Tumor suppressor Par-4 activates autophagy-dependent ferroptosis

Karthikeyan Subburayan, Faisal Thayyullathil, Siraj Pallichankandy, Anees Rahman Cheratta, Ameer Alakkal, Mehar Sultana, Nizar Drou, Muhammad Arshad, L. Palanikumar, Mazin Magzoub, Vivek M. Rangnekar, Sehamuddin Galadari

Research output: Contribution to journalArticlepeer-review


Ferroptosis is a unique iron-dependent form of non-apoptotic cell death characterized by devastating lipid peroxidation. Whilst growing evidence suggests that ferroptosis is a type of autophagy-dependent cell death, the underlying molecular mechanisms regulating ferroptosis are largely unknown. In this study, through an unbiased RNA-sequencing screening, we demonstrate the activation of a multi-faceted tumor-suppressor protein Par-4/PAWR during ferroptosis. Functional studies reveal that genetic depletion of Par-4 effectively blocks ferroptosis, whereas Par-4 overexpression sensitizes cells to undergo ferroptosis. More importantly, we have determined that Par-4-triggered ferroptosis is mechanistically driven by the autophagic machinery. Upregulation of Par-4 promotes activation of ferritinophagy (autophagic degradation of ferritin) via the nuclear receptor co-activator 4 (NCOA4), resulting in excessive release of free labile iron and, hence, enhanced lipid peroxidation and ferroptosis. Inhibition of Par-4 dramatically suppresses the NCOA4-mediated ferritinophagy signaling axis. Our results also establish that Par-4 activation positively correlates with reactive oxygen species (ROS) production, which is critical for ferritinophagy-mediated ferroptosis. Furthermore, Par-4 knockdown effectively blocked ferroptosis-mediated tumor suppression in the mouse xenograft models. Collectively, these findings reveal that Par-4 has a crucial role in ferroptosis, which could be further exploited for cancer therapy.

Original languageEnglish (US)
Article number732
JournalCommunications Biology
Issue number1
StatePublished - Dec 2024

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • General Biochemistry, Genetics and Molecular Biology
  • General Agricultural and Biological Sciences


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