A High-Loading Zn Single-Atom Nanozyme Targets the Zn/HIF-1α/GLUT1 Axis to Disrupt Glucose Metabolic Reprogramming...

Highly metastatic osteosarcoma exhibits marked resistance to conventional therapies, driven by glucose-metabolic reprogramming together with disturbed zinc homeostasis. This study reveals that the TRPML1/HIF-1α/GLUT1 axis as a mechanistic link between lysosomal zinc homeostasis and glucose-metabolic regulation, thereby dictating tumor cell fate. On this basis, we developed a TRPML1-activation-based single-atom nanozyme platform with dual enzymatic activities (ZMG@CS) to synchronously collapse ionic and redox homeostasis within lysosomes. Following the lysosomal accumulation of ZMG@CS, high-density Zn single-atom sites enabled peroxidase-like catalysis, whereas the delivered glucose oxidase (GOx) acidified the local environment through glucose consumption, collectively amplifying oxidative stress. TRPML1 activation promoted Zn²⁺ flux and ROS signaling to inhibit HIF-1α activity, thereby suppressing GLUT1 and restricting glucose uptake. Consequently, NADPH/GSH regeneration was impaired, causing a collapse of reducing power and triggering disulfidptosis. Simultaneously, zinc overload and ROS cooperatively exacerbated lysosomal membrane damage, activated the NLRP3 inflammasome, and induced caspase-1-dependent pyroptosis. These dual death programs synergistically enhanced immunogenic cell death and further reversed the immunosuppressive tumor microenvironment. Together, this study establishes the TRPML1/HIF-1α/GLUT1 axis as a critical pathway linking lysosomal zinc signaling to glucose-metabolic vulnerability and provides a new therapeutic avenue for aggressive osteosarcoma.