# Pirin Transcriptionally Regulates PLA2G4A To Inhibit Ferroptosis in Colorectal Cancer via Lipid Profile Remodeling

## TL;DR

Pirin (PIR) suppresses ferroptosis in colorectal cancer by regulating lipid profiles through PLA2G4A, offering a new therapeutic strategy.

## Contribution

Identifies a novel NRF2–PIR–PLA2G4A regulatory axis that controls ferroptosis via lipid remodeling in colorectal cancer.

## Key findings

- PIR is upregulated in CRC and correlates with reduced ferroptosis sensitivity and tumor growth.
- PIR loss increases lipid peroxidation and ferroptosis, inhibiting CRC progression in models.
- Targeting the PIR–PLA2G4A axis enhances ferroptosis inducer efficacy and suppresses CRC.

## Abstract

Ferroptosis, an iron‐dependent cell death driven by lipid peroxidation, is a promising therapeutic target in colorectal cancer (CRC); however, its regulation remains unclear. Here, Pirin (PIR) is recognized as a ferroptosis suppressor that acts through lipid remodeling. PIR is upregulated in CRC tissues, correlating with reduced ferroptosis sensitivity and enhanced tumor growth, whereas PIR loss restricts CRC progression in vivo and in vitro. Intestinal epithelium–specific PIR deletion limits AOM/DSS‐induced tumorigenesis by increasing lipid peroxidation and promoting ferroptosis. Mechanistically, ferroptosis triggers a compensatory NRF2‐PIR axis, in which NRF2 binds to the PIR promoter to induce its expression. PIR deficiency downregulates PLA2G4A (encoding cPLA2α), a key arachidonic‐acid–metabolizing enzyme involved in ferroptosis control. Lipidomics has shown that PIR loss increases polyunsaturated fatty acid (PUFA)‐containing phospholipids and decreases monounsaturated (MUFA) and saturated (SFA) species, shifting membranes toward a ferroptosis‐permissive state. Restoration of PLA2G4A rescues ferroptosis resistance in PIR‐deficient cells. Targeting this pathway, either by pharmacologic inhibition of PLA2G4A with AACOCF3 or by genetic disruption of the PIR–PLA2G4A axis, enhances the efficacy of ferroptosis inducers and suppresses CRC progression. This study defines an NRF2–PIR–PLA2G4A circuit that governs ferroptosis susceptibility via lipidome remodeling and highlights its therapeutic potential in CRC.

This study identifies Pirin (PIR), an iron‐binding protein, as a critical ferroptosis suppressor in colorectal cancer through lipid membrane remodeling. PIR, induced by NRF2 during ferroptotic stress, transcriptionally regulates PLA2G4A to shift cellular lipid composition away from ferroptosis‐permissive polyunsaturated phospholipids. Disrupting the NRF2–PIR–PLA2G4A axis sensitizes tumors to ferroptosis inducers and restricts cancer progression, revealing a therapeutic vulnerability in colorectal cancer treatment.