Neuropeptide Precursor VGF Promotes Neuroendocrine Differentiation and Cancer-Associated Fibroblast Activation in Small Cell Lung Cancer

Abstract Small cell lung cancer (SCLC) is a highly aggressive malignancy with limited therapeutic options. Neuroendocrine differentiation is a prominent feature of SCLC. This study identified VGF, a secreted neuropeptide precursor, as a critical regulator of neuroendocrine differentiation in SCLC, particularly the ASCL1+ subtype. VGF orchestrated upregulation of the transcription factor ASCL1 through a CREB-dependent mechanism, thereby promoting neuroendocrine differentiation. Furthermore, VGF mediated the transformation of fibroblasts into cancer-associated fibroblasts (CAFs), establishing metabolic coupling between SCLC cells and CAFs via lactate exchange. A therapeutic strategy targeting VGF and monocarboxylate transporter 1 (MCT-1) disrupted neuroendocrine differentiation and SCLC-CAF metabolic coupling, demonstrating significant efficacy in both in vitro and in vivo models. Together, this study provides insights into the mechanisms underlying SCLC neuroendocrine differentiation and reveals targets and therapeutic strategies for advanced SCLC.