Ferroptosis in Septic Cardiomyopathy Is Alleviated by Ondansetron: The Critical Role of the HTR3A-ATF3 Axis in Mitochondrial and Oxidative Homeostasis

Background: Emerging evidence has established Ferroptosis as a vital factor in the pathogenesis of cardiovascular diseases, especially in septic cardiomyopathy (SCM). Meanwhile, ondansetron (OND), a well-established 5-HT3 receptor antagonist, has gained increasing attention for its pleiotropic effects. However, its potential to modulate Ferroptosis in the cardiovascular field remains unexplored. This study aims to fill this gap by exploring the potential of OND as an innovative therapeutic intervention for SCM. Methods: This study utilized both in vitro and in vivo models of septic cardiomyopathy (SCM), which was induced by lipopolysaccharide (LPS) stimulation in neonatal rat cardiomyocytes (NRCMs) and C57BL/6 mice. Through RNA Sequencing, as well as molecular and functional assessments-including echocardiography and ferroptosis-related measurements-we revealed the anti-ferroptotic effect of ondansetron (OND). Mechanistically, ATF3 was identified as a pivotal regulator, with its overexpression via AAV9 in vivo and ADV in vitro confirming its role in OND-induced cardioprotection. Results: Ondansetron (OND) showed potent anti-ferroptotic effects in both cellular and murine models of septic cardiomyopathy (SCM). Treatment with OND not only improved cardiac performance but also reduced ferroptotic markers, mitigated lipid peroxidation and iron overload, and bolstered antioxidant defense. Notably, OND administration attenuated oxidative and endoplasmic reticulum (ER) stress while restoring mitochondrial integrity. Mechanistically, the anti-ferroptotic activity of OND was mediated through the HTR3A/ATF3 axis: ATF3 overexpression negated OND's protective effects, while HTR3A antagonism with VUF10166 recapitulated its benefits. Conversely, HTR3A agonism with PBG attenuated Ferroptosis resistance, further implicating this pathway as central to OND's mechanism. Conclusions: This study demonstrated a novel pharmacological role for ondansetron (OND) in attenuating Ferroptosis in septic cardiomyopathy (SCM) via the HTR3A/ATF3 signaling pathway. This finding delineates a novel therapeutic avenue and supports the repurposing of OND beyond its traditional antiemetic use to cardiovascular applications.