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Disulfiram alleviates cardiac hypertrophic injury by inhibiting TAK1-mediated PANoptosis

LI Wei-Dong^*, SHEN Xuan-Yang, JIANG Xiao-Lu, WEN Hong-Fu, SHEN Yuan, ZHANG Mei-Qi, TAN Wen-Tao

Department of Emergency, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, China

Abstract

The study aims to examine the effects and potential mechanisms of disulfiram (DSF) on cardiac hypertrophic injury, focusing on the role of transforming growth factor-β-activated kinase 1 (TAK1)-mediated pan-apoptosis (PANoptosis). H9C2 cardiomyocytes were treated with angiotensin II (Ang II, 1 μmol/L) to establish an in vitro model of myocardial hypertrophy. DSF (40 μmol/L) was used to treat cardiomyocyte hypertrophic injury models, either along or in combination with the TAK1 inhibitor, 5z-7-oxozeaenol (5z-7, 0.1 μmol/L). We assessed cell damage using propidium iodide (PI) staining, measured cell viability with CCK8 assay, quantified inflammatory factor levels in cell culture media via ELISA, detected TAK1 and RIPK1 binding rates using immunoprecipitation, and analyzed the protein expression levels of key proteins in the TAK1-mediated PANoptosis pathway using Western blot. In addition, the surface area of cardiomyocytes was measured with Phalloidin staining. The results showed that Ang II significantly reduced the cellular viability of H9C2 cardiomyocytes and the binding rate of TAK1 and RIPK1, significantly increased the surface area of H9C2 cardiomyocytes, PI staining positive rate, levels of inflammatory factors [interleukin-1β (IL-1β), IL-18, and tumor necrosis factor α (TNF-α)] in cell culture media and p-TAK1/TAK1 ratio, and significantly up-regulated key proteins in the PANoptosis pathway [pyroptosis-related proteins NLRP3, Caspase-1 (p20), and GSDMD-N (p30), apoptosis-related proteins Caspase-3 (p17), Caspase-7 (p20), and Caspase-8 (p18), as well as necroptosis-related proteins p-MLKL, RIPK1, and RIPK3]. DSF significantly reversed the above changes induced by Ang II. Both 5z-7 and exogenous IL-1β weakened these cardioprotective effects of DSF. These results suggest that DSF may alleviate cardiac hypertrophic injury by inhibiting TAK1-mediated PANoptosis.

Key words: disulfiram; cardiac hypertrophy; TAK1; PANoptosis; H9C2 cardiomyocytes

Received: 　　Accepted:

Corresponding author: 李卫东　　E-mail:

DOI: 10.13294/j.aps.2025.0037

Citing This Article：

LI Wei-Dong, SHEN Xuan-Yang, JIANG Xiao-Lu, WEN Hong-Fu, SHEN Yuan, ZHANG Mei-Qi, TAN Wen-Tao. Disulfiram alleviates cardiac hypertrophic injury by inhibiting TAK1-mediated PANoptosis. Acta Physiol Sin 2025; 77 (2): 222-230 (in Chinese with English abstract).