BACKGROUND: Takotsubo syndrome (TTS) primarily manifests as a cardiomyopathy induced by physical or emotional stress, remains a poorly understood condition with no established treatments. In this study, we investigated the potential of sacubitril/valsartan (sac/val) to increase the survival of TTS patients and reduce inflammation and myocardial fibrosis in experimental models. AIM: This study aimed to evaluate whether sac/val could improve survival rates in TTS patients, mitigate cardiac remodeling in vivo, and explore its anti-inflammatory and antifibrotic mechanisms in vitro. METHODS: Clinical cases from the Chinese Takotsubo syndrome (ChiTTS) registry were analyzed to assess patient survival rates. In addition, we used isoprenaline (ISO)-induced TTS-like animal models, pre-treated with sac/val, to evaluate cardiac function and inflammatory response. Additionally, the effects of isoprenaline on cardiomyocytes and myocardial fibroblasts, as well as protection from rhBNP, were thoroughly studied. RESULTS: In TTS patients with a left ventricular ejection fraction (LVEF) ≤ 0.45, hyperglycemia, emotional stress, and inflammation were identified as independent risk factors. Moreover, the baseline characteristics of the TTS patients, heart rate, emotional triggers, female sex (%), WBC count, IL-6 concentration, PCT, ALT, AST and TG were significantly associated with decreasing left ventricular ejection fraction. In TTS patients, sac/val reduced inflammation, evidenced by lower levels of white blood cells and interleukin 6, compared to patients who did not receive sac/val by day 30. In animal models, Sac/val improved cardiac dysfunction in ISO-induced TTS-like cardiomyopathy and decreased myocardial inflammatory responses (IL-18 and Mac-3) by inhibiting the TLR4/NF-κB pathway and fibrosis through the inhibition of the TGFβ CONCLUSIONS: This study revealed that sac/val decreased inflammatory responses, myocardial edema, and fibrosis, resulting in an increased percentage of survivors in the TTS group. Similar to findings from in vivo and in vitro experiments, sac/val exerted cardioprotective effects by reducing the inflammatory response and reversing myocardial remodeling mediated by the TLR4/NF-κB and TGFβ