Metabolomic profiling reveals grade-specific niacinamide accumulation and its therapeutic potential via SIRT1-CD38-EMT axis modulation in cervical cancer progression.

Despite new therapies for cervical cancer, innovative strategies are essential to overcome drug resistance and high toxicity. The present study focuses on the metabolic profiling of cervical carcinoma using a non-targeted metabolomics approach using liquid chromatography-mass spectrometry. Our study identified over 70 metabolites in cervical tissue samples (both cancerous and adjacent normal) using HILIC and reversed-phase chromatography in the positive and negative ionization modes. Major metabolic alterations included changes in nicotinamide metabolism, ammonia recycling, amino acid metabolism and nucleotide metabolism, in a grade-dependent manner. Compared to normal tissue, HPV-positive tumors showed elevated nicotinamide metabolism, and phosphatidylethanolamine biosynthesis, whereas HPV-negative tumors showed enriched purine and pyrimidine metabolism. We validated our findings by analyzing transcriptomics datasets from the Gene Expression Omnibus database to understand the expression patterns of the underlying genes involved in the dysregulated pathways. We observed that nicotinamide metabolism exhibits significant effects in lower-grade cervical cancers and specific HPV genotypes. We treated cervical cancer cell lines with niacinamide (NAM), an amide form of niacin, to evaluate its therapeutic efficacy. NAM treatment modulated NAD(+) metabolism, affecting key players such as CD38, PARP, NAMPT, and SIRT1, promoting apoptosis and inhibiting cell proliferation in cervical cancer cells. Importantly, HPV-positive SiHa cells showed elevated NAD(+) metabolism relative to HPV-negative C33A cells, reflecting distinct metabolic adaptations that may influence tumor progression. The study highlights the metabolic shifts in cancer progression and provides insights into NAM's molecular mechanisms and therapeutic potential for precision medicine in cervical cancer.