Targeting the ChREBP/PKLR-lactate axis via Huachansu tablets restores CD8⁺T cell immunity in MASH-HCC.

Abstract

The incidence of metabolic dysfunction-associated steatohepatitis-related hepatocellular carcinoma (MASH-HCC) continues to rise worldwide, highlighting an urgent need for effective therapies. Natural products represent a vital source for anticancer drug discovery. Huachansu tablets (HCS), a clinically approved adjunctive antitumor agent, remain poorly characterized regarding their therapeutic efficacy and molecular mechanisms in MASH-HCC. This study found that HCS markedly suppressed the initiation and progression of MASH-HCC, alleviated metabolic abnormalities within the tumor microenvironment, and restored the antitumor function of CD8⁺T cells. In MASH-HCC mouse models, HCS significantly suppressed tumor progression and reprogrammed the tumor immune microenvironment. Further investigation revealed that HCS substantially reduced the production of tumor derived lactate and associated metabolites, thereby alleviating lactate mediated immunosuppression and restoring CD8⁺T cell effector function and antitumor immunity. Mechanistic studies identified PKLR as a key target through which HCS regulates tumor lactate metabolism. HCS inhibited ChREBP nuclear translocation, thereby downregulating PKLR expression and enzymatic activity, which subsequently attenuated glycolytic flux and reduced lactate production. Rescue experiments confirmed that HCS exerts its immunometabolic reprogramming effects primarily by targeting the ChREBP/PKLR-lactate metabolic axis. Moreover, combining HCS with anti-PD-1 therapy further enhanced CD8⁺T cell function and sensitized MASH-HCC to ICIs. Collectively, our findings reveal that HCS suppresses MASH-HCC progression through the coordinated remodeling of tumor metabolism and the immune microenvironment. Furthermore, the ChREBP/PKLR-lactate axis represents a promising therapeutic target, providing a mechanistic rationale for the clinical application of HCS in this disease.