溶酶体稳态的维持对于细胞生长至关重要。溶酶体依赖的降解和代谢维持了肿瘤细胞的存活。本文中，我们证明CCDC50作为一个溶磷自噬受体，通过控制溶酶体完整性和更新来促进肿瘤进展和浸润。CCDC50能够监测溶酶体损伤，识别损坏溶酶体上的galectin-3和K63链式多泛素化，并将其特异性地靶向自噬降解。CCDC50缺乏会导致破裂溶酶体的积累，自噬通路受阻，产生过多的活性氧，从而导致细胞死亡和肿瘤抑制。在人类黑色素瘤中，CCDC50表达与恶性程度、进展到转移以及总体生存率不良相关。针对CCDC50抑制了肿瘤生长和肺转移，并增强了对BRAFV600E的抑制效果。因此，我们证明了CCDC50介导的损伤溶酶体清除在支持肿瘤生长中的关键作用，从而确定了黑色素瘤的一个潜在治疗靶点。 © 2023 The Authors.

The maintenance of lysosome homeostasis is crucial for cell growth. Lysosome-dependent degradation and metabolism sustain tumor cell survival. Here, we demonstrate that CCDC50 serves as a lysophagy receptor, promoting tumor progression and invasion by controlling lysosomal integrity and renewal. CCDC50 monitors lysosomal damage, recognizes galectin-3 and K63-linked polyubiquitination on damaged lysosomes, and specifically targets them for autophagy-dependent degradation. CCDC50 deficiency causes the accumulation of ruptured lysosomes, impaired autophagic flux, and superfluous reactive oxygen species, consequently leading to cell death and tumor suppression. CCDC50 expression is associated with malignancy, progression to metastasis, and poor overall survival in human melanoma. Targeting CCDC50 suppresses tumor growth and lung metastasis, and enhances the effect of BRAFV600E inhibition. Thus, we demonstrate critical roles of CCDC50-mediated clearance of damaged lysosomes in supporting tumor growth, hereby identifying a potential therapeutic target of melanoma.© 2023 The Authors.