Emerging links between TLR4 signaling and ferroptosis in heart failure

Iron is an essential nutrient for living organisms, and the maintenance of its homeostatic balance within the body is a critical factor in ensuring normal physiological functions. Cardiomyocyte ferroptosis has emerged as a potential contributor to heart failure progression, involving complex regulatory mechanisms that remain incompletely understood. While the TLR4 signaling pathway was traditionally regarded as a therapeutic target for chronic inflammatory conditions, emerging evidence indicates that its activation may contribute to ferroptosis in cardiomyocytes. The proposed mechanisms through which TLR4 signaling may regulate cardiomyocyte ferroptosis are systematically summarized, and several therapeutic strategies targeting TLR4-associated ferroptosis are evaluated. Furthermore, promising avenues for future investigation are discussed, with particular emphasis on the need for direct mechanistic validation in cardiomyocytes and in vivo models, which may ultimately inform novel therapeutic strategies for heart failure.