Western diet induces iron-dependent enteric neurodegeneration via ferroptosis.

Overview

1. Division of Digestive Diseases, Emory University School of Medicine, Atlanta, Georgia, USA
2. Atlanta VA Health Care System, Atlanta, Georgia, USA
3. Department of Anesthesiology, and
4. Department of Surgery, The Ohio State University, Columbus, Ohio, USA
5. Department of Neuroscience and Anatomy, Virginia Commonwealth University, Richmond, Virginia, USA
6. Department of Orthopaedics, and
7. Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University School of Medicine, Atlanta, Georgia, USA

Abstract

The Western diets (WD), high in saturated fats such as palmitic acid (PA), promotes enteric neurodegeneration and motility disorders. Using murine models, in vitro systems, and human myenteric ganglia, we investigated whether a WD and PA drive iron-dependent ferroptotic injury in the enteric nervous system (ENS). Mice were fed a control diet (CD) or a WD for 12 weeks, with or without systemic AAV9-MaCPNS2 delivery of Nfe2l2 to enteric neurons. Colonic motility was assessed by a bead expulsion assay. We assessed ferroptosis using convergent readouts including iron dysregulation (transferrin receptor 1 [TfR1], ferritin heavy chain 1 [FTH1], labile and mitochondrial iron [Fe2+]), lipid peroxidation (C11-BODIPY and 4-hydroxynonenal [4-HNE]), glutathione peroxidase 4 (GPX4) suppression, and pharmacologic inhibition by ferrostatin 1 (Fer-1) in primary enteric neurons, murine myenteric plexuses, and human networks of myenteric ganglia (nhMPG). WD-fed mice exhibited delayed colonic transit, increased TfR1 and FTH1, and vulnerability of nNOS neurons; these changes were reversed by nuclear factor erythroid 2–related factor 2; (Nfe2l2, also known as Nrf2) overexpression. RNA-seq of PA-treated immortalized murine fetal enteric neurons (IM-FENs) revealed disrupted neurotransmitter signaling, reduced mitochondrial and antioxidant programs, and increased iron import and lipid peroxidation signatures. PA increased labile Fe2+, mitochondrial ROS, membrane depolarization, Ca2+ dysregulation, 4-HNE, and mitoferrin 2 (Mfrn2), whereas Fer-1 preserved mitochondrial integrity, viability, and ENS function. In human nhMPG, PA induced enteric neuronal iron loading and ferroptosis, supporting the translational relevance to diet-associated enteric neuropathy.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• geo:GSE298679 — at NCBI GEO; found in “Data availability.”

Data availability

The RNA-seq dataset generated and analyzed in this study has been deposited in the NCBI Gene Expression Omnibus (GEO) database (GEO GSE298679 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE298679)). Values for all data points in graphs are reported in the Supporting Data Values file. All other data supporting the findings of this study are available within the article and its supplemental material or from the corresponding author upon reasonable request.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 29 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 15 authors, 4 keywords, 12 MeSH terms, 3 funders, 61 references.

Cite

This paper

Balasubramaniam, A., Pavlov, D., Du, Y., Reeves, J., Harzman, A., Liu, Y., Cingolani, F., Yuan, X., Patel, J. M., Mwangi, S. M., He, P., Hart, C. M., Hu, W., Christofi, F. L., & Srinivasan, S. (2026). Western diet induces iron-dependent enteric neurodegeneration via ferroptosis. The Journal of clinical investigation, 136(11), e196113. https://doi.org/10.1172/jci196113

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