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. 2024 Apr;44(4):1011-1023.
doi: 10.1111/liv.15839. Epub 2024 Jan 31.

Impact of ACSL4 on the prognosis of hepatocellular carcinoma: Association with cancer-associated fibroblasts and the tumour immune microenvironment

Katsuya Toshida  1 , Shinji Itoh  1 , Norifumi Iseda  1 , Takahiro Tomiyama  1 , Shohei Yoshiya  1 , Takeo Toshima  1 , Yu-Chen Liu  2 , Takeshi Iwasaki  3 , Daisuke Okuzaki  2   4   5 , Koji Taniguchi  6 , Yoshinao Oda  3 , Masaki Mori  7 , Tomoharu Yoshizumi  1
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Impact of ACSL4 on the prognosis of hepatocellular carcinoma: Association with cancer-associated fibroblasts and the tumour immune microenvironment

Katsuya Toshida et al. Liver Int. 2024 Apr.

Abstract

Background & aims: Recently, the association between hepatocellular carcinoma (HCC) and ferroptosis has been the focus of much attention. The expression of long chain fatty acyl-CoA ligase 4 (ACSL4), a marker of ferroptosis, in tumour tissue is related to better prognosis in various cancers. In HCC, ACSL4 expression indicates poor prognosis and is related to high malignancy. However, the mechanism remains to be fully understood.

Methods: We retrospectively enrolled 358 patients with HCC who had undergone hepatic resection. Immunohistochemistry (IHC) for ACSL4 was performed. Factors associated with ASCL4 expression were investigated by spatial transcriptome analysis, and the relationships were investigated by IHC. The association between ACSL4 and the tumour immune microenvironment was examined in a public dataset and investigated by IHC.

Results: Patients were divided into ACSL4-positive (n = 72, 20.1%) and ACSL4-negative (n = 286, 79.9%) groups. ACSL4 positivity was significantly correlated with higher α-fetoprotein (p = .0180) and more histological liver fibrosis (p = .0014). In multivariate analysis, ACSL4 positivity was an independent prognostic factor (p < .0001). Spatial transcriptome analysis showed a positive correlation between ACSL4 and cancer-associated fibroblasts; this relationship was confirmed by IHC. Evaluation of a public dataset showed the correlation between ACSL4 and exhausted tumour immune microenvironment; this relationship was also confirmed by IHC.

Conclusion: ACSL4 is a prognostic factor in HCC patients and its expression was associated with cancer-associated fibroblasts and anti-tumour immunity.

Keywords: acyl‐CoA synthetase long chain family member 4; cancer associated fibroblast; hepatocellular carcinoma; spatial transcriptomic analysis; steatosis.

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References

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