Yoda1/Piezo1 Alleviates Lipopolysaccharide-Induced Cardiac Injury via AMPK-Mediated Mitophagy.

The role of the mechanosensitive ion channel Piezo1 in septic cardiomyopathy remains unclear. This study investigated the role of Piezo1 in septic cardiomyopathy, focusing on the effects of its activation by Yoda1, an effective selective Piezo1 agonist, in LPS-induced cardiac injury models. In vivo, Yoda1 treatment improved cardiac function, enhanced mitophagy, and activated AMPK signaling in LPS-treated mice. In vitro, Yoda1 protected primary cultured cardiomyocytes from LPS-induced oxidative stress, improved mitochondrial function, and increased PINK1/Parkin-mediated mitophagy, whereas the Piezo1 inhibitor GsMTx4 had minimal effects. Western blot analysis confirmed the activation of the PINK1/Parkin and AMPK pathways by Yoda1 in cardiomyocytes. Notably, inhibiting AMPK signaling reduced the protective effects of Yoda1, underscoring the crucial role of AMPK in mitophagy regulation. These findings indicate that Yoda1 may serve as a potential therapeutic agent for LPS-induced cardiac injury, acting primarily through the regulation of mitophagy via the Piezo1/AMPK/PINK1/Parkin signaling pathway.