Abstract Lung adenocarcinoma (LUAD) remains a lethal malignancy plagued by therapy resistance and metabolic adaptability. This study identifies the scaffold protein RACK1 as a central regulator of LUAD pathogenesis and metabolic reprogramming. RACK1 is frequently upregulated in LUAD, where its expression correlates with advanced stage and poor prognosis. Mechanistically, RACK1 co-activates two pivotal metabolic pathways: it stabilizes LDHA by competing with its E3 ligase TRIM21, thereby enhancing glycolysis, and it scaffolds c-Src to phosphorylate and activate G6PD, fueling the pentose phosphate pathway. This dual metabolic switch promotes biomass production, redox balance, and drives aggressive tumor phenotypes. Crucially, combined targeting of RACK1 with c-Src or LDHA inhibition yielded synergistic anti-tumor effects in vivo, significantly surpassing monotherapies. Our findings establish RACK1 as a master metabolic regulator and propose a promising combinatorial therapeutic strategy for LUAD.
Wan et al. (Fri,) studied this question.