Regulation of neuronal invasion of small cell lung cancer by STMN2/β-alanine-controlled metabolic reprogramming [beta-alanine-RNAseq]

Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine malignancy characterized by rapid progression and a poor prognosis. The perineural invasion (PNI) phenomenon is prevalent in SCLC and represents a critical clinical-pathological feature; nevertheless, the mechanisms and its influence on disease progression and patient survival remain unclear. In this study, we established PNI as an independent adverse prognostic factor of SCLC based on surgical cohort evidence. We further demonstrated that the neural microenvironment upregulates STMN2, a neuron-specific microtubule-destabilizing protein, in SCLC cells. Mechanistically, STMN2 activates the β-alanine metabolic pathway in a concentration-dependent manner, leading to increased intracellular β-alanine levels and thereby enhancing tumor cell migration and invasion. In vivo experiments confirmed that STMN2 knockdown significantly suppresses neural invasion in SCLC, an effect reversible upon exogenous β-alanine supplementation. Together, these findings identify a neural-STMN2-β-alanine-invasion axis in SCLC. This work not only provides novel mechanistic insights into neural invasion but also highlights a promising therapeutic target for countering PNI, underscoring its substantial translational relevance.