Gut microbial metabolite butyrate improves anticancer therapy by regulating intracellular calcium homeostasis

Hepatology. 2023 Jul 1;78(1):88-102. doi: 10.1097/HEP.0000000000000047. Epub 2023 Jan 3.


Background and aims: Gut microbiota are recognized to be important for anticancer therapy, yet the underlying mechanism is not clear. Here, through the analysis of clinical samples, we identify the mechanism by which the gut microbial metabolite butyrate inhibits HCC and then explore new strategies for HCC treatment.

Approach and results: In our study, we demonstrate that gut microbial metabolite butyrate improves anticancer therapy efficacy by regulating intracellular calcium homeostasis. Using liquid chromatography-mass spectrometry analysis, we found that butyrate metabolism is activated in HCC patients compared with healthy individuals. Butyrate levels are lower in the plasma of HCC patients by gas chromatography-mass spectrometry (GC-MS) analysis. Butyrate supplementation or depletion of short-chain Acyl-CoA dehydrogenase (SCAD) gene (ACADS), encoding a key enzyme for butyrate metabolism, significantly inhibits HCC proliferation and metastasis. The profiling analysis of genes upregulated by butyrate supplementation or ACADS knockdown reveals that calcium signaling pathway is activated, leading to dysregulation of intracellular calcium homeostasis and production of reactive oxygen species. Butyrate supplementation improves the therapy efficacy of a tyrosine kinase inhibitor sorafenib. On the basis of these findings, we developed butyrate and sorafenib coencapsulated mPEG-PLGA-PLL nanoparticles coated with anti-GPC3 antibody (BS@PEAL-GPC3) to prolong the retention time of drugs and enhance drug targeting, leading to high anticancer efficacy. BS@PEAL-GPC3 nanoparticles significantly reduce HCC progression. In addition, BS@PEAL-GPC3 nanoparticles display excellent HCC targeting with excellent safety.

Conclusions: In conclusion, our findings provide new insight into the mechanism by which the gut microbial metabolites inhibit HCC progression, suggesting a translatable therapeutics approach to enhance the clinical targeted therapeutic efficacy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents* / therapeutic use
  • Butyrates* / pharmacology
  • Calcium / metabolism
  • Carcinoma, Hepatocellular* / drug therapy
  • Gastrointestinal Microbiome*
  • Homeostasis
  • Liver Neoplasms* / drug therapy
  • Sorafenib* / therapeutic use


  • Butyrates
  • Calcium
  • Sorafenib
  • Antineoplastic Agents