Collectively, our findings not only identify a novel mechanism that ALDH2 alleviates septic myocardial injury (targeting noncanonical pyroptosis via interaction with GSDMD, HMGB1, and RAGE) but also provide the preclinical evidence that targeting ALDH2—via agonists like Alda‐1 or other ALDH2‐upregulating strategies—could serve as a valuable therapeutic approach for sepsis‐induced cardiac injury. This evidence concerns the gene AGER and Sepsis.