LncRNA HCP5 remodels G6PD dual post-translational modification to mediate metabolic adaptations driving osimertinib resistance in lung adenocarcinoma.

Osimertinib represents the standard treatment for EGFR-mutant lung adenocarcinoma (LUAD); however, acquired resistance limits its clinical efficacy. Elucidating the underlying mechanisms of resistance is crucial for developing novel therapeutic strategies. This study aimed to investigate the role of the long non-coding RNA HCP5 in mediating resistance to osimertinib. HCP5 was identified via bioinformatics analysis of GEO datasets. Its expression was evaluated in patient-derived tumor tissues and serum using fluorescence in situ hybridization and RT-qPCR. Osimertinib-resistant cell models were established. Functional assays included HCP5 modulation, metabolomics, and mechanistic studies such as RNA immunoprecipitation, co-immunoprecipitation, and ubiquitination/acetylation assays. In vivo validation utilized a xenograft model and an orthotopic lung transplantation tumor model. Integrated bioinformatics analysis identified HCP5 as the only lncRNA consistently overexpressed in TKI-resistant LUAD cells. Clinically, HCP5 was markedly elevated in both serum and tumor tissues of osimertinib-resistant patients, and correlated with poorer progression-free survival. Functionally, HCP5 overexpression increased osimertinib IC50 by over 10-fold, while its knockdown restored sensitivity. Mechanistically, HCP5 physically interacts with G6PD, shielding it from VHL-mediated ubiquitination to enhance its protein stability. Simultaneously, HCP5 recruits SIRT2 to promote G6PD deacetylation, dimerization, and enzymatic activation, thereby driving pentose phosphate pathway (PPP) metabolic reprogramming. In vivo, HCP5 overexpression compromised osimertinib's antitumor effect, which was rescued by co-treatment with the PPP inhibitor 6-aminonicotinamide. HCP5 drives osimertinib resistance through dual post-translational regulation of G6PD-blocking ubiquitination and promoting deacetylation-leading to metabolic adaptation. Targeting the HCP5-G6PD axis is a potential treatment strategy to overcome osimertinib resistance in LUAD.