Short-chain fatty acids regulate erastin-induced cardiomyocyte ferroptosis and ferroptosis-related genes Original paper

What was studied?

This original research study tested whether gut microbiota–derived short-chain fatty acids (SCFAs) can modulate cardiomyocyte ferroptosis under ischemic stress and whether the stress-response transcription factor ATF3 sits in that regulatory path. The authors combined human myocardial infarction single-nucleus transcriptomics to map ferroptosis-related gene activity across cardiac regions with in vitro cardiomyocyte injury models. They then exposed cardiomyocytes to sodium acetate, propionate, butyrate, or a physiologically patterned SCFA mixture and measured viability, lipid peroxidation, ferrous iron, and expression of ATF3 and ferroptosis-linked genes and proteins.

Who was studied?

The human component used a published spatial multi-omic atlas of myocardial infarction that included control donor hearts and multiple infarction-related regions (including ischemic, border, and fibrotic zones), enabling region- and cell-type–specific ferroptosis gene scoring, particularly in cardiomyocytes. The experimental component studied commercially available cardiomyocyte lines rather than newly enrolled patients or animals, using human AC16 cells and murine HL1 cells. The team induced ferroptosis with erastin and modeled ischemia–reperfusion–like injury with hypoxia followed by reoxygenation, then evaluated how SCFAs shifted ferroptosis markers and ATF3-related regulatory signals in these cells.

What were the most important findings?

Single-nucleus data showed that ferroptosis pathway genes rise in infarction-stimulated regions and appear prominently in cardiomyocytes, supporting ferroptosis as a relevant injury program in post-MI remodeling. In cell models, SCFAs reduced erastin-driven lipid peroxidation and reversed erastin-associated increases in intracellular Fe²⁺, consistent with a ferroptosis-attenuating effect in that setting. In the hypoxia–reoxygenation model, SCFAs improved cardiomyocyte viability and tended to lower lipid peroxide signal, but they could also strengthen Fe²⁺ signal, indicating that iron handling may respond differently depending on the injury context. Mechanistically, SCFAs increased ATF3 mRNA yet decreased ATF3 protein in most conditions, and the authors highlighted putative ATF3 transcriptional regulators that shifted with SCFA exposure, pointing to post-transcriptional control as a key feature. For microbiome-signature use, the paper does not report taxa-level changes, so MMA by organism is not available; instead, the actionable microbiome-linked exposure is the SCFA metabolite class itself (acetate, propionate, butyrate) and its association with reduced lipid peroxidation in cardiomyocytes under ferroptosis pressure.

What are the greatest implications of this study/ review?

This study strengthens the clinical concept that microbial metabolites can reach the heart and alter cell-death vulnerability, specifically by shifting ferroptosis biology during ischemic stress. It also suggests a practical translational angle: targeting ferroptosis in myocardial ischemia/reperfusion may benefit from strategies that mimic or amplify protective SCFA signaling, while recognizing that dose and context matter because iron readouts did not move uniformly across models. The ATF3 discordance between mRNA and protein emphasizes that clinicians and translational teams should not assume transcriptional changes reflect protein-level control, and it highlights the need for pathway-anchored biomarkers (lipid peroxidation and iron status) when evaluating SCFA-based or microbiome-targeted interventions in cardiac injury.