Dietary DGLA-induced ferroptosis is suppressed by vitamin B12-mediated phosphatidylcholine synthesis

Madison S. Mortensen

Paige E. Silvia

Carissa Perez Olsen

Jennifer L. Watts

1,*

*Correspondence to: Jennifer L. Watts, School of Molecular Biosciences, Washington State University, Pullman, WA 99164, USA. E-mail: jwatts@wsu.edu

Ferroptosis Oxid Stress. 2026;2:202626. 10.70401/fos.2026.0045

Received: June 03, 2026Accepted: September 14, 2026Published: September 18, 2026

This manuscript is made available in its unedited form to allow early access to the reported findings. Further editing will be completed before final publication. As such, the content may include errors, and standard legal disclaimers are applicable.

Abstract

Aims: Ferroptosis is a form of cell death associated with uncontrolled lipid peroxidation of polyunsaturated fatty acids (PUFAs) leading to membrane destruction. We previously showed that dietary dihomo-gamma-linolenic acid (DGLA) induces ferroptosis in Caenorhabditis elegans germ cells in a dose-dependent manner, and that the sensitivity of germ cells to dietary DGLA is altered by many genetic, dietary, and chemical interventions.

Methods: The severity of germ cell death was documented after dietary supplementation of DGLA, vitamin B12, methionine, and choline, to wild type and mutant C. elegans. The presence of germ cells, gametes, and embryos was visualized in young adult worms with DAPI.

Results: The addition of vitamin B12 rescued DGLA-induced cell death. For this protection, vitamin B12 functions as a cofactor for methionine synthase (METR-1). In addition, dietary methionine and choline rescued germ cell death in the context of low-B12 diets as well as in ferroptosis-sensitive metr-1 and sams-1 mutant strains. The pcyt-1 mutant worms, with reduced capacity for phosphatidylcholine (PC) synthesis, were not responsive to dietary vitamin B12-mediated rescue of DGLA-induced ferroptosis, providing evidence that PC synthesis and homeostasis play key roles in ferroptosis susceptibility. Oleic acid supplementation rescues DGLA-induced cell death in wild type, but not in pcyt-1 mutant strains.

Conclusions: These studies reveal the requirement for dietary vitamin B12 and sufficient PC synthesis in protection from dietary DGLA-induced ferroptosis, highlighting the importance of phospholipid metabolism in ferroptosis regulation.

Keywords

Dihomo-gamma-linolenic acid, DGLA, lipids, ferroptosis, vitamin B12, phosphatidylcholine, germ cells, C. elegans

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Mortensen MS, Silvia PE, Olsen CP, Watts JL. Dietary DGLA-induced ferroptosis is suppressed by vitamin B12-mediated phosphatidylcholine synthesis. Ferroptosis Oxid Stress. 2026;2:202626. https://doi.org/10.70401/fos.2026.0045