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

Rong Tang; Minghe Jiang; Xiao Tang; Shengkui Chen; Hao Xu; Yudan Pan; Bifu Lin; Xiawei Wei; Qile Ye; Minsheng Wu; Pingping Qi

doi:10.1016/j.freeradbiomed.2025.06.051

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

Free Radic Biol Med. 2025 Jun 26:S0891-5849(25)00800-7. doi: 10.1016/j.freeradbiomed.2025.06.051. Online ahead of print.

Authors

Rong Tang¹, Minghe Jiang¹, Xiao Tang¹, Shengkui Chen¹, Hao Xu¹, Yudan Pan¹, Bifu Lin¹, Xiawei Wei¹, Qile Ye², Minsheng Wu³, Pingping Qi⁴

Affiliations

¹ Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine intensive care unit. Nanning, Guangxi, 533000, P. R. China.
² Department of Critical Care Medicine, The Second Affiliated Hospital of Harbin Medical University. Nanning, Guangxi, 533000, P. R. China. Electronic address: qileye@126.com.
³ Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine intensive care unit. Nanning, Guangxi, 533000, P. R. China. Electronic address: 704618565@qq.com.
⁴ The Second Affiliated Hospital of Guangxi Medical University Blood Transfusion Department. Nanning, Guangxi, 533000, P. R. China. Electronic address: Lvliang588@qq.com.

PMID: 40581164
DOI: 10.1016/j.freeradbiomed.2025.06.051

Abstract

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-hour 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.

Keywords: BNIP3; Narciclasine; Sepsis; ferroptosis; mitophagy.