P23 acts as a negative regulator of ferroptosis in NSCLC by blocking GPX4 degradation via chaperone-mediated autophagy

Mol Cancer. 2025 Oct 2;24(1):234. doi: 10.1186/s12943-025-02439-y.

Abstract

Ferroptosis has been identified as a tumor-inhibiting event in a variety of cancers; however, its molecular basis in non-small cell lung cancer (NSCLC) has not been completely elucidated. Notably, glutathione peroxidase 4 (GPX4) plays a crucial role in ferroptosis. Our previous research revealed that prostaglandin E synthase 3 (p23), a potential transcription factor, plays a crucial role in promoting cancer progression and metastasis through succinylation. Our study revealed a previously unknown antiferroptotic function of p23. Mechanistically, p23 stabilizes GPX4 by competitively binding heat shock cognate 71 kDa protein (HSC70) to suppress chaperone-mediated autophagy (CMA) activity, which subsequently inhibits ferroptosis and accelerates tumor growth. Notably, impairing p23 succinylation disrupts its interaction with HSC70, restoring CMA-mediated GPX4 degradation. Collectively, our findings suggest that targeting p23-regulated CMA pathways represents a potentially viable strategy to modulate ferroptosis in NSCLC.

Keywords: Chaperone-mediated autophagy; Ferroptosis; GPX4; HSC70; NSCLC; P23.

MeSH terms

  • Animals
  • Autophagy
  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Carcinoma, Non-Small-Cell Lung* / metabolism
  • Carcinoma, Non-Small-Cell Lung* / pathology
  • Cell Line, Tumor
  • Chaperone-Mediated Autophagy*
  • Ferroptosis*
  • Humans
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / metabolism
  • Lung Neoplasms* / pathology
  • Mice
  • Phospholipid Hydroperoxide Glutathione Peroxidase* / genetics
  • Phospholipid Hydroperoxide Glutathione Peroxidase* / metabolism
  • Prostaglandin-E Synthases* / genetics
  • Prostaglandin-E Synthases* / metabolism
  • Proteolysis

Substances

  • Phospholipid Hydroperoxide Glutathione Peroxidase
  • Prostaglandin-E Synthases