Neuromedin U promotes lung adenocarcinoma progression by enhancing nucleotide metabolism and potentiating fibrosis in the tumor microenvironment

Lung adenocarcinoma (LUAD) remains a leading cause of cancer mortality, with limited treatment options for EGFR-wild-type patients and persistent intrinsic resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in some EGFR-mutated cases. Neuromedin U (NMU), which encodes a neuropeptide previously associated with poor prognosis, has emerged as a candidate gene linked to reduced EGFR-TKI efficacy. Here, we identify NMU as a multifaceted effector of LUAD progression. Transcriptomic analyses across LUAD cohorts revealed that NMU expression correlates with poor survival and enrichment of purine metabolism signatures. Mechanistically, NMU upregulates key purine biosynthesis genes, including IMPDH1 , GMPS , and RRM1 , in a NTSR1-dependent manner. Targeted metabolomic profiling and ¹⁵ N-glutamine isotope tracing confirmed that NMU enhances IMPDH1-mediated guanine nucleotide synthesis, supporting increased proliferative capacity. Pharmacologic inhibition of NMU signaling or IMPDH1 suppressed LUAD cell viability and AKT signaling, with guanosine supplementation partially rescuing these effects, functionally validating the NMU-IMPDH1 axis. Concurrently, NMU expression was associated with elevated levels of fibrosis-related markers including COL1A1 , FN1 , and ACTA2 , alongside transcriptomic and histological features of extracellular matrix remodeling and stromal expansion. These findings, supported by co-culture assays and in vivo models, suggest that NMU may influence stromal remodeling, possibly via TGF-β signaling. Notably, in vivo NMU inhibition reduced both tumor growth and fibrotic features, and combination therapy with SR48692 (NTSR1 inhibitor) and osimertinib yielded superior therapeutic efficacy. Together, these results identify NMU as a key mediator of LUAD progression through both tumor-intrinsic metabolic reprogramming and stromal remodeling pathways. Targeting the NMU-IMPDH1 axis may offer a novel strategy to suppress tumor proliferation and reshape the tumor microenvironment in LUAD patients with high NMU expressing tumors.