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Hypoxia-inducible factor-1α (HIF-1α) or sonic hedgehog (SHH) is associated with hepatocellular carcinoma (HCC) progression. Hypoxia inhibits ferroptosis, which induces cancer cell death. However, the correlation between the combined HIF-1α and SHH up-regulation with prognosis, and the association between SHH and ferroptosis remain unclear. This study aimed to investigate them. We detected the expression of HIF-1α and SHH in HCC. Cox regression, clinical data, and Kaplan–Meier analyses were performed. In vitro cell experiments verified the relationship between HIF-1α and SHH, and observed the invasion of hypoxic HCC cells. The correlation between SHH and ferroptosis was also analyzed. HIF-1α and SHH expression levels were significantly correlated with HCC ( p  &lt; 0.0001). HIF-1α and SHH expression levels were found to be associated with TNM stage ( p  = 0.0121,  p  = 0.0078, respectively), vascular invasion ( p  &lt; 0.0001,  p  &lt; 0.0001, respectively), and recurrence ( p  = 0.0212,  p  = 0.0392, respectively). The combined upregulation of HIF-1α and SHH was an independent factor for predicting the overall survival (OS) of patients with HCC ( p  = 0.003), who had the shortest OS ( p  = 0.0009). SHH paralleled the increase in HIF-1α expression, which promotes cancer cell invasion. The upregulation of SHH was related to the inhibition of the expression of ferroptosis-related factors (FANCD2,  p  &lt; 0.0001 and FTH1,  p  = 0.0009) in HCC. Combined HIF-1α and SHH upregulation is a potentially poor prognosis indicator in patients with HCC because the upregulation of SHH inhibits ferroptosis in hypoxic cancer cells.

Combined HIF-1α and SHH Up-Regulation Is a Potential Biomarker to Predict Poor Prognosis in Postoperative Hepatocellular Carcinoma