Gut-Derived Sodium Butyrate Attenuates Liver Fibrosis by Inhibiting Aerobic Glycolysis via the HDAC3/c-Myc Signaling Axis.

Authors

Yong Sun, Huayue Wu, Yutong Zhou, Pengsheng Yin, Long Wu, Haiyang Li, Shi Zuo, Zhe Yang, Kun Cao

Published in

FASEB journal : official publication of the Federation of American Societies for Experimental Biology. Volume 40. Issue 14. Pages e72138. Jul 31, 2026.

Abstract

Liver fibrosis remains a major global health challenge, driving interest in bioactive metabolites from natural sources as potential therapies. Sodium butyrate (NaB), a gut microbiota-derived short-chain fatty acid with notable anti-fibrotic activity, shows promise, although its mechanisms remain unclear. This study aims to explore the molecular mechanisms through which NaB attenuates liver fibrosis. This study integrates bioinformatics and network pharmacology to predict the molecular targets through which NaB exerts its anti-fibrotic effects. Candidate targets were validated through molecular docking, histopathology, CETSA, and SPR. The inferred mechanisms were further validated in vitro (LX-2 cells) and in vivo (CCl₄-induced mice) using Western blot, IF Co-IP, RT-qPCR, ELISA, and histopathological staining. HDAC3 was identified as a key driver of liver fibrosis. As a natural HDAC3 inhibitor, NaB markedly attenuated CCl₄-induced hepatic injury and fibrosis, accompanied by reduced expression of HDAC3, c-Myc, glycolytic enzymes (HK2, PFKFB3, and PKM2), and fibrotic markers (α-SMA and type I collagen) in fibrotic liver tissues and LX-2 cells. Mechanistically, NaB exerts its anti-fibrotic effects by inhibiting HDAC3 expression and deacetylase activity, promoting c-Myc acetylation and downregulating its expression, thereby suppressing glycolytic metabolic reprogramming in hepatic stellate cells. These findings indicate that NaB attenuates liver fibrosis by inhibiting HDAC3/c-Myc-mediated metabolic reprogramming, revealing a gut-derived anti-fibrotic mechanism and potential therapeutic targets.

PMID:
42440300
Bibliographic data and abstract were imported from PubMed on 13 Jul 2026.

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