Streptococcus anginosus promotes hepatocellular carcinoma progression and BET inhibitor resistance by inducing BRD4 lactylation

Hepatocellular carcinoma (HCC) is a highly aggressive form of carcinoma with a poor prognosis. Diagnostic markers and potential therapeutic targets for HCC are urgently needed. Here, we demonstrate that fecal microbiota transplantation (FMT) using stool sa mples from HCC patients significantly promote the growth of patient-derived xenografts (PDXs). 16s-rRNA sequencing combined with qPCR reveal that Streptococcus anginosus (S. anginosus) is enriched in the stool samples of HCC patients and HCC-FMT mice. S. anginosus monocolonization recapitulates the tumor-promoting effects of HCC-FMT in germ-free (GF) mice. Mechanistically, S. anginosus plays a critical role in regulating the downstream pathways of BRD4 via its metabolites, thereby promoting the activation of oncogenic Myc and E2F signaling pathways, HCC progression and BET inhibitor (BETi) resistance. S. anginosus-derived lactate promotes BRD4 lactylation at the K317 site via AARS1, thereby inhibiting BRD4 ubiquitination and degradation. Notably, blockade of the S. anginosus-BRD4 lactylation axis improves the BETi responsiveness in both syngeneic mouse models and PDXs. Overall, our study highlights the oncogenic role of the S. anginosus-BRD4 signaling in the gut-liver axis and suggests its potential as a non-invasive biomarker and therapeutic target for HCC.