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Transcriptomic effects of dietary PUFAs in mouse dendritic cells

ABSTRACT: The immune system is shaped by the balance of n-3 and n-6 polyunsaturated fatty acids (PUFAs), but how these dietary lipids influence dendritic cells (DCs)— key inducers of adaptive immunity—remains largely unexplored. Importantly, whether an excess of n-6 PUFAs, a hallmark of modern diets, could undermine DC function and immune surveillance remains largely unexplored. Here, we uncover a striking link between dietary lipids and DC dysfunction. We found that an n-6 PUFA-rich diet promotes ferroptosis in DCs via suppression of the Nrf2 antioxidant pathway, impairing their antigen presenting capacity. Accordingly, interventions with dietary n-3 PUFAs or ferroptosis inhibitors reversed these effects, restoring DC function and enhancing responses to DC-based chemo-immunotherapy in a preclinical model of metastatic ovarian cancer. These findings suggest that dietary lipids are not just passive components of metabolism but active regulators of DC function and fate. These findings are critical for the creating novel nutritional interventions that improve vaccination and immunotherapy outcomes.

ORGANISM(S): Mus musculus

PROVIDER: GSE292400 | GEO | 2026/02/26

REPOSITORIES: GEO

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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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Transcriptomic effects of dietary PUFAs in mouse dendritic cells

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