bmp10 maintains cardiac function by regulating iron homeostasis.

Abstract

Heart disease remains the leading cause of death worldwide. Iron imbalance, whether deficiency or overload, contributes to heart failure. However, the molecular mechanisms governing iron homeostasis in the heart are poorly understood. Here, we demonstrate that mutation of bmp10, a heart-born morphogen crucial for embryonic heart development, results in severe anemia and cardiac hypertrophy in zebrafish. Initially, bmp10 deficiency causes cardiac iron deficiency, which later progresses to iron overload due to the dysregulated hepcidin/ferroportin axis in cardiac cells, leading to ferroptosis and heart failure. Early iron supplementation in bmp10^-/- mutants rescues erythropoiesis, while iron chelation in juvenile fishes significantly alleviates cardiac hypertrophy. We further demonstrate that the interplay between HIF1α-driven hypoxic signaling and the IL6/p-STAT3 inflammatory pathways is critical for regulating cardiac iron metabolism. Our findings reveal BMP10 as a key regulator of iron homeostasis in the vertebrate heart and highlight the potential of targeting the BMP10-hepcidin-iron axis as a therapeutic strategy for iron-related cardiomyopathy.