线粒体自噬通过调节癌干细胞（CSC）群体影响肿瘤发生性和恶性程度的多种癌症类型。在这里，我们报告顺铂治疗可通过调节口腔CSC中CLU（簇蛋白）水平激活更高的线粒体自噬。此外，CLU的增功能和失功能也表明了其特定的线粒体自噬作用，即清除受损的线粒体。CLU还通过激活Ser / Thr激酶AKT来调节线粒体分裂，从而触发丝氨酸616残基上的DNM1L / DRP1的磷酸化，启动线粒体分裂。更重要的是，我们还证明了CLU介导的线粒体自噬通过线粒体自噬降解MSX2（msh homeobox 2），防止其从抑制SOX2活性的核移位，从而促进口腔CSC的阳性调节并抑制癌干性和自我更新能力。然而，CLU敲低破坏了线粒体代谢，产生过度的线粒体超氧化物，这提高了口腔CSC对顺铂的敏感性。值得注意的是，我们的结果表明CLA介导的细胞保护依赖于SOX2的表达。通过遗传（shSOX2）和药理（KRX-0401）策略抑制SOX2能够逆转CLU介导的细胞保护作用，使口腔CSC对顺铂介导的细胞死亡更为敏感。

Mitophagy regulates cancer stem cell (CSC) populations affecting tumorigenicity and malignancy in various cancer types. Here, we report that cisplatin treatment led to the activation of higher mitophagy through regulating CLU (clusterin) levels in oral CSCs. Moreover, both the gain-of-function and loss-of-function of CLU indicated its mitophagy-specific role in clearing damaged mitochondria. CLU also regulates mitochondrial fission by activating the Ser/Thr kinase AKT, which triggered phosphorylation of DNM1L/DRP1 at the serine 616 residue initiating mitochondrial fission. More importantly, we also demonstrated that CLU-mediated mitophagy positively regulates oral CSCs through mitophagic degradation of MSX2 (msh homeobox 2), preventing its nuclear translocation from suppressing SOX2 activity and subsequent inhibition of cancer stemness and self-renewal ability. However, CLU knockdown disturbed mitochondrial metabolism generating excessive mitochondrial superoxide, which improves the sensitivity to cisplatin in oral CSCs. Notably, our results showed that CLU-mediated cytoprotection relies on SOX2 expression. SOX2 inhibition through genetic (shSOX2) and pharmacological (KRX-0401) strategies reverses CLU-mediated cytoprotection, sensitizing oral CSCs towards cisplatin-mediated cell death.