Lactylation-driven <i>NSUN2</i> -mediated RNA m5C modification promotes perineural invasion in pancreatic cancer

<b>Background:</b> Perineural invasion (PNI) is a key biological feature underpinning the high malignancy and poor prognosis of pancreatic ductal adenocarcinoma (PDAC). Lysine lactylation (Kla), a metabolite-stress-induced post-translational modification, plays crucial regulatory roles in diverse biological processes. The RNA methyltransferase <i>NSUN2</i> is essential for cancer invasion and metastasis. However, the mechanisms by which <i>NSUN2</i> contributes to lactylation-driven PNI in PDAC remain to be elucidated. <b>Methods:</b> We assessed tumor lactate / pan-lactylation, <i>NSUN2</i> lactylation, and PNI in human PDAC cohorts with survival follow-up. Functional studies used PDAC cell lines for migration/invasion assays, dorsal-root-ganglion (DRG) co-culture, and neurite-outgrowth assays under lactate or enzymatic perturbations. Mechanistic interrogation combined <i>NSUN2</i> knockout, CRISPR knock-in mutants at K692 (K692R/E), co-immunoprecipitation, RIP-seq, MeRIP-qPCR, and actinomycin-D chase to test mRNA binding, m5C modification, and stability of <i>CDCP1</i>/<i>STC1</i>. <i>In vivo</i> validation employed a sciatic nerve invasion model and a KPC genetically engineered mouse model to assess tumor-nerve infiltration and disease progression. <b>Results:</b> Lactylated <i>NSUN2</i> is markedly upregulated in mice and human PDAC with more severe PNI, and is significantly associated with poorer prognosis. Functionally, inhibiting lactylation or blocking <i>NSUN2</i> markedly attenuated tumor-nerve interactions and neural invasion. Mechanistically, lactate accumulation leads to the lactylation of <i>NSUN2</i> at lysine 692 (K692), subsequently inhibiting its ubiquitination and degradation. lactylation of <i>NSUN2</i> mediated m5C modification on <i>CDCP1</i> and <i>STC1</i> mRNA, enhanced their mRNA stability. <b>Conclusions:</b> This study identifies lactate-driven <i>NSUN2</i> K692 lactylation as a key driver of perineural invasion in PDAC. We define a lactate-<i>NSUN2</i>-m5C-<i>CDCP1</i>/<i>STC1</i> axis that links metabolic stress-induced lysine lactylation to mRNA methylation-dependent stabilization of pro-invasive transcripts, highlighting actionable therapeutic targets to restrain neural invasion and improve patient outcomes.