# FAK/SRC-JNK axis promotes ferroptosis via upregulating ACSL4 expression

## TL;DR

This study shows that the FAK/SRC-JNK signaling pathway promotes ferroptosis by increasing ACSL4 levels, offering new therapeutic strategies for cancer and acute pancreatitis.

## Contribution

The paper identifies FAK/SRC-JNK signaling as a novel regulator of ferroptosis through ACSL4 upregulation.

## Key findings

- FAK/SRC-JNK signaling increases ACSL4 expression, promoting ferroptosis.
- Specific transcription factors either enhance or suppress ACSL4 activity.
- Inhibiting FAK/SRC-JNK protects against acute pancreatitis by reducing ferroptosis.

## Abstract

Ferroptosis, an iron-dependent form of programmed cell death driven by toxic lipid peroxide accumulation, plays a critical role in various diseases, making its modulation a promising therapeutic strategy. In this study, we identified defactinib, a specific inhibitor of FAK as a novel ferroptosis suppressors. We demonstrate that FAK/SRC-JNK signaling positively regulates ferroptosis by upregulating ACSL4, a critical mediator of ferroptosis. We reveal that a subset of JNK downstream transcription factors, including ATF2, NFATC1, NFATC3, and SMAD4, promote ferroptosis through direct binding to the ACSL4 promoter and activation of its expression. In contrast, another subset of JNK-associated transcription factors, including c-Jun, STAT3, ELK1, and HSF1, inhibit ferroptosis by binding to the ACSL4 promoter and repressing its expression. The net effect of FAK/SRC-JNK signaling in our models is a significant upregulation of ACSL4 and promotion of ferroptosis. Notably, elevated FAK/SRC-JNK signaling sensitizes cancer cells to ferroptosis-inducing therapies, while inhibition of the FAK/SRC-JNK signaling pathway protects against acute pancreatitis by suppressing ferroptosis. These findings highlight the central role of FAK/ SRC-JNK signaling in controlling ferroptotic cell death and underscore the therapeutic potential of targeting FAK/ SRC-JNK mediated ferroptosis, offering new avenues for the treatment of cancer and acute pancreatitis.