HSP27 Promotes Cutaneous Squamous Cell Carcinoma Progression by Inhibiting Ferroptosis

ABSTRACT Cutaneous squamous cell carcinoma (CSCC) is a malignant tumor originating from epidermal keratinocytes. In various types of tumors, ferroptosis is a vital iron‐dependent form of regulated cell death. Recent studies suggest that heat shock protein 27 (HSP27), encoded by the heat shock protein family B member 1 ( HSPB1 ) gene, is involved in the regulation of ferroptosis, but the specific mechanism remains unclear. In this study, CSCC cell lines were transfected with lentivirus‐mediated HSPB1 ‐shRNA or lentivirus carrying overexpressed HSPB1 . CSCC cell lines, xenograft mouse models, and ferroptosis inhibitors or inducers were applied to verify the mechanism and function of HSP27. Downregulation of HSP27 inhibited the proliferation, migration, and invasion of CSCC cells, whereas upregulation of HSP27 showed the opposite results. Similarly, tumor volume and weight were reduced after HSP27 was downregulated in vivo. Further studies revealed that HSP27 promoted the growth of CSCC cells and tumors by inhibiting ferroptosis, and the downregulation of HSP27 enhanced ferroptosis induced by Erastin. Ferrostatin‐1 or Erastin successfully reversed the phenotype triggered by HSP27 alterations. HSP27 can induce the growth of CSCC by inhibiting ferroptosis, and is expected to become a new target for the treatment of CSCC.