Activation of the KPNA2-mediated nuclear import of PPARα by KIF13B mitigates alcohol-associated liver steatosis.

Authors

Kaikai Lu, Si Mei, Lianxin Zhang, Li-You Lian, Yingyu Lu, Aiden Xian, Xianqin Shen, Xin Zhang, Yinqi Zhao, Yijun Tao, Yitong Xu, Wenxi Zhang, Guolin Miao, Jingxuan Chen, Yufei Han, Sijing Shi, Wen-Yue Liu, Weiguang Zhang, Ling Zhang, Yuhui Wang, Wei Huang, Ming-Hua Zheng, Xunde Xian

Published in

Gut. Aug 21, 2026. Epub Aug 21, 2026.

Abstract

Alcohol-associated liver disease (ALD) is a major global health burden with no approved targeted therapies. Emerging evidence implicates kinesin family member 13B (KIF13B) in lipid metabolism, primarily in cardiovascular disease but its role in ALD remains unexplored.
To investigate the role and underlying mechanism of KIF13B in ALD pathogenesis and evaluate its therapeutic potential.
ALD was modelled in global and hepatocyte-specific Kif13b knockout mice using the modified chronic-plus-binge ethanol-feeding model (the NIAAA model). Human liver tissues from patients with ALD were analysed for clinical relevance. In vitro studies employed primary mouse hepatocytes and HepG2 cells treated with ethanol and palmitic acid.
Hepatic KIF13B expression was markedly reduced in both ethanol-fed mice and patients with ALD. KIF13B deficiency exacerbated ethanol-induced steatosis by impairing peroxisome proliferator-activated receptor alpha (PPARα) nuclear translocation without affecting its total expression. Mechanistically, KIF13B directly bound and stabilised karyopherin subunit alpha 2 (KPNA2), a critical nuclear import factor, thereby facilitating PPARα nuclear localisation and transcriptional activation of fatty acid oxidation genes. While the PPARα agonist fenofibrate effectively alleviated steatosis in wild-type mice, its efficacy was blunted in Kif13b-deficient mice. Conversely, the KPNA2-targeting compound foslinanib restored PPARα nuclear transport and ameliorated steatosis in Kif13b-deficient settings. Notably, combined treatment with fenofibrate and the KPNA2-targeting compound foslinanib exerted a more pronounced therapeutic effect in ameliorating hepatic steatosis.
This study identifies KIF13B as a novel regulator of hepatic lipid homeostasis in ALD via the KIF13B-KPNA2-PPARα axis, enhancing KPNA2 mediated nuclear import, particularly in combination with PPARα activation, represents a promising therapeutic strategy for ALD.

PMID:
42629199
Bibliographic data and abstract were imported from PubMed on 22 Aug 2026.

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