Hippuric acid contributes to NK-cell activation with dependence on TLR2 in chronic hepatitis B complicated by MASLD.

The coexistence of chronic hepatitis B and metabolic dysfunction-associated steatotic liver disease (CHB-MASLD) has been linked to accelerated fibrosis progression and less favorable clinical outcomes, but the immunopathological mechanisms remain incompletely understood. In the present study, we observed that CHB-MASLD patients exhibited significantly increased peripheral natural killer (NK) cell frequency and activation, with transcriptomic analysis revealing enrichment of inflammatory effector gene signatures. Notably, TLR2 was found to be upregulated in NK cells from CHB-MASLD patients and the frequency of TLR2-expressing NK cells correlated with metabolic parameters and liver stiffness. In vitro, metabolic-stress modeling increased TLR2 expression and enhanced NK-cell cytokine production. Untargeted plasma metabolomics identified hippuric acid as a candidate metabolite enriched in CHB-MASLD, and its abundance was associated with metabolic parameters and liver stiffness. Hippuric acid was involved in promoting NK-cell activation, and this effect was partially attenuated by TLR2 blockade. Furthermore, co-culture with hippuric acid-stimulated NK cells was associated with increased activation-related readouts in LX-2 cells, which were partially attenuated by TLR2 blockade. Collectively, these findings support an immunometabolic link among metabolic dysfunction, peripheral NK-cell activation, and a partially TLR2-dependent response to hippuric acid in CHB-MASLD, offering new insights into the immunopathology of CHB-MASLD.