Urolithin B ameliorates post-myocardial infarction cardiac dysfunction via TREM1-mediated autophagy activation and pyroptosis inhibition.

BACKGROUND

Myocardial infarction is a major cause of death worldwide. The existing standard therapies have limitations such as reperfusion injury, and new intervention strategies are urgently needed. Urolithin B (UB) is a natural phytochemical with multi-target biological activity. It has high bioavailability and good safety. Preliminary preclinical evidence indicates that it can improve cardiac function, but the specific mechanism remains to be elucidated.

METHODS

To investigate these mechanisms, we conducted a series of in vivo and in vitro experiments to evaluate the effect of UB on myocardial cells after myocardial infarction. The differences in the levels of pyroptosis and autophagy in vivo were confirmed through bioinformatics analysis, immunofluorescence, and Western blot. The inhibitory effect of UB on pyroptosis and its promotive effect on autophagy were further demonstrated using immunofluorescence, electron microscopy, and Western blot. The downstream mechanisms of UB were explored via RNA sequencing combined with bioinformatics analysis.

RESULTS

Our findings revealed a significant increase in both autophagy and pyroptosis levels within myocardial infarction. Notably, treatment with UB led to a marked inhibition of macrophage pyroptosis alongside an enhancement of autophagy levels. Further investigations identified macrophage triggering receptor-1 (TREM1) as the critical downstream target of UB. TREM1 was observed to promote myocardial cell proliferation, while also activating pyroptosis and inhibiting autophagy in macrophages.

CONCLUSION

This study is the first to elucidate the dual modulation of autophagy and pyroptosis by UB in the context of myocardial infarction, highlighting its potential as a novel therapeutic agent. Our results suggest that UB's targeting of TREM1 may facilitate cardiac repair mechanisms, presenting a promising adjunct to conventional treatments for myocardial infarction. Future research should aim to further validate these findings and explore the clinical applicability of UB in enhancing cardiac recovery.