pNaktide reverses metabolic reprogramming and disease progression of ATP1A1-deficiency clear cell renal cell carcinoma.

Abstract

ATP1A1 has been reported to exhibit differential expression across various tumors; however, its specific role in clear cell renal cell carcinoma (ccRCC) remains uncharted. This study investigates the role of ATP1A1 in ccRCC, assessing its potential as a prognostic marker and therapeutic target. Through database analysis and clinical sample evaluation, we found that ATP1A1 expression is significantly downregulated in ccRCC and closely correlates with poor patient prognosis. Both in vitro and in vivo experiments further confirmed that ATP1A1 exerts tumor-suppressive effects by inhibiting SRC kinase activity. Additionally, co-expression gene analysis suggests that ATP1A1 may regulate ccRCC development by targeting metabolic reprogramming. We also discovered that the overexpression of ATP1A1 induces a metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS), resulting in increased levels of reactive oxygen species (ROS) and subsequent apoptosis. Moreover, we evaluated the therapeutic potential of pNaktide, a peptide that mimics ATP1A1 function. Our research indicates that pNaktide effectively inhibits ccRCC proliferation both in vitro and in vivo by suppressing the SRC signaling pathway and inducing metabolic changes akin to those observed with ATP1A1 overexpression. Studies utilizing nude mouse models further confirmed that pNaktide significantly reduces tumor volume and weight, supporting its potential as a therapeutic agent. In summary, this study demonstrates that low ATP1A1 expression is a critical factor in ccRCC progression and that pNaktide, by restoring ATP1A1-like functions, presents a promising therapeutic strategy for ccRCC.