STK11/LKB1 突变 NSCLC 中同时发生的 KEAP1 突变激活 NFE2L2/NRF2，以补偿代谢适应过程中 STK11-AMPK 活性的损失。表征代谢应激期间 STK11-AMPK 和 KEAP1-NFE2L2 通路之间的调控串扰对于理解同时发生的突变的影响至关重要。在这里，我们发现代谢应激增加了 SQSTM1/p62 的表达和磷酸化，这对于激活 NFE2L2 和 AMPK、协同抗氧化防御和肿瘤生长至关重要。 SQSTM1驱动的NFE2L2和AMPK的双重激活是通过诱导KEAP1的巨自噬/自噬降解和促进溶酶体膜上AXIN-STK11-AMPK复合物的形成来实现的。相比之下，代谢应激诱导的 SQSTM1 表达和磷酸化也需要 STK11-AMPK 活性，这表明 AMPK 和 SQSTM1 之间存在双正反馈环。从机制上讲，SQSTM1 表达通过 PPP2/PP2A 依赖性 TFEB 和 TFE3 去磷酸化而增加，这是由低葡萄糖代谢和 AMPK 依赖性质子还原引起的溶酶体脱酸诱导的。此外，MAP3K7/TAK1 增加了 SQSTM1 磷酸化，MAP3K7/TAK1 被 ROS 和 pH 依赖性溶酶体 Ca2 分泌激活。重要的是，SQSTM1 在 S24 和 S226 处的磷酸化对于 AMPK 和 NFE2L2 的激活至关重要。值得注意的是，代谢应激引起的影响被乳酸提供的质子消除了。总的来说，我们的数据揭示了 AMPK 和 SQSTM1 之间的新型双正反馈回路，导致 AMPK 和 NFE2L2 双重激活，这可能解释了为什么 STK11 和 KEAP1 会同时发生突变，并为肺癌提供有希望的治疗策略。

Co-occurring mutations in KEAP1 in STK11/LKB1-mutant NSCLC activate NFE2L2/NRF2 to compensate for the loss of STK11-AMPK activity during metabolic adaptation. Characterizing the regulatory crosstalk between the STK11-AMPK and KEAP1-NFE2L2 pathways during metabolic stress is crucial for understanding the implications of co-occurring mutations. Here, we found that metabolic stress increased the expression and phosphorylation of SQSTM1/p62, which is essential for the activation of NFE2L2 and AMPK, synergizing antioxidant defense and tumor growth. The SQSTM1-driven dual activation of NFE2L2 and AMPK was achieved by inducing macroautophagic/autophagic degradation of KEAP1 and facilitating the AXIN-STK11-AMPK complex formation on the lysosomal membrane, respectively. In contrast, the STK11-AMPK activity was also required for metabolic stress-induced expression and phosphorylation of SQSTM1, suggesting a double-positive feedback loop between AMPK and SQSTM1. Mechanistically, SQSTM1 expression was increased by the PPP2/PP2A-dependent dephosphorylation of TFEB and TFE3, which was induced by the lysosomal deacidification caused by low glucose metabolism and AMPK-dependent proton reduction. Furthermore, SQSTM1 phosphorylation was increased by MAP3K7/TAK1, which was activated by ROS and pH-dependent secretion of lysosomal Ca2+. Importantly, phosphorylation of SQSTM1 at S24 and S226 was critical for the activation of AMPK and NFE2L2. Notably, the effects caused by metabolic stress were abrogated by the protons provided by lactic acid. Collectively, our data reveal a novel double-positive feedback loop between AMPK and SQSTM1 leading to the dual activation of AMPK and NFE2L2, potentially explaining why co-occurring mutations in STK11 and KEAP1 happen and providing promising therapeutic strategies for lung cancer.