黑色素瘤重新调整其新陈代谢，以快速适应治疗诱发的压力条件，使其持续存在并最终发展出抗药性。我们报告了黑色素瘤细胞亚群通过一种由过氧化物酶体和UDP-葡糖基脂醇酰基转移酶（UGCG）介导的协同代谢重编程来容忍MAPK通路抑制剂（MAPKi）。通过抑制PEX3表达来损害过氧化物酶体生物发生，可以增强MAPKi的促凋亡效应，通过诱导酰胺的形成，而UGCG介导的酰胺代谢则限制了这种效应。共同靶向PEX3和UGCG能够选择性地消除一部分代谢活跃的、耐药的CD36+黑色素瘤存留细胞，从而使黑色素瘤对MAPKi敏感，并延迟耐药性的发展。在患有MAPKi复发的黑色素瘤中发现了过氧化物酶体基因和UGCG的水平上升，并同时抑制PEX3和UGCG能够恢复多种耐药模型中MAPKi的敏感性。最后，在临床前黑色素瘤模型中，由PEX3-PEX19相互作用的新型抑制剂、UGCG抑制剂和MAPKi组合疗法展示了强大的抗肿瘤活性，因此是黑色素瘤治疗的一种有前景的方法。

Melanomas reprogram their metabolism to rapidly adapt to therapy-induced stress conditions, allowing them to persist and ultimately develop resistance. We report that a subpopulation of melanoma cells tolerate MAPK-pathway inhibitors (MAPKi) through a concerted metabolic reprogramming mediated by peroxisomes and UDP-glucose ceramide glycosyltransferase (UGCG). Compromising peroxisome biogenesis, by repressing PEX3 expression, potentiated the pro-apoptotic effects of MAPKi via an induction of ceramides, an effect limited by UGCG-mediated ceramide metabolism. Co-targeting PEX3 and UGCG selectively eliminated a subset of metabolically active, drug-tolerant CD36+ melanoma persister cells, thereby sensitizing melanoma to MAPKi and delaying resistance. Increased levels of peroxisomal genes and UGCG were found in patient-derived MAPKi-relapsed melanomas, and simultaneously inhibiting PEX3 and UGCG restored MAPKi sensitivity in multiple models of therapy resistance. Finally, combination therapy comprised of a newly identified inhibitor of the PEX3-PEX19 interaction, a UGCG inhibitor and MAPKi demonstrated potent anti-tumor activity in pre-clinical melanoma models, thus representing a promising approach for melanoma treatment.