SerpinB7 promotes c-Myc-mediated glycolysis by interacting with ANXA2 to facilitate the progression of non-small cell lung cancer

Metabolic reprogramming, particularly aberrant glycolysis, is a hallmark of NSCLC progression; however, the regulatory mechanisms remain incompletely understood. Here, we identify SerpinB7, an endogenous serine protease inhibitor, as a novel oncogenic regulator of glycolytic reprogramming in NSCLC. SerpinB7 is significantly overexpressed in NSCLC tissues and correlates with poor prognosis. Mechanistically, SerpinB7 functions in a non-canonical, protease-independent manner by directly binding to Annexin A2 (ANXA2), protecting it from NEDD4L-mediated ubiquitination and degradation, thereby stabilizing ANXA2 protein levels.As an RNA-binding protein, ANXA2 interacts with c-Myc via its C-terminal domain, enhancing c-Myc driven transcription of glycolytic genes. This establishes a previously unrecognized SerpinB7-ANXA2-c-Myc regulatory axis that promotes glycolytic activation and malignant transformation in NSCLC cells. Importantly, immunohistochemical analysis of clinical specimens confirms the co-overexpression of SerpinB7 and ANXA2 in tumors, underscoring the clinical relevance of this pathway. Targeting SerpinB7 using siRNAs encapsulated in ferritin protein shells effectively suppresses NSCLC tumor growth and metastasis. These findings reveal SerpinB7 as a tumor-specific modulator of glycolysis and a potential metabolic target in NSCLC.