YBX1-LDHB axis orchestrates pyruvate production from lactate to promote ICC initiation and development

Previous work from our group established that Y-box binding protein 1 (YBX1) plays a pivotal role in the initiation and progression of intrahepatic cholangiocarcinoma (ICC); however, its specific biological functions and underlying regulatory mechanisms remain unclear. The current study demonstrates that YBX1 is highly expressed in ICC tissues, and its highly expression correlates significantly with a poor prognosis in patients with ICC. In vitro experiments revealed that YBX1 overexpression significantly enhanced the proliferation of ICC cells. Conversely, YBX1 knockout robustly inhibited tumor growth in both in vitro and in vivo models. Mechanistically, YBX1 upregulated the expression of lactate dehydrogenase B (LDHB) by increasing its transcriptional activity and stabilizing LDHB mRNA. Elevated LDHB expression drives the conversion of lactate to pyruvate, which is further metabolized to acetyl coenzyme A. This metabolic reprogramming enhances the activity of tricarboxylic acid (TCA) cycle and production of adenosine triphosphate, thereby providing essential energy support for the proliferation of ICC cells. Corroboratively, inhibiting LDHB via CRISPR-Cas9-mediated knockout suppressed ICC cell proliferation, whereas LDHB overexpression accelerated the ICC tumor progression. Lactate induces YBX1 nuclear translocation, which in turn activates LDHB transcription. Collectively, our findings demonstrate the oncogenic roles of YBX1 and LDHB in ICC progression, identify lactate as a key energy source sustaining the activity of TCA cycle and oxidative phosphorylation, and highlight the YBX1-LDHB axis as a potential therapeutic target.