在肿瘤扩张过程中，乳腺癌（BC）细胞经常因葡萄糖缺乏而经历活性氧积累和线粒体损伤。然而，BC细胞应对葡萄糖短缺引起的氧化应激的机制仍不清楚。在这里，我们发现 MANF（中脑星形胶质细胞衍生的神经营养因子）介导的线粒体自噬促进 BC 细胞在葡萄糖饥饿条件下存活。 MANF 介导的线粒体自噬还促进葡萄糖饥饿的 BC 细胞中的脂肪酸氧化。此外，在葡萄糖饥饿期间，SENP1介导的MANF去SUMO化通过抑制MANF的核易位增加细胞质MANF表达，从而使MANF分布在线粒体中。 MANF 通过与线粒体中关键的线粒体自噬调节因子 PRKN（parkin RBR E3 泛素蛋白连接酶）结合来介导线粒体自噬。在葡萄糖饥饿条件下，蛋白质氧化会抑制 PRKN 活性；然而，MANF 的 CXXC 基序减轻了 PRKN RING II 结构域中的蛋白质氧化并恢复其 E3 连接酶活性。此外，MANF-PRKN 相互作用对于 BC 肿瘤的生长和转移至关重要。高 MANF 表达预示 BC 患者预后不良。我们的结果强调了在葡萄糖饥饿期间 MANF 介导的线粒体自噬在 BC 细胞中的促生存作用，表明 MANF 作为潜在的治疗靶点。

During tumor expansion, breast cancer (BC) cells often experience reactive oxygen species accumulation and mitochondrial damage because of glucose shortage. However, the mechanism by which BC cells deal with the glucose-shortage-induced oxidative stress remains unclear. Here, we showed that MANF (mesencephalic astrocyte derived neurotrophic factor)-mediated mitophagy facilitates BC cell survival under glucose-starvation conditions. MANF-mediated mitophagy also promotes fatty acid oxidation in glucose-starved BC cells. Moreover, during glucose starvation, SENP1-mediated de-SUMOylation of MANF increases cytoplasmic MANF expression through the inhibition of MANF's nuclear translocation and hence renders mitochondrial distribution of MANF. MANF mediates mitophagy by binding to PRKN (parkin RBR E3 ubiquitin protein ligase), a key mitophagy regulator, in the mitochondria. Under conditions of glucose starvation, protein oxidation inhibits PRKN activity; nevertheless, the CXXC motif of MANF alleviates protein oxidation in RING II-domain of PRKN and restores its E3 ligase activity. Furthermore, MANF-PRKN interactions are essential for BC tumor growth and metastasis. High MANF expression predicts poor outcomes in patients with BC. Our results highlight the prosurvival role of MANF-mediated mitophagy in BC cells during glucose starvation, suggesting MANF as a potential therapeutic target.