SLC25A1 drives lipid metabolic reprogramming promoting liver injury leading to hepatocellular carcinoma

Cancer metabolism especially lipid metabolic reprogramming is considered one of the most important metabolic processes involved in hepatocellular carcinoma (HCC). Solute carrier family 25 member A1 (SLC25A1) is a citrate transporter present in mitochondrial membrane and emerged to play role in lipid metabolic reprogramming. This study aimed to elucidate the mechanistic role of SLC25A1 in lipid metabolic reprogramming and its therapeutic potential in HCC.

In the current study, enhanced expression of SLC25A1 gene was observed in toxicant induced mouse model of HCC suggesting a correlation with initiation and development of HCC. However, the precise mechanistic involvement of SLC25A1 in HCC is unclear underscoring the need of an in depth study. Clinical relevance of SLC25A1 in HCC was primarily evaluated using The Cancer Genome Atlas database. The in silico results not only demonstrated a strong correlation between the expression of SLC25A1 and HCC but also associated it with poor survival. In depth gain of function analysis using mammalian expression vector, SLC25A1-PCMV3 in human cell lines exhibited enhanced cellular growth, invasion, and migration potentials of cells expressing SLC25A1. Notably, the overexpression of SLC25A1 was associated with increased de novo lipogenesis, consistent with metabolic reprogramming favoring cytosolic citrate utilizationas evident by upregulation of FASN, ACACA, ACLY, SCD1 and downregulation of IDH2 and OGDH. Virtual screening and molecular docking studies presented rutin, a natural flavonoid, as a potential inhibitor of SLC25A1. In vitro inhibition of SLC25A1 by treatment with rutin significantly suppressed SLC25A1 expression leading to reduced lipogenesis.

Collectively, these findings propose SLC25A1 is associated with metabolic reprogramming in HCC and contribute to tumor progression.by promoting lipogenesis. Thus offering a promising therapeutic target for early intervention and treatment.