Narciclasine mitigates sepsis-induced cardiac dysfunction by enhancing BNIP3-mediated mitophagy and suppressing ferroptosis.

Sepsis-induced myocardial dysfunction (SIMD) remains a major contributor to sepsis-related mortality, driven by overwhelming inflammation, oxidative damage and impaired mitochondrial quality control. Narciclasine (Narc), a plant-derived diterpenoid, has demonstrated antioxidant and anti-inflammatory properties in various disease models. Here, we investigated whether Narc attenuates SIMD by inhibiting ferroptosis and promoting mitophagy. In both lipopolysaccharide (LPS) and cecal ligation and puncture (CLP) mouse models, prophylactic administration of Narc markedly improved 72-h survival and restored left ventricular ejection fraction (LVEF), fractional shortening (FS) and cardiac output in a dose-dependent manner. Biochemical assays revealed that SIMD hearts displayed iron overload, lipid peroxidation (elevated malondialdehyde) and glutathione depletion-hallmarks of ferroptosis-while Narc treatment replenished glutathione, reduced malondialdehyde levels, downregulated transferrin receptor (TFRC) and upregulated GPX4 and HO-1 expression. In neonatal rat cardiomyocytes challenged with LPS or the ferroptosis inducer erastin, Narc dose-dependently preserved cell viability, inhibited lipid peroxidation (BODIPY-C11 staining) and maintained intracellular glutathione. Concurrently, Narc ameliorated mitochondrial dysfunction: Seahorse analysis showed enhanced basal and maximal respiration, JC-1 staining demonstrated stabilized membrane potential, and immunofluorescence confirmed increased PINK1/PARK2 recruitment and LC3-ATP5B colocalization, indicating BNIP3-dependent mitophagy. Network pharmacology and molecular docking identified BNIP3 as a central target; siRNA-mediated BNIP3 knockdown abolished Narc's anti-ferroptotic and pro-mitophagic effects in vitro, and AAV9-driven BNIP3 silencing negated its survival and functional benefits in vivo. Together, these data establish that Narc mitigates SIMD by suppressing ferroptosis and preserving mitochondrial integrity through BNIP3-mediated mitophagy. This dual mechanism highlights Narc as a promising candidate for therapeutic intervention in sepsis-related cardiac injury.