Targeting FOSL2 via knockdown: a druggable strategy for protecting against hepatic ischemia/reperfusion injury through ATF4 suppression

Macrophage-mediated inflammatory response is a critical pathogenic component in hepatic ischemia/reperfusion injury (HIRI) development. Although FOS-like antigen 2 (FOSL2) plays a pivotal role in regulating macrophage polarization, its role and potential mechanisms in HIRI remain unclear. The findings demonstrated that FOSL2 exhibited elevated expression levels in both the liver tissues and macrophages of the liver tissues in IR rats. Knockdown of FOSL2 significantly alleviated HIRI-induced liver injury, accompanied by the suppression of hepatic tissue apoptosis and oxidative stress. Furthermore, FOSL2 knockdown led to a reduction in the pro-inflammatory M1 phenotype and an increase in the anti-inflammatory M2 phenotype of Kupffer cells (KCs). Concomitantly, FOSL2 expression was markedly upregulated in KCs following lipopolysaccharide (LPS) stimulation, and FOSL2 silencing potently promoted the phenotypic switch of KCs from the pro-inflammatory M1 to the anti-inflammatory M2 state. Additionally, knockdown of FOSL2 in KCs attenuated KC-induced hepatocyte apoptosis and oxidative stress. Transcriptomic analysis conducted on liver tissues from HIRI rats with or without FOSL2 knockdown identified a significant downregulation of activating transcription factor 4 (ATF4), with a log2 fold change of −1.51 and a p-value < 0.05. Mechanistically, FOSL2 bound to the promoter region of ATF4 to drive its transcription, and ATF4 overexpression abrogated the phenotypic and functional effects elicited by FOSL2 silencing. Collectively, our findings illustrate that FOSL2 knockdown exerts a protective role against IR-induced hepatic stress, highlighting the importance of FOSL2 as a potential therapeutic target for HIRI.