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

Lysine lactylation (Kla) links cellular metabolism to gene regulation, but its significance in intrahepatic cholangiocarcinoma (ICC) remains unclear.

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.

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.

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.