Alternate day fasting attenuates metabolic dysfunction-associated arterial thrombotic risk via increasing indole-3-propionic acid.

Metabolic dysfunction-associated arterial thrombosis poses a major health challenge worldwide. Emerging studies have highlighted the metabolic benefits of alternate day fasting (ADF), providing insight into its potential therapeutic effect on thrombotic events. Here, we show that ADF attenuates platelet hyperreactivity and thrombotic tendency in obese mice by reshaping the gut microbiota. Further metabolomic analysis identifies indole-3-propionic acid (IPA), a gut microbial derived metabolite, as a key contributor of thrombosis-ameliorating effects of ADF. Mechanistically, IPA preserves the intraplatelet Rho GTPase cycle homeostasis and suppresses downstream signaling pathways, thus inhibiting the platelet activation cascade and alleviating thrombus formation without affecting hemostasis in vivo. Moreover, patients with metabolic disturbance-associated arterial thrombosis exhibit significantly lower plasma IPA levels, which demonstrates strong predictive value for thrombotic risk and inversely correlates with platelet reactivity. Here, we show ADF's protective role in metabolic dysfunction-associated thrombogenesis and validate IPA as a safe, effective antithrombotic agent with novel mechanistic insights.