Acute kidney injury (AKI) is in high prevalence worldwide but with no therapeutic strategies. Programmed cell death in tubular epithelial cells has been reported to accelerate a variety of AKI, but the major pathways and underlying mechanisms are not defined. Herein, we identified that pyroptosis was responsible for AKI progression and related to ATP depletion in renal tubular cells. We found that FAM3A, a mitochondrial protein that assists ATP synthesis, was decreased and negatively correlated with tubular cell injury and pyroptosis in both mice and patients with AKI. Knockout of FAM3A worsened kidney function decline, increased macrophage and neutrophil cell infiltration, and facilitated tubular cell pyroptosis in ischemia/reperfusion injury model. Conversely, FAM3A overexpression alleviated tubular cell pyroptosis, and inhibited kidney injury in ischemic AKI. Mechanistically, FAM3A promoted PI3K/AKT/NRF2 signaling, thus blocking mitochondrial reactive oxygen species (mt-ROS) accumulation. NLRP3 inflammasome sensed the overload of mt-ROS and then activated Caspase-1, which cleaved GSDMD, pro-IL-1β, and pro-IL-18 into their mature forms to mediate pyroptosis. Of interest, NRF2 activator alleviated the pro-pyroptotic effects of FAM3A depletion, whereas the deletion of NRF2 blocked the anti-pyroptotic function of FAM3A. Thus, our study provides new mechanisms for AKI progression and demonstrates that FAM3A is a potential therapeutic target for treating AKI.

中文翻译：

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FAM3A 在预防肾小管细胞焦亡和急性肾损伤中发挥关键作用


急性肾损伤（AKI）在全球范围内发病率很高，但尚无治疗策略。据报道，肾小管上皮细胞的程序性细胞死亡会加速多种 AKI，但主要途径和潜在机制尚未明确。在此，我们确定细胞焦亡是 AKI 进展的原因，并与肾小管细胞中 ATP 消耗有关。我们发现，FAM3A（一种协助 ATP 合成的线粒体蛋白）在 AKI 小鼠和患者中均减少，且与肾小管细胞损伤和细胞焦亡呈负相关。在缺血/再灌注损伤模型中，FAM3A的敲除会加剧肾功能衰退，增加巨噬细胞和中性粒细胞浸润，并促进肾小管细胞焦亡。相反，FAM3A 过表达可减轻肾小管细胞焦亡，并抑制缺血性 AKI 中的肾损伤。从机制上讲，FAM3A 促进 PI3K/AKT/NRF2 信号传导，从而阻止线粒体活性氧 (mt-ROS) 积累。 NLRP3 炎症小体感知到 mt-ROS 的过载，然后激活 Caspase-1，将 GSDMD、pro-IL-1β 和 pro-IL-18 裂解成成熟形式，从而介导细胞焦亡。有趣的是，NRF2 激活剂减轻了 FAM3A 缺失的促焦亡作用，而 NRF2 的缺失则阻断了 FAM3A 的抗焦亡功能。因此，我们的研究提供了 AKI 进展的新机制，并证明 FAM3A 是治疗 AKI 的潜在治疗靶点。