2. Academic Validation
  3. HSD17B4 deficiency causes dysregulation of primary cilia and is alleviated by acetyl-CoA

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

  • Nat Commun. 2025 Mar 18;16(1):2663. doi: 10.1038/s41467-025-57793-8.
Ji-Eun Bae # 1,  Soyoung Jang # 1 2,  Joon Bum Kim 2,  Na Yeon Park 1 2,  Doo Sin Jo 3,  Hyejin Hyung 2,  Pansoo Kim 3,  Min-Seon Kim 4,  Hong-Yeoul Ryu 2 5,  Hyun-Shik Lee 2 5,  Dong-Seok Lee 2,  Myriam Baes 6,  Zae Young Ryoo 7,  Dong-Hyung Cho 8 9 10
Affiliations

Affiliations

  • 1 Organelle Institute, Kyungpook National University, Daegu, Republic of Korea.
  • 2 School of Life Sciences, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea.
  • 3 ORGASIS Corp, Suwon, Gyeonggi-do, Republic of Korea.
  • 4 Division of Endocrinology and Metabolism, Asan Medical Center, Seoul, Republic of Korea.
  • 5 KNU G-LAMP Project Group, KNU Institute of Basic Sciences, Kyungpook National University, Daegu, Republic of Korea.
  • 6 Laboratory of Cell Metabolism, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.
  • 7 School of Life Sciences, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea. jaewoong64@knu.ac.kr.
  • 8 Organelle Institute, Kyungpook National University, Daegu, Republic of Korea. dhcho@knu.ac.kr.
  • 9 School of Life Sciences, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea. dhcho@knu.ac.kr.
  • 10 ORGASIS Corp, Suwon, Gyeonggi-do, Republic of Korea. dhcho@knu.ac.kr.
  • # Contributed equally.
PMID: 40102401 DOI: 10.1038/s41467-025-57793-8
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.

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