Bacteroides cellulosilyticus-derived 2-hydroxyphenylacetic acid rectifies hepatic lipid homeostasis in MASLD by targeting the PPAR&#x3b3;-CD36 axis.

Kaiwei Chen; Zizhen Yang; Jixing Peng; Chunyan Liu; Ying Yu; Xinchi Cai; Bei Liu; Shuao Li; Tiantian Chen; Samil Jung; Yu Tian; Qianyue Xu; Xing Rao; Zhinan Wu; Haoyu Wang; Yan Di; Linna Wang; Jianxun Wang; Myeong-Sok Lee; Yuanqiang Zou; Ningning He; Shangyong Li

doi:10.1080/19490976.2026.2725392

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Bacteroides cellulosilyticus-derived 2-hydroxyphenylacetic acid rectifies hepatic lipid homeostasis in MASLD by targeting the PPARγ-CD36 axis.

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Abstract

The gut microbiota plays an important role in the occurrence and development of metabolic dysfunction-associated steatotic liver disease (MASLD), but the specific molecular mechanisms involved have not been fully elucidated. In this study, human cohort studies were performed to identify that the relative abundance of Bacteroides cellulosilyticus (B. cellulosilyticus) was significantly decreased in patients with MASLD. Through the integration of metagenomic and metabolomic analyses, it was confirmed that B. cellulosilyticus and its metabolite 2-hydroxyphenylacetic acid (2HPAA) are key factors regulating the occurrence and development of MASLD. Single-cell sequencing and lipidomic analyses revealed that 2HPAA can enter the liver through the enterohepatic circulation to exert regulatory effects. Specifically, 2HPAA inhibits the peroxisome proliferator-activated receptor γ (PPARγ) signaling pathway, thereby suppressing the expression of the fatty acid transporter CD36. Meanwhile, 2HPAA regulates lipid metabolism in hepatocytes by significantly enhancing palmitate conversion efficiency and inhibiting CD36 palmitoylation. This dual regulatory effect on CD36 expression and palmitoylation can reduce lipid accumulation in hepatocytes and ultimately alleviate MASLD progression. These findings reveal the mechanism by which B. cellulosilyticus and 2HPAA alleviate MASLD by targeting the PPARγ-CD36 pathway. This work provides a new perspective for the study of gut microbiota-host interactions in regulating liver diseases.

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PPAR gamma CD36 Antigens Humans Phenylacetates Lipid Metabolism Homeostasis Fatty Liver Bacteroides Liver Hepatocytes Signal Transduction Gastrointestinal Microbiome 2-Hydroxyphenylacetic acid Bacteroides cellulosilyticus CD36 palmitoylation MASLD lipid homeostasis Journal Article

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Kaiwei Chen, Zizhen Yang, Jixing Peng, Chunyan Liu, Ying Yu, Xinchi Cai, Bei Liu, Shuao Li, Tiantian Chen, Samil Jung, Yu Tian, Qianyue Xu, Xing Rao, Zhinan Wu, Haoyu Wang, Yan Di, Linna Wang, Jianxun Wang, Myeong-Sok Lee, Yuanqiang Zou, Ningning He, Shangyong Li. 2026-09-01. Bacteroides cellulosilyticus-derived 2-hydroxyphenylacetic acid rectifies hepatic lipid homeostasis in MASLD by targeting the PPARγ-CD36 axis.. https://doi.org/10.1080/19490976.2026.2725392

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Journal Article resource 2-Hydroxyphenylacetic acid subject Bacteroides subject Bacteroides cellulosilyticus subject CD36 Antigens subject CD36 palmitoylation subject Fatty Liver subject Gastrointestinal Microbiome subject Hepatocytes subject Homeostasis subject Humans subject Journal Article subject Lipid Metabolism subject Liver subject MASLD subject Phenylacetates subject

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