Abstract
Sorafenib is the first-line treatment of advanced hepatocellular carcinoma (HCC). However, there is a lack of validated biomarkers to predict sorafenib sensitivity. In this study we investigated the role of ACSL4, a positive-activating enzyme of ferroptosis, in sorafenib-induced cell death and HCC patient outcome. We showed that ACSL4 protein expression was negatively associated with IC50 values of sorafenib in a panel of HCC cell lines (R = −0.952, P < 0.001). Knockdown of ACSL4 expression by specific siRNA/sgRNA significantly attenuated sorafenib-induced lipid peroxidation and ferroptosis in Huh7 cells, and also rescued sorafenib-induced inhibition of xenograft tumor growth in vivo. We selected 29 HCC patients with surgery as primary treatment and sorafenib as postoperative adjunct therapy from a hospital-based cohort. A high proportion (66.7%) of HCC patients who had complete or partial responses to sorafenib treatment (according to the revised RECIST guideline) had higher ACSL4 expression in the pretreated HCC tissues, compared with those who had stable or progressed tumor growth (23.5%, P = 0.029). Since ACSL4 expression was independent of sorafenib treatment, it could serve as a useful predictive biomarker. Taken together, this study demonstrates that ACSL4 is essential for sorafenib-induced ferroptosis and useful for predicting sorafenib sensitivity in HCC. This study may have important translational impacts in precise treatment of HCC.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (81672370 and 81972291), the Guangxi Natural Science Foundation Key Grant (2018GXNSFDA050006), the Key laboratory of High-Incidence-Tumor Prevention & Treatment (Guangxi Medical University), Ministry of Education (GKE2018-02), the Hundred-Talent Program (2016) and the Guangxi Medical University Training Program for Distinguished Young Scholars (2017) (all awarded to GDL); and the National Natural Science Foundation of China (31601120, awarded to JZ).
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JF and PZL equally performed the majority of the experiments and analyzed the data; GZZ collected HCC patient pathological samples and analyzed the clinical data; YW prepared the figures; XWH provided technical support; HQD, PHC, ZJL and WJS performed the literature review; CYH and XPY collected HCC patient clinical data; SCH provided project guidance; TP, JZ and GDL designed the research and summarized the data; and JF and GDL wrote the paper.
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Feng, J., Lu, Pz., Zhu, Gz. et al. ACSL4 is a predictive biomarker of sorafenib sensitivity in hepatocellular carcinoma. Acta Pharmacol Sin 42, 160–170 (2021). https://doi.org/10.1038/s41401-020-0439-x
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DOI: https://doi.org/10.1038/s41401-020-0439-x
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