LGALS3BP Links Centrosomes and Mitochondria to Maintain Energetic Fitness and Restrain Compensatory Lipid Catabolic Reprogramming in Hepatocellular Carcinoma

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BACKGROUND/AIM: Hepatocellular carcinoma (HCC) exhibits substantial metabolic plasticity that supports tumor progression and therapeutic resistance. LGALS3BP has been primarily characterized as a secreted immunomodulatory protein; however, its cell-intrinsic role in regulating subcellular organization and metabolism in HCC remains poorly understood. MATERIALS AND METHODS: Transcriptomic analyses of public HCC cohorts were performed to assess metabolic programs associated with LGALS3BP expression. Proteomic profiling was conducted to define the LGALS3BP interactome. Mitochondrial function was evaluated by measuring adenosine triphosphate (ATP) levels, mitochondrial membrane potential (ΔΨm), and AMP-activated protein kinase (AMPK) activation. Lipid metabolic programs were assessed by gene expression analyses and lipid accumulation assays. Clinical relevance was independently validated in an institutional HCC cohort. RESULTS: Low LGALS3BP expression was associated with activation of peroxisome proliferator-activated receptor alpha (PPARα)-driven peroxisomal and lipid catabolic gene programs. Proteomic analyses revealed that LGALS3BP associates with centrosomal γ-tubulin ring complex components and mitochondrial proteins, suggesting a role in centrosome-mitochondria subcellular organization. Functionally, LGALS3BP deficiency resulted in impaired mitochondrial energetic fitness, reduced ATP production, and activation of AMPK. This energetic stress was accompanied by induction of PPARα and compensatory lipid catabolic transcriptional programs. Consistent inverse associations between LGALS3BP expression and PPARα-peroxisome-related genes, including PPARA, ACOX1, EPHX2, and SCP2, were observed across public HCC datasets and were independently validated in an institutional HCC patient cohort. CONCLUSION: LGALS3BP acts as a cell-intrinsic organizer that links centrosomal architecture to mitochondrial energetic homeostasis in HCC. Loss of this organizational axis induces mitochondrial energetic stress and promotes compensatory PPARα-peroxisome-mediated lipid catabolic reprogramming, highlighting a previously unrecognized connection between subcellular organization and metabolic plasticity in liver cancer.

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