GADD45B promotes apoptosis in intestinal injury through DNA demethylation

Intestinal ischemia/reperfusion (I/R) injury is a common pathophysiological phenomenon that is widely present in various primary intestinal diseases and systemic critical illnesses, potentially leading to multiple organ dysfunction and failure, with high morbidity and mortality. Therefore, investigating the underlying mechanisms of intestinal I/R and identifying potential therapeutic targets are of paramount importance.

Recently, Professor Xiaofeng Tian’s research team at Dalian Medical University published a study on April 09, 2026, in the Chinese Medical Journal titled ” Growth arrest and DNA damage-inducible β (GADD45B) promotes apoptosis in intestinal ischemia/reperfusion through DNA demethylation of MST1/Hippo.” This study reported that GADD45B interacts with TET1 to promote MST1 DNA demethylation, thereby inducing MST1 expression, subsequently activating the Hippo pathway and exacerbating apoptosis following intestinal I/R.

GADD45B is a key stress sensor that mediates various cellular responses, regulating multiple biological processes such as cell survival, DNA demethylation and repair, apoptosis, inflammation, and cell cycle arrest. Previous studies have shown that GADD45B is among the top 20 differentially expressed genes following intestinal I/R injury in humans. Moreover, previous RNA-seq results indicated that GADD45B expression is significantly upregulated in a mouse model of intestinal I/R. Therefore, the role of GADD45B in intestinal I/R warrants further investigation.

This study found that GADD45B expression was significantly increased in H/R-induced Caco-2 cells and a mouse intestinal I/R model. Specific knockdown of GADD45B in vivo and in vitro reduced cell apoptosis and alleviated intestinal and remote organ injury. In vitro overexpression of GADD45B exacerbated intestinal injury and cell apoptosis induced by H/R in Caco-2 cells. These findings suggest that GADD45B is a key target contributing to intestinal injury and cell apoptosis following intestinal I/R. Subsequently, transcriptomic KEGG enrichment analysis identified the Hippo pathway as the downstream target pathway of GADD45B in intestinal I/R injury and identified its downstream target protein, mammalian sterile 20-like kinase 1 (MST1). To further investigate the mechanism by which GADD45B regulates the Hippo pathway, the authors knocked down and overexpressed GADD45B in Caco-2 cells. Using methylation-specific PCR (MSP) and chromatin immunoprecipitation (ChIP) assays, they found that GADD45B induces MST1 expression through DNA demethylation. TET enzymes are a class of common demethylases that reduce DNA methylation levels at gene promoters, thereby stimulating the expression of specific genes. Previous studies have shown that GADD45B can bind to TET1 and directly mediate region-specific demethylation. To further investigate the molecular basis of GADD45B-mediated MST1 DNA demethylation, the authors first confirmed that TET1 expression was significantly upregulated after intestinal I/R, consistent with the observed trend of GADD45B. Subsequently, ChIP, Co-IP, and MSP assays further confirmed that GADD45B promotes MST1 DNA demethylation through its physical interaction with TET1.

In summary, this study demonstrates the pro-apoptotic role of GADD45B in intestinal I/R, explores its downstream pathways and targets, and further confirms the critical role of epigenetics in intestinal I/R. Mechanistically, GADD45B interacts with TET1 to promote MST1 DNA demethylation, thereby activating the Hippo pathway and exacerbating intestinal I/R injury. These findings suggest that GADD45B is a key regulatory factor in intestinal I/R injury and targeting the GADD45B/TET1/MST1 axis may represent a viable therapeutic strategy.