Histone Lactylation-mediated PKM2 promotes gemcitabine resistance in pancreatic adenocarcinoma via the AKT/mTOR/SREBP1 Axis.

BACKGROUND: Pancreatic adenocarcinoma (PAAD) is a highly malignant tumor. The efficacy of its first-line chemotherapeutic agent, gemcitabine (GEM), is frequently compromised by acquired resistance. Although pyruvate kinase M2 (PKM2) is a potential target for mitigating GEM resistance, the underlying mechanism remains unclear. METHODS: Two PAAD gemcitabine-resistant cell lines, Panc-1/Gem and SW1990/Gem, were constructed, and intracellular lactate levels were quantified. Histone lactylation levels were detected via western blotting (WB). Five pairs of GEM-resistant and GEM-sensitive PAAD tissue samples were collected for immunohistochemistry detection. PKM2 expression in PAAD and resistant cells was examined through bioinformatics analysis, qRT-PCR, and WB. PKM2 knockdown and overexpression models were constructed in GEM-resistant cells. Cell viability, apoptosis, DNA damage, and GEM sensitivity were subsequently assessed using CCK-8, flow cytometry, comet assay, and immunofluorescence. The association between PKM2 and H3K18la was examined by ChIP assay. The mechanism involving the AKT/mTOR/SREBP1 axis was explored using bioinformatics analysis and experimental validation. RESULTS: Histone lactylation levels were elevated in PAAD and GEM-resistant cells. Furthermore, histone lactylation mediated PKM2 upregulation, which promoted cell viability, reduced apoptosis, attenuated DNA damage, and consequently induced GEM resistance. Mechanistically, histone lactylation upregulated PKM2 expression, stimulating the AKT/mTOR/SREBP1 signaling pathway, ultimately promoting GEM resistance in PAAD. CONCLUSION: This investigation suggests a potential mechanism by which histone lactylation-mediated PKM2 upregulation accelerates GEM resistance in PAAD through activating the AKT/mTOR/SREBP1 pathway.