BBOX1 Deficiency Exacerbates Liver Fibrosis Through Carnitine Biosynthesis Disruption Rescued by Carnitine Supplementation.

BACKGROUND AND AIM: Liver fibrosis is a major global health burden with limited treatments. Emerging evidence suggests that metabolic dysregulation can create a state that makes the liver more prone to fibrosis. Carnitine, synthesized by γ-butyrobetaine hydroxylase (BBOX1), is crucial for fat metabolism, but the role of the BBOX1-carnitine axis in liver fibrosis is unclear. This study aimed to elucidate the functional impact of BBOX1 deficiency on hepatic fibrogenesis and to delineate the underlying mechanistic pathway.

METHODS

We analysed human liver transcriptomic data. Bbox1 knockout (KO) mice and wild-type (WT) littermates were subjected to thioacetamide (TAA)-induced liver fibrosis, with or without dietary L-carnitine supplementation. Comprehensive analyses included metabolomic and transcriptomic profiling, histopathological evaluation, and focused investigation of calcium-dependent signalling pathways.

RESULTS

BBOX1 expression was significantly downregulated in human cirrhotic livers and correlated with reduced systemic carnitine levels. Bbox1-KO mice exhibited profound hepatic carnitine depletion and a metabolically primed state. With TAA challenge, KO mice developed exacerbated liver fibrosis and inflammation compared to WT controls. This susceptibility was driven by the aberrant activation of the TRPC6-Ca2+/CAMK2B-inflammatory signalling axis. Moreover, dietary L-carnitine supplementation completely rescued the aggravated fibrotic phenotype in KO mice.

CONCLUSION

BBOX1 is a key regulator of liver carnitine metabolism. Its deficiency creates a pro-fibrotic state by abnormally activating the TRPC6-Ca2+/CAMK2B pathway. Our findings position carnitine as a protector of calcium balance in the liver and identify L-carnitine supplementation as a potential targeted treatment to slow fibrosis progression.