HBB contributes to individualized aconitine-induced cardiotoxicity in mice via interfering with ABHD5/AMPK/HDAC4 axis

Ya-juan Guo1, Jing-jing Yao1, Zhen-zhen Guo1, Ming Ding1, Kun-lin Zhang2, Qing-hong Shen1, Yu Li1, Shao-fang Yu1, Ting Wan1, Fu-ping Xu3, Ying Wang1, Xiao-xiao Qi1, Jin-jun Wu1, Jian-xin Chen4, Zhong-qiu Liu1,2, Lin-lin Lu1
1 Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People’s Republic of China, Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou 510006, China
2 State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
3 Guandong Provincial hospital of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China
4 Beijing University of Chinese Medicine, Beijing 100029, China
Correspondence to: Jian-xin Chen:, Zhong-qiu Liu:, Lin-lin Lu:,
DOI: 10.1038/s41401-023-01206-3
Received: 20 May 2023
Accepted: 19 November 2023
Advance online: 11 March 2024


The root of Aconitum carmichaelii Debx. (Fuzi) is an herbal medicine used in China that exerts significant efficacy in rescuing patients from severe diseases. A key toxic compound in Fuzi, aconitine (AC), could trigger unpredictable cardiotoxicities with high-individualization, thus hinders safe application of Fuzi. In this study we investigated the individual differences of AC-induced cardiotoxicities, the biomarkers and underlying mechanisms. Diversity Outbred (DO) mice were used as a genetically heterogeneous model for mimicking individualization clinically. The mice were orally administered AC (0.3, 0.6, 0.9 mg· kg−1 ·d−1) for 7 d. We found that AC-triggered cardiotoxicities in DO mice shared similar characteristics to those observed in clinic patients. Most importantly, significant individual differences were found in DO mice (variation coefficients: 34.08%–53.17%). RNA-sequencing in AC-tolerant and AC-sensitive mice revealed that hemoglobin subunit beta (HBB), a toxic-responsive protein in blood with 89% homology to human, was specifically enriched in AC-sensitive mice. Moreover, we found that HBB overexpression could significantly exacerbate AC-induced cardiotoxicity while HBB knockdown markedly attenuated cell death of cardiomyocytes. We revealed that AC could trigger hemolysis, and specifically bind to HBB in cell-free hemoglobin (cf-Hb), which could excessively promote NO scavenge and decrease cardioprotective S-nitrosylation. Meanwhile, AC bound to HBB enhanced the binding of HBB to ABHD5 and AMPK, which correspondingly decreased HDAC-NT generation and led to cardiomyocytes death. This study not only demonstrates HBB achievement a novel target of AC in blood, but provides the first clue for HBB as a novel biomarker in determining the individual differences of Fuzi-triggered cardiotoxicity.

Keywords: aconitine; cardiotoxicity; individual differences; hemoglobin subunit beta; nitrogen monoxide; ABHD5/AMPK/HDAC4 axis

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