Nuclear Pan‐Lysine Lactylation Immunoreactivity Is Associated With Poor Prognosis in Intrahepatic Cholangiocarcinoma

AIM: Lysine lactylation (Kla) links cellular metabolism to gene regulation, but its significance in intrahepatic cholangiocarcinoma (ICC) remains unclear. METHODS: Nuclear pan-Kla immunoreactivity was evaluated in 118 patients who underwent curative-intent resection for ICC. Associations with clinicopathological features, overall survival (OS), recurrence-free survival (RFS), and FDG-PET-derived SUVmax were analyzed. Functional assays and bulk RNA sequencing were performed in cholangiocarcinoma cells treated with lactate, the p300 inhibitor A-485, or the LDH inhibitor oxamate. RESULTS: High nuclear pan-Kla immunoreactivity was associated with microscopic intrahepatic metastasis and poorer OS and RFS, and remained independently associated with both outcomes after multivariable adjustment. Adding Kla modestly increased the optimism-corrected C-index for OS, whereas RFS discrimination was not improved. Lactate increased pan-Kla signals but produced minimal phenotypic and transcriptional changes. In contrast, p300 or LDH inhibition reduced pan-Kla signals and was accompanied by reduced cell viability, colony formation, and wound closure; however, these effects cannot be attributed specifically to reduced Kla because A-485 and oxamate are not Kla-specific. RNA sequencing showed suppression of E2F target and G2M checkpoint programs. In an exploratory PET subgroup, the Kla H-score correlated weakly with SUVmax, and patients with high Kla and high SUVmax had the poorest outcomes. CONCLUSIONS: Nuclear pan-Kla immunoreactivity was independently associated with poor postoperative outcomes in resected ICC. Pharmacological modulation of lactylation-related pathways was accompanied by suppression of proliferative and cell cycle-related programs, although Kla-specific causality remains to be established.