Reprogramming gut microbiota and targeting CXCL1: The multifaceted mechanism of PLP1 in ameliorating alcohol-induced liver disease.
5 affiliations
- 1Center for Xin'an Medicine and Modernization of Traditional Chinese Medicine of IHM, Wannan Medical University, Wuhu 241002, China.
- 2Anhui Provincial Engineering Laboratory for Screening and Re-evaluation of Active Compounds of Herbal Medicines in Southern Anhui, Wannan Medical University, Wuhu 241002, China.
- 3Anhui Provincial Engineering Research Center for Polysaccharide Drugs, Wannan Medical University, Wuhu 241002, China.
- 4Institute of Clinical Pharmacology of Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Hefei 230032, China.
- 5Wuhu Modern Technology Research and Development Center of Chinese Herbal Medicine and Functional Food, Anhui College of Traditional Chinese Medicine, Wuhu 241002, China.
Abstract
Hepatic inflammation and gut barrier dysfunction are core pathologies of alcohol-associated liver disease (ALD), yet effective therapies remain limited. Pueraria lobata polysaccharide (PLP1), a key active constituent of P. lobata Radix, has demonstrated hepatoprotective potential; however, its underlying mechanisms remain poorly understood. In this study, we sought to elucidate the therapeutic mechanism of PLP1 against experimental ALD by integrating proteomics, metabolomics, and gut microbiota analyses. We demonstrated that PLP1 initially functions through a microbiota-dependent pathway, transferable by fecal microbiota transplantation (FMT), to restore gut barrier integrity and suppress the gut‒LPS‒TLR4 inflammatory axis. Furthermore, PLP1 exerted a direct, microbiota-independent effect, maintaining its therapeutic efficacy in antibiotic-depleted mice. Mechanistically, PLP1 directly and specifically targets CXCL1, promoting its ubiquitin-mediated proteasomal degradation as confirmed by biophysical assays. The functional necessity of this interaction was definitively established via comprehensive genetic manipulation of CXCL1 in vitro and in vivo. Specifically, CXCL1 overexpression reversed PLP1's benefits, whereas CXCL1 knockdown mimicked its effects and occluded any additional benefit from PLP1. Overall, PLP1 ameliorates ALD by independently targeting both extrinsic and intrinsic inflammatory triggers. This study reveals the multifaceted pharmacology of a natural polysaccharide and validates a dual-pronged therapeutic strategy for ALD.
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BibTeX
@article{yang2026reprogramming,
title = {{Reprogramming gut microbiota and targeting CXCL1: The multifaceted mechanism of PLP1 in ameliorating alcohol-induced liver disease.}},
author = {Zhu Yang and Qiuyue Lv and Qiangbao Xu and Yan Chen and Yiping Yang and Zihan Li and Hui Che and Guodong Wang and Wei Wei and Jiangping Wu and Jun Han},
journal = {Acta pharmaceutica Sinica. B},
year = {2026},
month = jul,
doi = {10.1016/j.apsb.2026.06.057},
url = {https://europepmc.org/article/MED/42948751},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Reprogramming gut microbiota and targeting CXCL1: The multifaceted mechanism of PLP1 in ameliorating alcohol-induced liver disease.
AU - Zhu Yang
AU - Qiuyue Lv
AU - Qiangbao Xu
AU - Yan Chen
AU - Yiping Yang
AU - Zihan Li
AU - Hui Che
AU - Guodong Wang
AU - Wei Wei
AU - Jiangping Wu
AU - Jun Han
PY - 2026
DA - 2026/07/02
JO - Acta pharmaceutica Sinica. B
DO - 10.1016/j.apsb.2026.06.057
UR - https://europepmc.org/article/MED/42948751
AB - Hepatic inflammation and gut barrier dysfunction are core pathologies of alcohol-associated liver disease (ALD), yet effective therapies remain limited. Pueraria lobata polysaccharide (PLP1), a key active constituent of P. lobata Radix, has demonstrated hepatoprotective potential; however, its underlying mechanisms remain poorly understood. In this study, we sought to elucidate the therapeutic mechanism of PLP1 against experimental ALD by integrating proteomics, metabolomics, and gut microbiota analyses. We demonstrated that PLP1 initially functions through a microbiota-dependent pathway, transferable by fecal microbiota transplantation (FMT), to restore gut barrier integrity and suppress the gut‒LPS‒TLR4 inflammatory axis. Furthermore, PLP1 exerted a direct, microbiota-independent effect, maintaining its therapeutic efficacy in antibiotic-depleted mice. Mechanistically, PLP1 directly and specifically targets CXCL1, promoting its ubiquitin-mediated proteasomal degradation as confirmed by biophysical assays. The functional necessity of this interaction was definitively established via comprehensive genetic manipulation of CXCL1 in vitro and in vivo. Specifically, CXCL1 overexpression reversed PLP1's benefits, whereas CXCL1 knockdown mimicked its effects and occluded any additional benefit from PLP1. Overall, PLP1 ameliorates ALD by independently targeting both extrinsic and intrinsic inflammatory triggers. This study reveals the multifaceted pharmacology of a natural polysaccharide and validates a dual-pronged therapeutic strategy for ALD.
SN - 2211-3835
SN - 2211-3843
ER -