Antioxidants rescue murine mesangial cells from docosahexaenoic acid-induced ferroptosis

ABSTRACT: Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have long been associated with health benefits, including anti-inflammatory effects, but only few studies investigated the effects on kidney health. Preclinical data from animal models suggest that n-3 PUFAs may reduce glomerulosclerosis, albuminuria and inflammation, but the molecular mechanisms remain elusive. In this study, we investigated the potential protective effects of docosahexaenoic acid (DHA) on murine mesangial cells. However, stimulation with DHA alone led to a substantial reduction in viability and ultimately to cell death. Proteomic profiling identified a significant upregulation of ferroptosis, including the increased abundance of the key pro-ferroptotic protein HMOX1 and simultaneous downregulation of the pro-ferroptotic proteincs TFRC and ACSL4. These finding indicate an imbalance of cellular pro- and anti-ferroptotic self-protection mechanisms in DHA-treated cells. On the contrary, treatment with Ferrostatin-1, a known ferroptosis inhibitor, preserved cellular metabolic activity and prevented cell death, strongly supporting a role of ferroptosis in DHA-induced cytotoxicity. Furthermore, co-treatment with DHA and an antioxidant cocktail also significantly attenuated DHA-induced cell death and induced upregulation of several key anti-ferroptotic proteins, including TXNRD1 and GPX4, while further downregulating pro-ferroptotic proteins such as TFRC and ASCL4. Our findings provide novel insights into the ferroptotic response induced by DHA in mesangial cells and highlight the potential of antioxidant co-treatment to counteract this effect. This underscores the importance of a balance between pro- and anti-ferroptotic mechanisms in therapeutic strategies using n-3 PUFAs to promote kidney health.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Kidney

SUBMITTER: Proteomics Facility  

LAB HEAD: Dr. Eva Nüsken

PROVIDER: PXD065885 | Pride | 2026-01-12

REPOSITORIES: Pride