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Background <p>Cholesterol (CHO)/bile acids (BAs) homeostasis is critically involved in hepatocellular carcinoma (HCC), yet the underlying mechanisms and the specific regulatory role of CYP8B1-a key enzyme maintaining this balance-remain poorly defined. This study seeks to clarify the roles of CYP8B1 and its regulated CHO/BA homeostasis in the initiation and progression of HCC driven by aberrant RAS/ERK signaling.</p> Method <p>Utilizing TCGA data analysis, clinical sample examination (including protein/mRNA level assessments and serum measurements), in vitro cell line studies, an HCC animal model (with histopathological classification and inhibitor treatments), and dietary interventions (a high-CHO diet and Taurodeoxycholic acid [TDCA, a main secondary BA] treatment) to investigate the roles of Ras/ERK and CYP8B1 in CHO/BA homeostasis and HCC progression.</p> Results <p>Clinical HCC data and cell lines frequently show ERK hyperactivation with concomitant CYP8B1 reduction and CHO accumulation. In Hras12V transgenic mice (Ras-Tg), CHO was accumulated in hepatic tumor tissues (T), peri-tumoral tissues (P), and serum compared with wild-type (WT) mice, and this accumulation predominantly resulted from the attenuation of BA biosynthesis induced by reduced CYP8B1 activity. Inhibition of ERK activity by AZD6244 (a p-ERK inhibitor) notably elevated CYP8B1 activity and BAs levels and reduced CHO level in Ras-Tg. Further investigation revealed that SREBP2 is critically involved in the ERK-mediated regulation of CYP8B1 and CHO/BA homeostasis. Intriguingly, although CYP8B1 activity were extremely down-regulated in T compared with P, CHO was significantly lower in T than in P, and the combination of the extreme up-regulation of apolipoprotein (APO) A1 and APOB in T with disordered expression of serum high-density lipoprotein (HDL) and low-density lipoprotein (LDL) might reflect active efflux of CHO from hepatoma cells. Notably, further elevation of the CHO level with a high-CHO diet perturbed multiple signaling pathways (mTOR, NF-κB, GSK3β/β-catenin, caspase 3, and BAX/BCL2) and suppressed hepatic tumor progression but not tumorigenesis. Intriguingly, feeding TDCA significantly inhibits hepatic tumorigenesis and development by inhibiting ERK and mTOR pathways.</p> Conclusion <p>CYP8B1 repressed by Ras/ERK plays crucial roles in CHO/BA homeostasis which facilitate hepatic tumor progression. These findings provide a novel theoretical foundation and therapeutic perspective for HCC treatment.</p>

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CYP8B1 suppressed by Ras/ERK leads to cholesterol accumulation and bile acids reduction and facilitates hepatic tumorigenesis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月23日

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  • Juan Li,
  • Huiling Li,
  • Lili Dong,
  • Liang Yao,
  • Xiaoying Dong,
  • Yingyan Guo,
  • Chunwen Pu,
  • Aiguo Wang,
  • Jun Chen

摘要

Background

Cholesterol (CHO)/bile acids (BAs) homeostasis is critically involved in hepatocellular carcinoma (HCC), yet the underlying mechanisms and the specific regulatory role of CYP8B1-a key enzyme maintaining this balance-remain poorly defined. This study seeks to clarify the roles of CYP8B1 and its regulated CHO/BA homeostasis in the initiation and progression of HCC driven by aberrant RAS/ERK signaling.

Method

Utilizing TCGA data analysis, clinical sample examination (including protein/mRNA level assessments and serum measurements), in vitro cell line studies, an HCC animal model (with histopathological classification and inhibitor treatments), and dietary interventions (a high-CHO diet and Taurodeoxycholic acid [TDCA, a main secondary BA] treatment) to investigate the roles of Ras/ERK and CYP8B1 in CHO/BA homeostasis and HCC progression.

Results

Clinical HCC data and cell lines frequently show ERK hyperactivation with concomitant CYP8B1 reduction and CHO accumulation. In Hras12V transgenic mice (Ras-Tg), CHO was accumulated in hepatic tumor tissues (T), peri-tumoral tissues (P), and serum compared with wild-type (WT) mice, and this accumulation predominantly resulted from the attenuation of BA biosynthesis induced by reduced CYP8B1 activity. Inhibition of ERK activity by AZD6244 (a p-ERK inhibitor) notably elevated CYP8B1 activity and BAs levels and reduced CHO level in Ras-Tg. Further investigation revealed that SREBP2 is critically involved in the ERK-mediated regulation of CYP8B1 and CHO/BA homeostasis. Intriguingly, although CYP8B1 activity were extremely down-regulated in T compared with P, CHO was significantly lower in T than in P, and the combination of the extreme up-regulation of apolipoprotein (APO) A1 and APOB in T with disordered expression of serum high-density lipoprotein (HDL) and low-density lipoprotein (LDL) might reflect active efflux of CHO from hepatoma cells. Notably, further elevation of the CHO level with a high-CHO diet perturbed multiple signaling pathways (mTOR, NF-κB, GSK3β/β-catenin, caspase 3, and BAX/BCL2) and suppressed hepatic tumor progression but not tumorigenesis. Intriguingly, feeding TDCA significantly inhibits hepatic tumorigenesis and development by inhibiting ERK and mTOR pathways.

Conclusion

CYP8B1 repressed by Ras/ERK plays crucial roles in CHO/BA homeostasis which facilitate hepatic tumor progression. These findings provide a novel theoretical foundation and therapeutic perspective for HCC treatment.