Loss of branched-chain amino acid (BCAA) metabolism mediated by IGF2BP1-LPAL2-YBX1 interaction promotes malignancy in gallbladder cancer.

Reprogrammed cellular metabolism plays a critical role in the development and progression of various cancers. However, the mechanisms by which these metabolic changes drive malignancy in gallbladder cancer (GBC) remain unclear. In this study, we identified significant alterations in branched-chain amino acid (BCAA) metabolism in GBC through comprehensive transcriptomic and metabolic analyses. Reduced activity of the BCAA catabolic enzymes ACADS, ACADSB, and BCKDHA was associated with poor prognosis in GBC patients. Dietary reduction of BCAAs in mouse model of GBC significantly slowed tumor growth. The lncRNA LPAL2 was found to correlate with the expression of BCAA catabolic enzymes. In vivo and in vitro assays demonstrated that LPAL2 inhibited GBC cell proliferation, downregulated intracellular BCAA levels, and suppressed mTORC1 activation. Furthermore, LPAL2 and ACADS were identified as independent prognostic factors for survival. Mechanically, IGF2BP1 maintaining LPAL2 stability through methylation. Additionally, LPAL2 decreased YBX1 stability by promoting its ubiquitination-mediated degradation, while YBX1 inhibited the transcription of certain BCAA catabolic enzymes through binding to their promoters. In summary, the LPAL2-YBX1 interaction regulates BCAA metabolism to influence GBC cell proliferation, which could be targeted for therapeutic interventions in GBC treatment.