Cardiomyocyte-fibroblast interaction regulates ferroptosis and fibrosis after myocardial injury

Abstract

Neonatal mouse hearts have transient renewal capacity which is lost in juvenile and adult hearts. After myocardial infarction (MI) in neonatal hearts, an initial loss of cardiomyocytes occurs but it is unclear through which type of regulated cell death (RCD). In the current studies, we induced MI in neonatal and juvenile mouse hearts, and show that ischemic cardiomyocytes primarily undergo ferroptosis, a non-apoptotic and iron-dependent form of RCD. We demonstrate that cardiac fibroblasts (CFs) protect cardiomyocytes from ferroptosis through paracrine factors and direct cell-cell interaction. CFs show strong resistance to ferroptosis due to high ferritin expression. Meanwhile, the fibrogenic role of CFs, typically considered detrimental to heart function, is negatively regulated by paired-like homeodomain 2 (Pitx2) signaling from cardiomyocytes. In addition, Pitx2 prevents ferroptosis in cardiomyocytes by regulating ferroptotic genes. Understanding the regulatory mechanisms of cardiomyocyte survival and death can identify potentially translatable therapeutic strategies for MI.

PITX2 functions as a transcription factor for GPX4 and protects pancreatic cancer cells from ferroptosis

“…Our previous study has found that the co-culture of pancreatic stellate cells and pancreatic cancer cells after PITX2 knockdown inhibited tumor cell growth. Recently, studies have shown a close association between PITX2 and ferroptosis, with PITX2 regulating ferroptosis-related proteins such as GPX4 and LPCAT3 11 . Based on the above ndings, there is an urgent need to elucidate whether PITX2 affects pancreatic cancer by regulating ferroptosis and to understand the signi cance of this regulation on the development of pancreatic cancer.…”