UPP1/ARNT positive feedback loop drives gastric cancer progression through metabolism reprogramming.

UPP1 has been reported to be involved in the tumorigenesis of pancreatic ductal adenocarcinoma and lung adenocarcinoma. However, the role and mechanism of UPP1 in GC remain unclear. This study aims to reveal the biological function of UPP1 in GC and the mechanisms regulating GC progression. Analysis of public databases and clinical samples revealed that UPP1 was significantly upregulated in GC tissues and associated with poor prognosis. Functionally, UPP1 knockdown inhibited GC cell proliferation and migration in vitro and suppressed tumor growth in vivo. Mechanistically, UPP1 promoted metabolic reprogramming by activating hypoxia-related pathways and enhancing mitochondrial translation. UPP1/ARNT axis formed a positive feedback loop that upregulated the expression of key metabolic enzymes HK2, GLUT1, and LDHA. These upregulated enzymes modulated glycolytic and oxidative phosphorylation levels to influence cellular functions. Moreover, genetic inactivation of UPP1 sensitized tumors to metformin and doxycycline. In addition, UPP1 affected PD-L1 levels through NF-κB pathway, thereby influencing the tumor microenvironment of GC. Our findings reveal a novel role for UPP1 in linking metabolic reprogramming to immune evasion in GC. Targeting this pathway with doxycycline or metformin exploits this metabolic vulnerability and enhances anti-tumor immunity, which could be a promising strategy.