HA0926-03.raw	Raw

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Project description:Ferroptosis is a form of regulated cell death driven by lipid peroxidation of polyunsaturated fatty acids (PUFAs). Endogenous PUFAs are nonconjugated PUFAs and their peroxidation proceeds via the hydrogen-atom transfer (HAT) mechanism. We previously reported that lipids with conjugated double bonds undergo lipid peroxidation mostly via a different mechanism, peroxyl radical addition (PRA), and were much more readily oxidizable than nonconjugated ones. In this study, we aim to elucidate the effects of various unsaturated lipids in sensitizing ferroptosis. We found that while some peroxidation-reactive lipids, such as 7-dehydrocholesterol, vitamins D3 and A, and coenzyme Q10, suppress ferroptosis, both nonconjugated and conjugated PUFAs enhanced cell death induced by RSL3, a ferroptosis inducer. Importantly, we showed that conjugated linolenic acid (CLA 18:3) could act as a ferroptosis inducer by itself and conjugated linoleic acid (CLA 18:2) was more potent in sensitizing cells to RSL3-induced cell death than any nonconjugated PUFAs. We next sought to elucidate the mechanism underlying the different ferroptosis-inducing potency of conjugated and nonconjugated PUFAs. Lipidomics revealed that conjugated and nonconjugated PUFAs are incorporated into distinct cellular lipid species. Furthermore, the different peroxidation mechanisms predict the formation of higher levels of reactive electrophilic aldehydes from conjugated PUFAs than nonconjugated PUFAs, which was confirmed by aldehyde-trapping and mass spectrometry. RNA sequencing revealed that protein processing in the endoplasmic reticulum and proteasome are among the most significantly upregulated pathways in cells treated with CLA 18:3, suggesting increased ER stress and activation of unfolded protein response. Significantly, using click chemistry, we observed increased protein adduction by oxidized lipids in cells treated with an alkynylated CLA 18:2 probe. These results suggest that protein damage by lipid electrophiles is a key step in ferroptosis.

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Riboflavin metabolism shapes FSP1-driven ferroptosis resistance

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