Research Progress on the Roles of PCK2 in Metabolic Adaptationand Regulated Cell Death in Tumor Cells

Metabolic reprogramming is a hallmark of cancer and provides tumor cells with metabolic flexibility to adapt to nutrient deprivation, oxidative stress, and therapeutic pressure. PCK2 (phosphoenolpyruvatecarboxykinase 2), a mitochondrial isoform of phosphoenolpyruvate carboxykinase, catalyzes the conversion of oxaloacetate to phosphoenolpyruvate and participates in the coordination of gluconeogenesis, tricarboxylic acid cycleflux, glutamine metabolism, and redox homeostasis. Increasing evidence indicates that PCK2 is also involved in theregulation of proteostasis, inflammatory signaling, ferroptosis, cuproptosis, epithelial-mesenchymal transition, and treatment resistance. Importantly, the biological role of PCK2 in cancer is highly context-dependent. In some tumortypes or stress conditions, PCK2 supports tumor cell survival and metabolic adaptation, whereas in other settings itmay be involved in malignant phenotypes such as tumor cell proliferation, migration, and invasion, or enhance sensitivity to regulated cell death. This review summarizes the molecular characteristics and regulatory mechanisms ofPCK2, discusses its divergent functions across multiple cancer types, and evaluates its potential as a biomarker andtherapeutic target. A better understanding of the metabolic and molecular contexts that determine PCK2 functionmay facilitate the development of precision strategies targeting cancer metabolism.

CSTR: 32200.14.cjcb.2026.10.0007