HSD17B4 deficiency causes dysregulation of primary cilia and is alleviated by acetyl-CoA

Ji-Eun Bae, Soyoung Jang, Joon Bum Kim, Na Yeon Park, Doo Sin Jo, Hyejin Hyung, Pansoo Kim, Min-Seon Kim, Hong-Yeoul Ryu, Hyun-Shik Lee, Dong-Seok Lee, Myriam Baes, Zae Young Ryoo () and Dong-Hyung Cho ()
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Ji-Eun Bae: Kyungpook National University
Soyoung Jang: Kyungpook National University
Joon Bum Kim: Kyungpook National University
Na Yeon Park: Kyungpook National University
Doo Sin Jo: ORGASIS Corp
Hyejin Hyung: Kyungpook National University
Pansoo Kim: ORGASIS Corp
Min-Seon Kim: Asan Medical Center
Hong-Yeoul Ryu: Kyungpook National University
Hyun-Shik Lee: Kyungpook National University
Dong-Seok Lee: Kyungpook National University
Myriam Baes: KU Leuven
Zae Young Ryoo: Kyungpook National University
Dong-Hyung Cho: Kyungpook National University

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract Primary cilia are dynamic sensory organelles orchestrating key signaling pathways, and disruption of primary ciliogenesis is implicated in a spectrum of genetic disorders. The peroxisomal bifunctional enzyme HSD17B4 is pivotal for peroxisomal β-oxidation and acetyl-CoA synthesis, and its deficiency profoundly impairs peroxisomal metabolism. While patients with HSD17B4 deficiency exhibit ciliopathy-like symptoms due to dysfunctional primary cilia, the molecular connection between HSD17B4 and ciliopathy remains poorly understood. Here, we demonstrate that HSD17B4 deficiency impairs primary ciliogenesis and alters cilia-mediated signaling, suggesting a potential link between peroxisomal metabolism and ciliary function. Notably, elevation of acetyl-CoA rescues ciliary defects via HDAC6-mediated ciliogenesis in HSD17B4-deficient cells. Strikingly, acetate administration restores motor function, enhances primary cilia formation, and preserves the Purkinje layer in Hsd17B4-knockout mice. These findings provide insights into the functional link between HSD17B4 and primary cilia, highlighting acetyl-CoA as a potential therapeutic target for HSD17B4 deficiency and ciliopathy.

Date: 2025
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DOI: 10.1038/s41467-025-57793-8

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