Porcupine inhibitor CGX1321 alleviates heart failure with preserved ejection fraction in mice by blocking WNT signaling

Hao Wu1,2, Lu-xun Tang3, Xue-mei Wang4, Liang-peng Li1,2, Xiao-kang Chen1,2, Yan-ji He1,2, De-zhong Yang1,2, Yu Shi1,2, Jia-ling Shou1,2, Zong-shu Zhang5, Liang Wang5, Bing-jun Lu1,2, Songzhu Michael An5,6, Chun-yu Zeng1,1,2,7,8,9, Wei Eric Wang1,1,1,2
1 .Department of Geriatrics, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
2 Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing 400042, China
3 Department of Cardiovascular Medicine, The General Hospital of Western Theater Command PLA, Chengdu 610083, China
4 School of Medicine, Chongqing University, Chongqing 400044, China
5 Guangzhou Curegenix Co. Ltd., International Business Incubator, Guangzhou Science City, Guangzhou 510663, China
6 Curegenix, Inc., Burlingame, CA 94010, USA
7 State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, The Third Military Medical University, Chongqing 400042, China
8 Heart Center of Fujian Province, Union Hospital, Fujian Medical University, Fuzhou 350001, China
9 Department of Cardiology, Chongqing General Hospital, Chongqing 401147, China
Correspondence to: Chun-yu Zeng:, Wei Eric Wang:,
DOI: 10.1038/s41401-022-01025-y
Received: 14 May 2022
Accepted: 5 November 2022
Advance online: 6 December 2022


Heart failure with preserved ejection fraction (HFpEF) is highly prevalent, and lacks effective treatment. The aberration of WNT pathway underlies many pathological processes including cardiac fibrosis and hypertrophy, while porcupine is an acyltransferase essential for the secretion of WNT ligands. In this study we investigated the role of WNT signaling pathway in HFpEF as well as whether blocking WNT signaling by a novel porcupine inhibitor CGX1321 alleviated HFpEF. We established two experimental HFpEF mouse models, namely the UNX/DOCA model and high fat diet/L-NAME (“two-hit”) model. The UNX/DOCA and “two-hit” mice were treated with CGX1321 (3 mg·kg−1·d−1) for 4 and 10 weeks, respectively. We showed that CGX1321 treatment significantly alleviated cardiac hypertrophy and fibrosis, thereby improving cardiac diastolic function and exercise performance in both models. Furthermore, both canonical and non-canonical WNT signaling pathways were activated, and most WNT proteins, especially WNT3a and WNT5a, were upregulated during the development of HEpEF in mice. CGX1321 treatment inhibited the secretion of WNT ligands and repressed both canonical and non- canonical WNT pathways, evidenced by the reduced phosphorylation of c-Jun and the nuclear translocation of β-catenin and NFATc3. In an in vitro HFpEF model, MCM and ISO-treated cardiomyocytes, knockdown of porcupine by siRNA leads to a similar inhibitory effect on WNT pathways, cardiomyocyte hypertrophy and cardiac fibroblast activation as CGX1321 did, whereas supplementation of WNT3a and WNT5a reversed the anti-hypertrophy and anti-fibrosis effect of CGX1321. We conclude that WNT signaling activation plays an essential role in the pathogenesis of HFpEF, and porcupine inhibitor CGX1321 exerts a therapeutic effect on HFpEF in mice by attenuating cardiac hypertrophy, alleviating cardiac fibrosis and improving cardiac diastolic function.
Keywords: heart failure with preserved ejection fraction (HFpEF); cardiac hypertrophy; cardiac fibrosis; WNT signaling pathway; porcupine inhibitor; CGX1321

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