FAM3A plays a key role in protecting against tubular cell pyroptosis and acute kidney injury through PI3K/AKT/NRF2-dependent pathway

Acute kidney injury (AKI) is in a high prevalence worldwide, but there is no therapeutic strategies nowadays. Renal tubular cell death plays a key role in the initiation and progression of AKI. However, the underlying mechanisms have not been elucidated. In this study, we found that tubular cell pyroptosis was primarily responsible to AKI progression, which is highly related with ATP depletion. FAM3A is a mitochondrial protein responsible for ATP synthesis. Herein, we found that FAM3A was decreased in AKI mice, especially in those pyroptotic tubular cells. FAM3A also decreased in clinical patients with AKI, and negatively correlated with inflammation and tubular cell injury. Gene ablation of FAM3A strongly induced NLRP3 inflammasome, Caspase-1, GSDMD, IL-1β, and IL-18, the pyroptotic markers in tubular epithelial cells, as well as triggered inflammation and mitochondrial dysfunction. Conversely, overexpression of FAM3A greatly ameliorated pyroptosis and inflammation, and reversed fatty-acid oxidation function in tubular cells. Mechanically, FAM3A activated PI3K/AKT/NRF2 pathway, which improved mitochondrial dysfunction and prevented cell pyroptosis. To activate NRF2 could strongly inhibit tubular cell pyroptosis, inflammation, mitochondrial dysfunction, and renal function decline in FAM3A knockout mice. Hence, our study provides the new mechanisms for AKI progression. We also demonstrated that FAM3A is a potential therapeutic target for treating AKI.