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The following is a summary of “N4-acetylcytidine modification of ITGB5 mRNA mediated by NAT10 promotes perineural invasion in pancreatic ductal adenocarcinoma,” published in the March 2025 issue of the Journal of Experimental & Clinical Cancer Research by Huang et al.

Perineural invasion (PNI) is a prominent pathological feature of pancreatic ductal adenocarcinoma (PDAC), occurring at a high frequency and serving as a major contributor to disease progression, increased tumor aggressiveness, and poor survival outcomes. Despite its strong correlation with unfavorable prognosis, the molecular mechanisms driving PNI in PDAC remain inadequately understood. This study aims to elucidate the epigenetic regulatory pathways underlying PNI, focusing on the role of N4-acetylcytidine (ac4C) RNA modification in PDAC progression. To achieve this, researchers analyzed clinical samples from two independent cohorts using ultra-performance liquid chromatography tandem mass spectrometry (UPLC/MS-MS) to identify significantly altered RNA modifications in PDAC tissues exhibiting PNI lesions. Functional validation of PNI potential was conducted using dorsal root ganglion coculture systems and sciatic nerve injection models. 

Additionally, a comprehensive integration of RNA sequencing (RNA-seq), acetylated RNA immunoprecipitation sequencing (acRIP-seq), and ac4C sequencing (ac4C-seq), combined with CRISPR-based genome editing techniques, was employed to investigate the regulatory impact of ac4C modifications on the integrin beta 5 (ITGB5) transcript. The findings reveal that ac4C is significantly upregulated in PDAC tissues with PNI involvement, with in vitro and in vivo experiments demonstrating that overexpression of N-acetyltransferase 10 (NAT10), the writer enzyme responsible for ac4C modification, enhances PNI in PDAC. Mechanistic analysis further revealed that reduced ac4C modification in NAT10-knockdown PDAC cells led to diminished stability of ITGB5 mRNA, which in turn disrupted the ITGB5-pFAK-pSrc signaling cascade, a key pathway implicated in tumor cell adhesion and invasion.

CRISPR-based functional assays confirmed the pivotal role of NAT10-mediated ac4C modification in regulating ITGB5 expression and sustaining PNI progression. Furthermore, a therapeutic intervention strategy employing small-molecule inhibitors targeting both NAT10 and focal adhesion kinase (FAK) significantly mitigated PNI in vivo, highlighting a potential avenue for clinical application. In conclusion, this study uncovers a previously unrecognized epigenetic mechanism involving ac4C-mediated mRNA modification in PDAC-associated PNI and underscores the therapeutic potential of targeting NAT10 and focal adhesion signaling to improve patient outcomes. These findings provide novel insights into PDAC pathobiology and offer promising directions for the development of targeted interventions aimed at mitigating perineural invasion and enhancing survival in patients with pancreatic cancer.

Source: jeccr.biomedcentral.com/articles/10.1186/s13046-025-03362-2