Elesclomol‐Induced Copper Influx Attenuates Lung Adenocarcinoma Progression With Involvement of the ER Stress/PCK2 Axis

ABSTRACT Copper ionophores such as elesclomol (ES) have been identified as effective agents capable of inducing cuproptosis, a recently characterized form of regulated cell death driven by copper overload. However, the interplay among copper toxicity, endoplasmic reticulum stress, and metabolic rewiring in lung adenocarcinoma (LUAD) remains poorly understood. Here, we demonstrate that ES selectively transports extracellular copper into human LUAD cells, inducing ER stress and upregulating PCK2, a gluconeogenic enzyme with context‐dependent roles in cancer. RNA sequencing and functional assays revealed that PCK2 elevation under copper overload affects glucose metabolism and lipid metabolism to suppress malignant phenotypes. Clinically, high PCK2 expression is correlated with favorable prognosis in LUAD patients, as evidenced by analyses of public datasets. Knocking down PCK2 paradoxically increased proliferation and cell motility, suggesting that PCK2 plays a tumor‐suppressive role under copper stress. KRAS G12D transgenic mice‐derived lung cancer organoids were used to validate the in vitro therapeutic effects of ES + Cu by regulating PCK2 expression. In vivo experiments revealed that ES inhibited tumor growth and upregulated PCK2. Taking together, our findings reveal that the ES‐ER stress‐PCK2 axis is a critical mediator of copper‐induced metabolic disruption, providing a rationale for targeting cuproptosis pathways in LUAD therapy.