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The increased prevalence of hepatocellular carcinoma ( HCC ) without viral infection, namely,  NHCC , is a major public health issue worldwide.  NHCC  is frequently derived from non‐alcoholic fatty liver ( NAFL ) and non‐alcoholic steatohepatitis, which exhibit dysregulated fatty acid ( FA ) metabolism. This raises the possibility that  NHCC  evolves intracellular machineries to adapt to dysregulated  FA  metabolism. We herein aim to identify  NHCC ‐specifically altered  FA  and key molecules to achieve the adaptation. To analyze  FA , imaging mass spectrometry ( IMS ) was performed on 15  HCC  specimens. The composition of saturated  FA  ( SFA ) in  NHCC  was altered from that in typical  HCC . The stearate‐to‐palmitate ratio ( SPR ) was significantly increased in  NHCC . Associated with the  SPR  increase, the  ELOVL 6 protein level was upregulated in  NHCC . The knockdown of   ELOVL 6  reduced  SPR , and enhanced endoplasmic reticulum stress, inducing apoptosis of Huh7 and HepG2 cells. In conclusion,  NHCC  appears to adapt to an  FA ‐rich environment by modulating  SPR  through  ELOVL 6.

Stearate‐to‐palmitate ratio modulates endoplasmic reticulum stress and cell apoptosis in non‐B non‐C hepatoma cells