2. Academic Validation
  3. Dual Keap1-Dependent actions of pubescenoside A against ulcerative colitis: Promoting DDX5 ubiquitination degradation and Nrf2 nuclear translocation to suppress inflammation

Dual Keap1-Dependent actions of pubescenoside A against ulcerative colitis: Promoting DDX5 ubiquitination degradation and Nrf2 nuclear translocation to suppress inflammation

  • Free Radic Biol Med. 2025 Aug 21:240:426-438. doi: 10.1016/j.freeradbiomed.2025.08.040.
Hongli Zhang 1,  Ziyu Lan 1,  Hui Wang 1,  Haojie Yao 2,  Ruiyan Zheng 2,  Zijing Chen 2,  Xiang Luo 1,  Peng Wu 3,  Yuanyuan Cheng 4,  Zhongqiu Liu 5
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, State Key Laboratory of Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China; Chinese Medicine Guangdong Laboratory, Hengqin, Guangdong, 519031, China.
  • 2 Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, State Key Laboratory of Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China.
  • 3 Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, State Key Laboratory of Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China; Chinese Medicine Guangdong Laboratory, Hengqin, Guangdong, 519031, China. Electronic address: wupeng@gzucm.edu.cn.
  • 4 Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, State Key Laboratory of Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China; Chinese Medicine Guangdong Laboratory, Hengqin, Guangdong, 519031, China. Electronic address: chengyuanyuan@gzucm.edu.cn.
  • 5 Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, State Key Laboratory of Traditional Chinese Medicine Syndrome, State Key Laboratory of Dampness Syndrome of Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China; Chinese Medicine Guangdong Laboratory, Hengqin, Guangdong, 519031, China. Electronic address: liuzq@gzucm.edu.cn.
PMID: 40849001 DOI: 10.1016/j.freeradbiomed.2025.08.040
Abstract

Ulcerative colitis (UC) is a chronic inflammatory disorder of the colon, characterized by a complex clinical syndrome. Pubescenoside A (PBA), a phenylpropanoid derived from Ilex pubescens, exhibits significant anti-inflammatory effects; however, the impact and underlying mechanism of PBA on UC remain unclear. Therefore, the aim of this study is to investigate the potential mechanism of PBA against UC using in vivo and in vitro experiments. Pubescenoside A effectively enhances weight loss in UC mice, decreases the disease activity index (DAI). Regarding colonic morphology, PBA ameliorates colorectal stenosis and shortening, reduces intestinal mucosal ulceration, diminishes inflammatory cell infiltration, and tends to normalize glandular arrangement. Furthermore, PBA effectively suppresses pro-inflammatory factors. Mechanism studies have shown that PBA can directly target Kelch-like ECH associated protein 1 (Keap1), subsequently promoting the interaction between Keap1 and DEAD-box RNA helicase 5 (DDX5) to enhance ubiquitination and degradation of DDX5, leading to a down-regulation of C-C motif chemokine ligand 3 (CCL3) expression. Additionally, PBA disrupts the Keap1/Nrf2 complex, facilitating Nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear entry to inhibit the Nuclear factor-κB (NF-κB) pathway. Importantly, in Gpt-lgr5-creERT2 Keap1flox/flox mice, the anti-UC effect of PBA was attenuated. Our results indicated that PBA mitigated UC by targeting Keap1, thereby promoting the ubiquitination degradation of DDX5 and facilitating the nuclear entry of Nrf2.

Keywords

DDX5; Keap1; Nrf2; Pubescenoside A; Ulcerative colitis.

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