Modulation of Ferroptosis by the Irx3-Etfa Pathway Protects Against Cardiac Hypertrophy

Pathological cardiac hypertrophy is a major contributor to heart failure and is often accompanied by ferroptosis and mitochondrial dysfunction. However, the upstream transcriptional mechanisms governing these processes remain poorly defined. We performed integrative bioinformatics analysis using transverse aortic constriction (TAC)-induced hypertrophic heart datasets to identify mitochondria-related differentially expressed genes (MitoDEGs), followed by transcription factor prediction and experimental validation in both in vivo and in vitro models. Adeno-associated virus-mediated overexpression and knockdown strategies were used to assess the regulatory effects of Irx3 and its downstream target Etfa. We identified Etfa as a hub MitoDEG directly regulated by the transcription factor Irx3, which was significantly upregulated in hypertrophic hearts. Mechanistically, Irx3 directly bound to the Etfa promoter and restored Etfa expression in hypertrophic cardiomyocytes. Through integrated transcriptomic analysis, an angiotensin II-induced cardiomyocyte hypertrophy model, and a TAC mouse model, we demonstrate that the Irx3-Etfa axis attenuates hypertrophic remodeling by suppressing ferroptosis. In vitro, overexpression of Irx3 or Etfa alleviates cardiomyocyte hypertrophy and ferroptotic injury, whereas Etfa knockdown abolishes the protective effects of Irx3. In vivo, Irx3 overexpression improves cardiac function, reduces ferroptosis, and limits structural remodeling in TAC mice. These findings reveal a novel transcriptional pathway connecting mitochondrial metabolism to ferroptosis regulation and suggest the Irx3-Etfa axis as a promising therapeutic target for pathological cardiac hypertrophy.