FAM3A plays a key role in protecting against tubular cell pyroptosis and acute kidney injury

Abstract Acute kidney injury (AKI) is in high prevalence worldwide, but with no therapeutic strategies. Targeting programmed cell death in tubular epithelial cells has been reported to improve a variety of AKI, but the main pathways and mechanisms of programmed cell death are controversial. In further analysis of previous single-cell RNA-seq data, we identified that pyroptosis was primarily responsible to AKI progression, highly relating with ATP depletion. Herein, we found that FAM3A, a mitochondrial protein responsible for ATP synthesis, was decreased and negatively correlated with tubular injury and pyroptosis in both mice and patients with AKI. Knockout of FAM3A further worsened tubular damage and renal function deterioration, increased macrophage and neutrophil infiltration, and facilitated tubular cell pyroptosis in ischemia/reperfusion injury (IRI) model. Conversely, FAM3A overexpression improved kidney injury and alleviated pyroptosis in IRI or cisplatin AKI. Mechanistically, FAM3A depletion suppressed PI3K/AKT/NRF2 signaling, thus leading to mitochondrial dysfunction and mt-ROS accumulation. NLRP3 inflammasome sensed the overloaded mt-ROS and activated Caspase-1. The activated Caspase-1 then cleaved GSDMD, pro-IL-1β, and pro-IL-18 into their mature forms to mediate pyroptosis. The pro-pyroptotic effects of FAM3A depletion were alleviated after treatment whit NRF2 activator, while the anti-pyroptotic function of FAM3A was blocked by deletion of NRF2. Hence, our study provides new mechanisms for AKI progression and demonstrated that FAM3A is a potential therapeutic target for treating AKI.