Jellyfish stings‐induced cardiac failure was ameliorated through AAG‐mediated glycogen‐driven ATP production

Jellyfish stings have become a common injury among fishermen and divers. Severe jellyfish stings could worsen cardiac function and even cause cardiac complications, ultimately leading to cardiac failure (CF). Currently, there are no effective drugs available. Single cell sequencing revealed alpha‐1 acid glycoprotein (AAG), an energy regulatory protein targeting to glycogen, was highly expressed in jellyfish stings‐induced CF patients. However, the mechanism remains elusive. It is postulated that AAG could increase glycogen metabolism, protecting against jellyfish stings‐induced CF. AAG deletion exacerbated CF, while exogenous and endogenous AAG ameliorated CF. AAG also rescued the decline triggered by the AAG knockout (KO). Intriguingly, AAG improved cardiac function and metabolic adaptation by glycogen‐driven ATP production, shifting mitochondrial/glycolytic ATP production towards glycolysis. Sorted by single‐cell RNA sequencing and spatial transcription technology, CC‐chemokine receptor 5 (CCR5) and Peroxisome proliferator‐activated receptor‐gamma coactivator‐1alpha (PGC‐1α) were differentially expressed. Mechanistically, CCR5 inhibitor MVC abolished AAG's protective effect and PGC‐1α overexpression. Collectively, jellyfish stings‐induced CF was ameliorated through AAG‐mediated glycogen‐driven ATP production, promoting glycolytic/mitochondrial metabolic switches to rely energetically primarily on glycolysis, which might serve as a therapeutic target of CF.