DHA Targets RAB1B to Mediate the Driving Force Transmission of Copper Ion Vesicular Endocytosis Under Copper Overload for Promoting Cuproptosis and Ferroptosis in Hepatic Stellate Cells.

Liver fibrosis represents a central pathological process in chronic liver diseases and poses a severe threat to human health. Cuproptosis, a copper ion-dependent form of regulated cell death, offers a potential therapeutic strategy for liver fibrosis. This study demonstrated that dihydroartemisinin (DHA) transiently upregulates SLC31A1, thereby promoting copper influx. Under copper overload, SLC31A1 undergoes ubiquitin-mediated degradation, while DHA targets RAB1B to activate RAB10-dependent vesicular endocytosis as a compensatory mechanism for sustained copper accumulation. This endocytic process alters cellular biomechanical properties and strengthens RAB1B-VDAC1 interaction to promote mitochondrial copper uptake. Following cuproptosis, iron-sulfur cluster proteins undergo degradation, leading to massive iron release and subsequent ferroptosis, establishing a cascading dual cell death mechanism. Mechanistically, RAB1B regulates KAT2A-mediated succinylation of USP11, thereby inhibiting USP11's deubiquitinating activity and accelerating SLC31A1 degradation. For in vivo applications, we engineered biomimetic nanoliposomes coated with HSC membranes and surface-functionalized with CD47, FNIII10, and ApoE. This system integrates immune evasion, hepatic accumulation, and HSC-specific recognition capabilities, demonstrating remarkable targeting efficacy and mechanistic consistency in primary HSCs and rodent models. These findings reveal that DHA enhances copper-laden vesicular endocytosis by targeting RAB1B, thereby triggering cuproptosis and ferroptosis, and provide novel molecular targeting strategies for liver fibrosis therapy.