# FOXO3 upregulates and activates GSDME to trigger myeloma cell pyroptosis

## TL;DR

This study identifies FOXO3 as a new regulator of GSDME, which triggers cell death in multiple myeloma, offering a potential new treatment strategy.

## Contribution

FOXO3 is newly identified as a transcriptional activator of GSDME, linking it to pyroptosis in multiple myeloma.

## Key findings

- GSDME is the most downregulated pyroptosis-related gene in multiple myeloma cells and its low expression correlates with poor prognosis.
- FOXO3 directly upregulates GSDME and activates pyroptosis by increasing Caspase-3 and BNIPL family proteins.
- Corylin, a flavonoid, activates FOXO3 and GSDME, showing anti-myeloma activity through pyroptosis.

## Abstract

Induction of pyroptosis is considered as a novel strategy for the treatment of multiple myeloma, but the potential targets remain unknown. In the present study, we found that GSDME, a key executor of pyroptosis, is the mostly downregulated pyroptosis-related gene in MM cells and its low expression predicts poor prognosis of MM patients. Out of expectation, GSDME transcription is not markedly affected by epigenetic manners in MM cells. In contrast, GSDME expression is controlled by the transcription factor FOXO3. FOXO3 binds to the two recognition sites and upregulates GSDME. Moreover, FOXO3 specifically upregulates the BNIPL family proteins and activates Caspase-3 and GSDME therefore triggering MM cell pyroptosis. In addition, similar to GSDME, FOXO3 is also downregulated in MM and its restoration suppresses myeloma tumor growth. Furthermore, we found corylin, a flavonoid derived from Psoralea Fructus, activates the transcription of both FOXO3 and GSDME. As expected, corylin displays potent anti-MM activity in association with pyroptosis by upregulating FOXO3 and GSDME. In conclusion, FOXO3 is a novel transcription factor of GSDME. Restoration/activation of the FOXO3/GSDME axis could be a promising novel strategy for the treatment of MM.